Biomedical subjects

Hans F Merk

Publications and source records attributed to Hans F Merk.

28 records · Page 2Linked to original sources

PubMed2003

Linkage disequilibrium between tumor necrosis factor (TNF)-alpha-308 G/A promoter and TNF-beta NcoI polymorphisms: Association with TNF-alpha response of granulocytes to endotoxin stimulation.

OBJECTIVE: Controversial data have been reported on the association between the tumor necrosis factor (TNF)-alpha-308 G[U279C]A promoter polymorphism or the TNF-alpha I polymorphism with TNF-alpha plasma concentrations. The purpose of this study was to evaluate whether there is a linkage disequilibrium between the two polymorphisms. Moreover, the influence of these polymorphisms on the TNF-alpha synthesis of activated granulocytes was studied. DESIGN: Analysis of TNF-alpha concentrations of human whole blood after endotoxin stimulation. SETTING: Medical research laboratory. PATIENTS: Healthy human volunteers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Healthy human volunteers were genotyped for both TNF polymorphisms by means of polymerase chain reaction. TNF-alpha plasma concentrations were determined with chemiluminescence after incubation of whole blood with endotoxin. A strong (p <.0001) linkage disequilibrium was found for the TNF-beta I and the TNF-alpha-308 genetic polymorphisms. Almost all individuals homozygous for the TNF-B2 allele of the TNF-beta I polymorphism were also TNF-alpha-308 G homozygotes. Carriers of the TNF-alpha-308 genotype AG had a significantly higher TNF-alpha production capacity than G homozygotes. The TNF-beta I genotype TNF-B1/TNF-B2 was associated with significantly higher TNF-alpha concentrations than the genotype TNF-B2/TNF-B2. Individuals homozygous for the TNF-B2 and the TNF-alpha-308 G alleles had a significantly reduced TNF-alpha response compared with individuals heterozygous for both TNF polymorphisms. CONCLUSIONS: A linkage disequilibrium between the two TNF polymorphisms was found. This study revealed a significant association between genotype and phenotype for both TNF polymorphisms. Heterozygosity for both TNF polymorphisms is associated with an increased TNF-alpha response.

Granulocytes↗

PubMed2003

Multiple patch-test reactions: a pilot evaluation of a combination approach to visualize patterns of multiple sensitivity in patch-test databases and a proposal for a multiple sensitivity index.

BACKGROUND: The variety of patterns of multiple sensitivity in patch-test data remains poorly defined. Studies addressing this topic have primarily concerned the occurrence of pairs of allergens, and some reports hypothesize a predisposing factor that influences the individual sensitivity of patients to multiple reactions. OBJECTIVE: The aim of this study was to address this topic by reanalyzing a matched data set from two patch-test units in Cleveland, OH, and one unit in Cologne, Germany, focusing on multiple reactions to identical allergens of the standard screening trays over the same 4-year period. METHODS: Based on the statistical FREQ procedure (SAS Institute Inc., Cary, NC), we propose a program for addressing the difficulties in computing and visualizing patterns of multiple sensitivity. Additionally, we propose the "multiple sensitivity index" (MSI) as an absolute measure for characterizing the occurrence of an allergen with others on a selected panel. RESULTS: For the seventeen allergens examined, 131072 possible combinations were evaluated in a total of 2881 patients. Of patients tested, 12.4% had multiple positive patch-test reactions to two to seven allergens. However, because of the small number of patients with the crucial number of possible combinations, no cluster patterns were evident in the three- to seven-allergen combinations. Pairs of allergens most frequently observed were nickel sulfate and potassium dichromate (n = 23), formaldehyde and quaternium-15 (n = 18), and nickel sulfate and formaldehyde (n = 13). We found that nickel sulfate, once again the most frequent sensitizer, occurred in the majority of noncombined cases (MSI = -0.280). CONCLUSION: Larger patch-test databases require evaluation to obtain further evidence of cluster patterns of multiple sensitivity and to validate the MSI.

Allergens↗

PubMed2003

[Pharmacotherapy of allergic diseases].

The treatment of allergic diseases involves the avoidance--if possible--of identified allergens and immunotherapy including a specific hyposensitization and pharmacotherapy. The present review will focus on pharmacotherapy with those drugs that are relevant to several allergic diseases and not primarily used for the treatment of the pathophysiological changes of specific organs involved such as in asthma. The latter will be discussed elsewhere. Glucocorticoids are an example of drugs which have been used for a long time. However, recent progress in our outstanding of their mechanism of action has led to the possibility of developing new compounds with potentially fewer undesirable side effects. Antihistamines have been developed into new drug generations which are still effective with fewer side effects and which can now be applied in a once-daily regimen thus promoting patient compliance. A major progress has been made in the treatment of atopic dermatitis by introducing topically available calcineurinantagonists such as tacrolimus and pimecrolimus. The future will be characterised by both the development of drugs that are more specific with regard to their inflammatory target, which can be detected by using humanizied murine antibodies, and the subsequent development of small molecular compounds with a function similar to that of antibodies. New technologies such as the chip technology or proteonomics allow for the selection of compounds suitable for further clinical development.

Allergens↗

PubMed2002

Clinical comparison of the efficacy and tolerability of once daily Canesten with twice daily Nizoral (clotrimazole 1% cream vs. ketoconazole 2% cream) during a 28-day topical treatment of interdigital tinea pedis.

