Biomedical subjects
E W Jeffes
Publications and source records attributed to E W Jeffes.
Photodynamic therapy of actinic keratosis with topical 5-aminolevulinic acid. A pilot dose-ranging study.
OBJECTIVE: To examine the safety and efficacy of photodynamic therapy using topical 5-aminolevulinic acid (ALA) and red light to treat actinic keratoses (AKs). DESIGN: Actinic keratoses were treated with topical ALA (concentrations of 0%, 10%, 20%, or 30%) under occlusion for 3 hours. Before photodynamic therapy, sites were examined for fluorescence. Sites were irradiated with an argon pumped dye laser (630 nm) at fluences of 10 to 150 J/cm2. SETTING: Academic medical center. PATIENTS: Forty patients with 6 clinically typical, previously untreated AKs per patient. MAIN OUTCOME MEASURE: Complete resolution and decrease in lesion area of the AK relative to baseline evaluated at weeks 1, 4, 8, and 16. RESULTS: Three hours after ALA administration, lesions showed moderate red fluorescence. Cutaneous phototoxic effects, localized erythema and edema, peaked at 72 hours. Patients experienced mild burning and stinging during light exposure. Eight weeks after a single treatment using 30% ALA, there was total clearing of 91% of lesions on the face and scalp and 45% of lesions, on the trunk and extremities. No significant differences were observed in clinical responses with treatment using 10%, 20%, or 30% ALA. All concentrations of ALA were more effective than treating AKs with vehicle and light. CONCLUSIONS: Topical photodynamic therapy with ALA is an effective treatment of typical AKs. Complete clearing of nonhypertrophic AKs can be achieved with 10%, 20%, or 30% ALA that is easily tolerated by the patient. Lesions on the face and scalp are more effectively treated than lesions on the trunk and extremities. Hypertrophic AKs did not respond effectively.
Elevated numbers of proliferating mononuclear cells in the peripheral blood of psoriatic patients correlate with disease severity.
Although psoriasis is characterized by the accumulation of activated proliferating lymphoid cells in the psoriatic skin lesion, it is not known whether these cells are activated and proliferating before entry into the psoriatic plaque. The current study evaluates the number and phenotype of proliferating lymphoid cells in the blood of psoriatic patients. Proliferation of peripheral blood mononuclear cells was evaluated on cytospun preparations of these cells using autoradiographic techniques after pulsing the mononuclear cells with 3H-methyl thymidine for 2 h. The phenotypes of the labeled peripheral blood mononuclear cells were determined combining autoradiography and immunohistochemistry with monoclonal antibodies directed at CD3, CD4, CD8, CD11c, CD22, and human leukocyte antigen-DR. The data demonstrated elevated numbers of proliferating lymphoid cells in the blood of psoriatic patients compared with normal nonpsoriatic volunteers (p < 0.01). Furthermore, the number of circulating proliferating mononuclear cells increased significantly with increasing psoriasis skin disease severity (correlation coefficient 0.95; p < 0.0001). When the phenotype of the proliferating cells in the blood was examined, the numbers of T cells (CD3+, CD4+, CD8+ cells), B cells (CD22+ cells), monocytes (CD11c+ cells), and human leukocyte antigen-DR+ cells were significantly elevated compared with nonpsoriatic skin (p < 0.01) and increased with increasing disease activity (correlation coefficient range 0.48-0.74; p < 0.05). The data suggest a generalized systemic activation of T, B, and monocytic cells that results in labeling of up to 0.16% of the circulating mononuclear cells with 3H-methyl thymidine (i.e., proliferating and presumably activated) when assayed in vitro.
Methotrexate therapy of psoriasis: differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and growth-inhibitory effects of methotrexate.
