Interferon gamma and tumor necrosis factor alpha mRNA expression in mycosis fungoides progression.
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Biomedical subjects
Publications and source records attributed to W Sterry.
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Diagnosis of clinically suspected lymph node metastases in melanoma patients can be confirmed with high sensitivity and specificity by fine needle aspiration (FNA) cytology. However, small lymph nodes or haemorrhagic metastases may yield negative or unevaluable cytology. We tested whether the sensitivity and specificity of presurgical diagnosis could be improved by a polymerase chain reaction (PCR) method, identifying tyrosine-mRNA in samples obtained by fine needle aspiration (FNA-PCR). PCR was positive in 17 of 18 histopathologically proven melanoma metastases, while conventional cytopathology detected 16 of 18. 4 of 9 disease-free melanoma patients with negative FNA cytology had positive PCR results, but controls gave negative results. FNA-PCR analysis cannot be recommended as superior to conventional FNA cytological examination. Whether the positive FNA-PCR in four of the nine clinically unsuspicious regional lymph nodes correlates with earlier disease progression or indicates lower specificity of the method will need further investigation.
BACKGROUND: Allergy to mare's milk is rare. Recently, however, mare's milk has been recommended for treatment of various ailments by practitioners of "alternative medicine," and it is available in health food stores. OBJECTIVE: We report a case of allergic reaction to mare's milk in a 51-year-old woman who was able to tolerate cow's milk. METHODS: The protein composition of mare's milk was determined by methods based on measurement of nitrogen content. The patient underwent prick and intracutaneous tests with commercially available bovine milk proteins and several mare's milk preparations, including mare's milk granulate and boiled mare's milk. RAST and immunoblotting were also performed. RESULTS: Results of skin testing and RAST with cow's milk were negative but demonstrated an IgE-mediated allergy to mare's milk. Immunoblotting revealed two allergen bands with molecular weights of 16 and 18 kd, most likely representing the whey proteins alpha-lactalbumin and beta-lactoglobulin. The bands disappeared after the mare's milk was boiled, indicating that the proteins are heat-labile. CONCLUSION: The results of this study demonstrate the existence of an IgE-mediated mare's milk allergy caused by low molecular weight heat-labile proteins, most likely alpha-lactalbumin and beta-lactoglobulin, which do not cross-react with the corresponding whey proteins in cow's milk.
To further evaluate the nature of the HLA association with psoriasis, HLA haplotypes of 60 patients with type 1 (early onset, positive family history) and 30 patients with type II (late onset, no family history) psoriasis were investigated by polymerase chain reaction sequence-specific oligonucleotide hybridization (HLA class II) and serology (HLA class I). Ethnically matched blood donors (146) served as controls. In type I, but not type II psoriasis, the Caucasian HLA extended haplotype (EH) Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303 named according to the B allele EH-57.1 was highly significantly overrepresented (p cor= 0.00021). This particular EH was present in 35% of type I psoriatics but only 2% of controls. EH-57.1+ individuals therefore carry a 26 times higher risk of developing type I psoriasis than individuals who are EH-57.1-negative Further analysis of individual HLA alleles revealed that within EH-57.1, HLA class I antigens (Cw6-B57) were associated to a much higher extent with type I psoriasis than the HLA class II alleles (DRB1*0701-DQA1*0201-DQB1* 0303). Pedigree analysis of three multiply affected families over three generations revealed a cosegregation of disease with EH-57.1. These results strongly suggest that a gene for familial psoriasis is associated with the class I side of the extended haplotype Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303.