Although methotrexate (MTX) is one of the most clinically effective therapies employed to treat psoriasis, the mechanism by which low-dose MTX acts to modulate the hyperplasia of psoriasis, leading to the restoration of clinically normal skin, is only partially understood. MTX has been considered a cytotoxic agent that mediates its effect primarily on proliferating or cycling epidermal cells. Recently, proliferating lymphoid cells have been identified in psoriatic lesions, raising the possibility that proliferating lymphoid cells could be another target cell that is killed by MTX. In this study, we examined the growth-inhibitory and cytotoxic effects of MTX on proliferating lymphoid cells [THP-1 (macrophage), and MOLT-4 (T cell)], epithelial cells (HeLa, and HaCat), and normal human keratinocytes (NHK) in vitro. The proliferating cells were exposed to MTX for 24 h, and placed in fresh media to mimic the transient MTX blood levels that result from once-weekly therapy. THP-1 and MOLT-4 were found to be 10-100 times more sensitive to the cytotoxic effects of MTX than were HeLa and HaCat, and more than 1000 times more sensitive than primary human keratinocytes. At MTX concentrations that would be expected to occur in vivo during once-weekly therapy, a large percentage (> 95%) of proliferating lymphoid targets would be killed, and only a small percentage (< 10%) of proliferating epidermal cells would be affected. This in vitro data suggests that in psoriasis proliferating lymphoid cells are more likely than epithelial cells to be a major cellular target of MTX in vivo.
Methotrexate and other chemotherapeutic agents used to treat psoriasis.
The oral chemotherapy agent methotrexate remains a mainstay for the treatment of moderate to severe psoriasis after 40 years experience. Extensive usage, both for psoriasis and rheumatoid arthritis patients, has continued the reasonable safety profile for this drug when appropriate precautions are taken. The availability of other treatment modalities for severe psoriasis permits a rotational system with periods of time when methotrexate is not used, thereby lessening the risk of long-term side effects. Other chemotherapeutic agents for psoriasis are described, but they are used infrequently.
Localized pustular skin eruption. Localized pustular drug eruption secondary to ampicillin.
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Therapy of recurrent high grade gliomas with surgery, and autologous mitogen activated IL-2 stimulated killer (MAK) lymphocytes: I. Enhancement of MAK lytic activity and cytokine production by PHA and clinical use of PHA.
Nineteen patients with recurrent high grade gliomas were treated in a phase I/II trial with aggressive debulking of the tumor, mitogen activated IL-2 stimulated peripheral blood lymphocytes (MAK cells), and rIL-2. Phytohemagglutin (PHA) was introduced into the tumor site in 16 patients prior to implanting MAK cells and IL-2 in an attempt to trigger more effective lysis of the tumor in vivo. In vitro both TNF bioactivity and cytolytic activity of long term cultured MAK (LMAK) cells were dramatically enhanced by adding PHA to the cultures of these activated PBL. Three of eleven patients (27%) had a decrease in size of the enhancing lesion on CT and/or MRI. Seven (37%) patients clinically improved. Median survival after therapy was 30 weeks. PHA was shown to be safe in vivo and more effective than IL-2 triggering enhanced effector function in vitro.
Localized bullous scabies. Uncommon presentation of scabies.
A previously unreported form of localized bullous scabies mimicking bullous pemphigoid is described. The patient presented with a localized, severely pruritic erythematous plaque with a cutaneous eruption consisting of several papules and a single tense bulla on an erythematous base. The histologic findings consisted of a subepidermal inflammatory bullous dermatosis with lymphocytes, neutrophils, and many eosinophils, and the results of direct immunofluorescence were negative. Correlation of the clinical course with the histologic and immunofluorescence findings were necessary to establish the diagnosis of infestation by Sarcoptes scabiei.
Verruciform xanthoma of the ear with coexisting epidermal dysplasia.
We report a case of verruciform xanthoma of the ear in a 79-year-old man. The case is unique in that it contained an area of solar keratosis. In situ hybridization using biotin-labeled probe cocktails for human papillomavirus types 6/11, 16/18, and 31/33/35 yielded negative results.