67 women with chronic recurrent or persistent vaginal candidosis between 5-79 years of age were seen in our outdoor department. In 34 cases, yeasts could be isolated in a vaginal swab taken at the first consultation. On average the patients reported 5 episodes per year during the last years. Typical symptoms consisted of pruritus vulvae, local inflammation and a curdy vaginal discharge. Nearly all of the women had received local or systemic antimycotic treatment for several times. In 53% (18 patients), C. albicans had been isolated, in 29% (10 patients) C. glabrata and in 9% (3 patients) C. krusei. While candidosis due to C. albicans and C. krusei was frequently associated with distressing complaints, infections with C. glabrata caused only very few symptoms. Independent of the species, severe and persistent infections were characterized by long term persisting specific IgM-antibody-titers and remarkable lack of IgG-antibodies. The laboratory parameters of WBC, CRP and immunelectrophoresis were normal. The minimum inhibitory concentrations (MIC) of 60 Candida strains against fluconacole were determined by microdilution assay. The MIC for C. albicans (n = 35) were between 0.78 and 3.125 micrograms/ml, for C. glabrata (n = 20) between 8 and 32 micrograms/ml and for C. krusei (n = 5) between 25 and 128 micrograms/ml. In 7 cases, local antimycotic treatment was sufficient. Correlating to the sensitivity, 18 women were treated with 100-800 mg fluconacole/d for 10-20 days. In 13 of them, clearance of symptoms and yeasts was achieved. The treatment of fluconacole-resistant strains with itraconazole (100-200 ml/d for 10-20 days) together with local application of nystatin (2 x 1 Mio. IE for 10 days) was without any effect. Three women with C. albicans, C. glabrata and C. krusei infection received a candidin-vaccination (0.005 BE/ml-500 BE/ml). In all of these cases, production of IgM-antibodies was induced. However, the clinical symptoms could not be influenced. Only in two cases it was not possible to reach a clearance of symptoms and yeasts. The results show the benefit of a precise differentiation before therapy. Serologic controls of antibody titers seem to be useful tools to control the efficacy of treatment.
Previous studies have shown that barrier requirements regulate epidermal liquid and DNA synthesis. In the present study, we examined the possibility that the integrity of the permeability barrier influences epidermal Langerhans cells involved with the immune response. Barrier disruption was achieved by treatment of human skin with acetone, sodium dodecylsulphate (SDS), or tape stripping, until a 10-20-fold increase in transepidermal water loss was achieved. Serial biopsies were performed 6-168 h after treatment, and Langerhans cells were complexed with anti-CD1a (Leu6) or S-100 antibodies, and visualized with an immunoperoxidase technique. Acetone treatment resulted in an increase in epidermal Langerhans cell density, reaching a maximum of 94% over control (P < 0.01) by 24 and 48 h post-treatment. Following SDS treatment or tape stripping, epidermal Langerhans cell density was increased by 100 and 175% (P < 0.01), respectively. There was a linear correlation between the degree of barrier disruption and the increase in epidermal Langerhans cell density. Studies with the Ki-S3 proliferation-associated nuclear antigen revealed a two- to threefold increase in epidermal proliferation after barrier disruption. The time curves of the increase in Langerhans cell density and the increase in epidermal proliferation were similar, suggesting that there was a coordinate regulation. In contrast with our previous studies employing patch test reactions to allergens or irritants, disruption of barrier function neither resulted in an increased dermal Langerhans cell density, nor influenced T lymphocytes (CD3+, Leu4+), macrophages (KiM8+), ICAM-1 or ELAM-1 expression in the skin. In addition, barrier disruption did not result in either dermal inflammation or epidermal spongiosis. In summary, these findings support our hypothesis that the permeability barrier influences epidermal Langerhans cell density, which is involved in maintaining an immunological barrier.
HISTORY AND CLINICAL FINDINGS: Acute, zigzag-shaped livid skin markings developed on both thighs of a 55-year-old woman who had been on dialysis for 6 years. Within 7 days these areas increased in size to about 10 cm in diameter and contained central dry and painful necroses. On legs, lower arms and hands hard subcutaneous nodules were palpable with a diameter up to 3 mm. For many years the phosphate and parathormone levels, as well as alkaline phosphatase activity had been raised. The patient had often failed to follow treatment recommendations. TESTS: There were increased serum concentrations of calcium (2.8 mmol/l) and phosphate (1.78 mmol/l). The calcium phosphate ion product was 4.98 (mmol/l)2. Furthermore, there were raised levels of alkaline phosphatase (315 U/l) and parathormone (1076 ng/l, normal: 10-65). X-ray film of the hands showed soft tissue and arterial calcifications, while histological examination of a deep skin biopsy revealed calcium phosphate emboli of the main vessels. TREATMENT AND COURSE: Excision of the cutaneous necroses was followed by parathyroidectomy at which only three parathyroid glands were identified and removed. The parathormone level fell postoperatively, but rose again after 4 weeks. The fourth parathyroid gland was then found and removed, after which the parathormone level fell below measurable levels. The skin ulcers healed completely 4 weeks after the second operation.
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The CD30-activation marker was detected as the Hodgkin-associated Ki-I antigen and is regarded as a target for the treatment of Hodgkin patients with immunotoxins. The CD30 is released from tumor cells and this soluble CD30 (sCD30) is an indicator of the disease activity. Since the shedding of sCD30 may be influenced by antibodies, we produced 6 new CD30-specific antibodies (Ki-2 to Ki-7) for the purpose of finding antibodies that might inhibit the formation of sCD30. Ki-2 to Ki-7 and the other anti-CD30 antibodies Ki-I, Ber-H2, HeFi-I, M44, M67, HRS-I, HRS-4 and C10 were employed for epitope mapping. The binding of a particular radio-labeled anti-CD30 antibody to Hodgkin's-disease-derived L540 cells was completed by addition of the various non-labeled anti-CD30 antibodies. Three non-overlapping regions, expressing different antigen-specific determinants, could be defined on the extracellular part of the CD30 molecule. Cluster A of determinants was recognized by Ki-2, Ki-4, Ki-6 and Ki-7, Ber-H2, HRS-I and HRS-4, while cluster B was detected by Ki-I, Ki-5 and M67. Cluster C, which probably contains the binding site for the CD30 ligand, was defined by Ki-3, M44, HeFi-I and C10. Co-culture experiments of L540 cells with the various antibodies followed by the isolation of sCD30 from culture supernatant fluids revealed that the release of sCD30 was most strongly increased by Ki-I and weakly enhanced by Ki-2, Ki-3, Ki-5 and HeFi-I, whereas it was almost completely inhibited by Ki-4 and to a slightly lesser extent by Ber-H2.
Early-stage mycosis fungoides shows similar clinical symptoms and histological and immunophenotypical features to several benign lymphoproliferative skin disorders. We analyzed T cell receptor gamma gene rearrangement by polymerase chain reaction in the search for monoclonal lymphoid subpopulations in skin infiltrates. Totally, 283 skin biopsies (paraffin-embedded and frozen material) from patients with different malignant and reactive skin diseases were investigated. Using primers for the T cell receptor gamma chain gene, monoclonality was detected in 59 out of 66 (89%) cases of pleomorphic cutaneous lymphoma, in 60 out of 78 (77%) patients with mycosis fungoides, in 11 out of 22 (50%) cases of parapsoriasis en plaques, in five out of 35 (14%) cases of pseudolymphoma, in six out of 15 (40%) patients with lymphomatoid papulosis, and in none out of 64 patients with inflammatory skin diseases. The results show that clonal T cell population can be detected in the majority of patients with cutaneous T cell lymphoma, but the findings have to be correlated with the histological and morphological features.
Primary malignant T cell lymphomas of the skin form a heterogenous group. Relevant classifications were recently made to separate different entities by various criteria. This is of great importance, because one should only rely on those therapeutical trials in which patients were included according such classifications. In this paper, we will mainly focus on therapeutic modalities for mycosis fungoides, which is the most frequent cutaneous T cell lymphoma and which may serve as a model disease. In principle, local (e.g., psoralens and ultraviolet A, PUVA) and systemic therapies (e.g., interferon-alpha 2a) can be applied. Very recently, we were able to demonstrate that even in initial stages of mycosis fungoides, the T cell clone is not restricted to the skin, but rather is present in low amounts in the peripheral blood. Therefore, systemic therapeutic modalities alone or in combination with local strategies (interferon-alpha 2a and acitretin/PUVA and interferon-alpha 2a) should be more effective, which will be proven by currently running clinical trials.