Generation of stimulated, lymphokine activated T killer (T-LAK) cells from the peripheral blood of normal donors and adult patients with recurrent glioblastoma.
Peripheral blood mononuclear cells (PBM) from normal donors and patients with recurrent glioma were activated initially for 48-72 h with phytohemagglutinin-P (PHA) and recombinant human interleukin-2 (IL-2), and then proliferated in vitro for up to 5 months with IL-2. These cells are termed mitogen-stimulated lymphokine-activated T killer (T-LAK) cells. We measured patterns of T-LAK cell growth, in vitro cytolytic activity on a panel of continuous and primary tumor cells, and the phenotypes of the cells in these cultures. Lymphocyte viability declined dramatically over the first 3-5 days; and then the remaining cells in these cultures began to divide and maintained a constant 30-36 h doubling time for long periods in vitro. Phenotyping revealed that cells in the initial few days of culture were heterogeneous, but became almost totally CD3 T cells after 7-10 days in culture. The T-LAK cells from individual normal donors and cancer patients demonstrated a non-genetically restricted cytolytic ability against a panel of both continuous cell lines and primary autologous and allogeneic glioblastoma cells in vitro. This technique provides a method of generating large numbers of autologous cytolytic T cells with non-restricted anti-tumor activity that can be derived from peripheral blood mononuclear cells.
A simple nonisotopic in vitro bioassay for LT and TNF employing sodium fluoride-treated L-929 target cells that detects picogram quantities of LT and TNF and is as sensitive as TNF assays done with ELISA methodology.
We have developed a highly sensitive in vitro bioassay for lymphotoxin (LT) and tumor necrosis factor (TNF). This system employs a monolayer of 20,000 L-929 target cells in each well of 96-well microplates that are incubated in dilutions of LT and TNF at 37 degrees C for 20-24 h, after which the viability of the L-929 target cells is assessed by spectrophotometric techniques. We find that incorporation of 2 mM NaF increases the sensitivity of L-929 cells to lysis by 10(3)-10(4) x for LT and 10(4)-10(5) x for TNF. This method allows the regular detection of less than 1-5 pg of bioactive protein. ELISA assays did not detect synthetic TNF and TNF fragments that were not biologically active in this assay. The L-929 bioassay requires no isotopes, is very reproducible, is as sensitive as ELISA techniques, and detects only biologically active LT and TNF.
Therapy of recurrent high-grade gliomas with surgery, autologous mitogen-activated IL-2-stimulated (MAK) killer lymphocytes, and rIL-2: II. Correlation of survival with MAK cell tumor necrosis factor production in vitro.
Seven patients with recurrent high-grade glioma were treated in a Phase I/II trial with surgical debulking, after which mitogen-activated IL-2-stimulated killer (MAK) lymphocytes and 10(5) units rIL-2 were implanted in the surgical defect. The therapy was well tolerated, and the mean survival of this group of patients was 29 weeks. Tumor necrosis factor (TNF) production by MAK lymphocytes stimulated with IL-2 in vitro was measured. A significant (r = .78, p = .04) correlation between survival of patients after therapy and the ability of the MAK lymphocytes to produce TNF in vitro was noted. A significant negative correlation (r = -.82, p = .02) was found when comparing TNF production and increasing tumor size measured on MRI. No correlation was found between TNF production in vitro and MAK lymphocytes lytic activity on K562 and U373 target cells. No correlation was found between survival and MAK cell lytic activity measured on K562 and U373 target cells. We conclude that TNF production in vitro and cytotoxic activity measured in vitro are measures of different antitumor activity in vivo and in vitro. TNF production during IL-2-stimulated proliferation may be an important in vitro assay in terms of predicting length of survival of recurrent high-grade gliomas.
Congenital circumareolar telangiectasias: a uniquely distributed vascular malformation.
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Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients.
Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor alpha (TNF-alpha) in vitro. BF is a protein with a molecular mass of 28 kDa on reducing sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE). The active material was purified to homogeneity by a combination of affinity chromatography, PAGE, and high-pressure liquid chromatography. Amino acid sequence analysis revealed that BF is derived from the membrane TNF receptor. Purified BF blocks the lytic activity of recombinant human and mouse TNF-alpha and recombinant human lymphotoxin on murine L929 cells in vitro. However, BF inhibits the lytic activity of TNF-alpha more effectively than it does that of lymphotoxin. The BF also inhibits the necrotizing activity of recombinant human TNF-alpha when coinjected into established cutaneous Meth A tumors in BALB/c mice. The BF may have an important role in (i) the regulation and control of TNF-alpha and lymphotoxin activity in cancer patients, (ii) interaction between the tumor and the host antitumor mechanisms, and (iii) use of systemically administered TNF-alpha in clinical trials with human cancer patients.
Recombinant human cytokines stimulate neutrophil adherence to IgG autoantibody-treated epithelial basement membranes.
We investigated the ability of the purified recombinant human cytokines: tumor necrosis factor-alpha (rTNF), granulocyte-macrophage colony-stimulating factor (rGM-CSF), interleukin-1 beta (rIL-1), interleukin-3, and tumor necrosis factor-beta (rTNF-beta) to stimulate neutrophil adherence (NA) to basement membranes (BMs) of stratified squamous epithelia pretreated with autoantibodies (ABM) specific for the BM matrix protein, type-VII collagen. rTNF, rGM-CSF, rIL-1, and rTNF-beta, but not IL-3, stimulated NA and stimulation was ABM- and cytokine-concentration-dependent. Stimulation was cytokine-specific and not due to endotoxin since it was significantly inhibited by cytokine-specific antibodies but not by polymyxin B (PB). rTNF and rGM-CSF were the most potent stimulators, were effective at concentrations less than 0.067 ng/ml, and stimulated NA greater than 600%. Relative potency was: rTNF = rGM-CSF greater than rTNF-beta greater than rIL-1. Stimulation by rTNF was due to a rapid, time-dependent effect on the neutrophil, and NA appeared to be dependent, in part, on the low-affinity neutrophil receptor for IgG, Fc(gamma)RIII, because it could be specifically inhibited by monoclonal antibody (3G8) to Fc(gamma)RIII. These results suggest that rTNF, rGM-CSF, rIL-1, and rTNF-beta may contribute individually or in combination to immune-mediated inflammation and tissue injury by stimulating immune adherence of neutrophils to tissue-bound autoantibodies and immune complexes.
Identification of TNF-LT blocking factor(s) in the serum and ultrafiltrates of human cancer patients.
Human serum ultrafiltrate (UFS) obtained from cancer patients contains material(s) which inhibit the cytolytic activity of tumor necrosis factor (TNF-alpha) and lymphotoxin (LT-TNF-beta) in vitro. These factors are found in UFS from patients with different types of cancers and are not detected in the sera of normal donors. Results from molecular sizing studies demonstrated that their molecular weights are over 30 kD. They appear to block by interfering with the early stages of cell lysis. It is not clear whether or not these TNF-LT blocking factor(s) are the same molecules. These factors may have adverse effects on the biological activities of TNF and LT in cancer patients.
The presence of antibodies to lymphotoxin and tumor necrosis factor in normal serum.
Lymphotoxin (LT) and tumor necrosis factor (TNF) are cytokines that probably play a role in several autoimmune diseases. In this report, we describe the detection, in normal nonimmune serum, of naturally occurring antibodies that bind to recombinant human LT and TNF. The naturally occurring antibodies that bind to LT and TNF could explain why normal immunoglobulin is effective therapy in idiopathic thrombocytopenic purpura and Kawasaki syndrome.
Stimulation of fibroblasts by paraprotein in scleromyxedema.
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