The diagnosis of cutaneous malignant lymphoma is based on clinical, histo-morphological and immunochemical findings and, now a days, on molecular biology analyses of the genotype in the lymphocytic infiltrate. By using the polymerase chain reaction (PCR) with specific primers for the Ig heavy chain gene and the T-cell receptor gamma chain gene, the detection of monoclonal cell populations in the skin infiltrate is possible. Since this method produces results within 3 days, since paraffin-embedded skin and lymph node biopsies and heparinized peripheral blood can be used and since no radioactivity is necessary, this technique has important advantages over traditional techniques such as Southern blot analyses. In addition, specific PCR analyses may allow a patient-specific monitoring during therapy and also may detect early relapses of the lymphoproliferative malignant disease.
The case report presented describes a new variant of annular elastolytic giant cell granuloma. Over a period of 10 years, a 40-year-old woman had developed reticular, brown to livid, partly atrophic skin lesions on the shoulders and decolletée. The patient had no subjective symptoms. Histology revealed a patchy lymphohistiocytic infiltrate in the dermis, with many giant cells. Elastic fibres were less frequently found in these infiltrates; in a few of the giant cells and macrophages fragments of elastic fibres were demonstrated within the cytoplasm. There were no deposits of mucin. For this new variant we propose the term "reticular elastolytic giant cell granuloma."
In this review we focus on the diagnostic importance of antinuclear antibodies (ANA), the biological function of the relevant autoantigens and on some methodological questions regarding the detection of ANA. The qualitative and quantitative evaluation of ANA has improved significantly in recent years with the introduction of several new test kits. A precondition for the rational use of those assays is knowledge of the diagnostic validity of the detected ANA with regard to the method used. ANA are autoantibodies that react with nucleic acids, protein-nucleic acid complexes and proteins of nuclei. The reasons for their in vivo production are unknown. ANA characterize several of the so-called connective tissue autoimmune diseases and their subtypes, either alone or in typical combinations. They differ significantly with regard to their prevalence and thus in their diagnostic validity. Specificity and prevalence do not correlate. ANA are not markers of disease activity except for antibodies against dsDNA. ANA levels can be interpreted correctly only in connection with clinical symptoms and other laboratory findings.
We report on dermatomyositis-like adverse cutaneous reactions following long-term maintenance therapy with hydroxyurea in two patients suffering from chronic myelogenous leukaemia (CML). In addition to non-specific side effects, such as xerosis, pruritus and hyperpigmentation, both patients presented with more specific skin changes, i.e. erythematous lesions, scaling, and partially atrophic areas distributed in a linear fashion on the dorsal aspects of the hands and fingers. In addition, teleangiectatic erythema of the face was present in both patients, and this was associated with oedema of the eyelids in one patient. Despite these dermatomyositis-like features there were no clinical signs of muscular involvement, and muscle-specific enzymes were within normal ranges. Skin biopsy specimens revealed an interface dermatitis characterized by a lichenoid cell infiltrate, vacuolar alteration of basal cells, necrotic keratinocytes within the spinous zone, focal hypergranulosis, ortho-hyperkeratosis and telangiectases in the upper part of the dermis. Analogous histopathological findings have been documented in lichen planus-like skin changes on the hands following hydroxyurea therapy. It seems doubtful whether there are actually any major differences between those skin changes described as dermatomyositis-like and those interpreted as lichen planus-like in patients receiving long-term hydroxyurea therapy.
Only five cases of the amelanotic variant of lentigo maligna melanoma of the face have been reported. We describe an additional four patients observed within the past 5 years, suggesting a much higher incidence of this variant than previously suspected.
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