The effects of two topical cream formulations containing clotrimazole 1% and ketoconazole 2%, respectively, were clinically compared in a double-blind, randomized manner for a 28-day therapy of interdigital tinea pedis in 106 treated patients. Ketoconazole was to be used twice daily whereas clotrimazole was administered only once daily. The primary response criterion defined as the number of patients with cure or improvement after 28 treatment days was comparable with 62.0% vs. 64.0% (clotrimazole vs. ketoconazole) for the full analysis set of 100 (50 vs. 50) patients. The mycological response revealed a negative culture and microscopy in 53.1% vs. 52.1% of the patients after 14, in 76.0% vs. 79.2% after 28, and in 83.7% vs. 76.9% after 56 days of observation, indicating a possibly better long-term efficacy of clotrimazole. The development of the overall score of tinea-related signs and symptoms did not show relevant differences between the two drugs and continuously decreased from 11+/-5 in both groups at baseline to 2+/-2 vs. 2+/-1 at day 56. As to the remission and improvement rates of single symptoms, better results were obtained under clotrimazole than under ketoconazole particularly for pruritus (97.8 vs. 89.6%) and burning/stinging (97.5 vs. 89.4%) which both are perceived as most bothersome by the patients. Furthermore, both substances appeared as comparably safe and well tolerable (8 vs. 7 adverse events with only 1 vs. 3 drug related). In conclusion, a successful therapy of tinea pedis can be achieved with both clotrimazole and ketoconazole within 28 days of treatment and once-daily clotrimazole is equally effective as twice-daily ketoconazole with favourable influences on the most irritating symptoms of the disease. Mycological and reliable clinical cure cannot be observed during two weeks after start of treatment.

Adolescent↗

PubMed2002

Phenotype diversity in familial cylindromatosis: a frameshift mutation in the tumor suppressor gene CYLD underlies different tumors of skin appendages.

Familial cylindromatosis (turban tumor syndrome; Brooke-Spiegler syndrome) (OMIM numbers 123850, 132700, 313100, and 605041) is a rare autosomal dominantly inherited tumor syndrome. The disorder can present with cutaneous adnexal tumors such as cylindromas, trichoepitheliomas, and spiradenomas, and tumors preferably develop in hairy areas of the body such as head and neck. In affected families, mutations have been demonstrated in the CYLD gene located on chromosome 16q12-13 and reveal the characteristic attributes of a tumor suppressor. Here, we studied familial cylindromatosis in a multigeneration family of German origin. Clinically, some individuals only revealed discrete small skin-colored tumors localized in the nasolabial region whereas one family member showed expansion of multiple big tumors on the trunk and in a turban-like fashion on the scalp. Histologically, cylindromas as well as epithelioma adenoides cysticum were found. We detected a frameshift mutation in the CYLD gene, designated 2253delG, underlying the disorder and were able to show that a single mutation can result in distinct clinical and histologic expression in familial cylindromatosis. The reasons for different expression patterns of the same genetic defect in this disease remain elusive, however. Identification of mutations in the CYLD gene enable us to rapidly confirm putative diagnoses on the genetic level and to provide affected families with genetic counseling.

Carcinoma, Skin Appendage↗

PubMed2002

Allergic contact dermatitis from phenylephrine in eyedrops.

Phenylephrine is widely used as an ophthalmic drug. However, there are only very few reports on allergic contact dermatitis induced by phenylephrine. In addition, little is known on cross reactivity patterns between the sympathomimetics phenylephrine, epinephrine and ephedrine which share a similar chemical structure. We report on a man who developed allergic contact dermatitis to Neosynerphin POS eyedrops containing phenylephrine hydrochloride. Cross reactivity between phenylephrine, epinephrine and ephedrine was studied by patch testing. Patch tests were performed with the European standard, an ophthalmics and preservatives series, Neosynerphin POS eyedrops, phenylephrine hydrochloride 10% aq., epinephrine and ephedrine (both 1.0 % aq.). Test sites were read after 48, 72 and 168 hours according to the recommendations of the ICDRG. Neosynerphin POS and phenylephrine hydrochloride 10 % aq. gave positive reactions, whereas epinephrine and ephedrine tested negative. Although phenylephrine is an epinephrine analog delayed type hypersensitivity to phenylephrine did not result in cross reactivity with chemically related epinephrine and ephedrine.

Cross Reactions↗

PubMed2002

Delayed-type hypersensitivity reaction to paraphenylenediamine is mediated by 2 different pathways of antigen recognition by specific alphabeta human T-cell clones.

BACKGROUND: Allergic contact dermatitis to paraphenylenediamine (PPD) is a frequent cause of morbidity and occupational disability. OBJECTIVE: The aim of the study was to characterize T-cell responses to PPD and Bandrowski's base (BB), an autoxidation product of PPD, by using polyclonal and monoclonal T-lymphocyte cultures. METHODS: PPD- and BB-driven proliferation of PBMCs and T-cell clones (TCCs) was assessed by means of tritiated thymidine incorporation. Surface markers were studied by means of flow cytometry, and cytokine generation was assessed with an ELISA. RESULTS: TCCs, with one exception, were CD4+/CD45RO+, and T-cell receptors were alphabeta+. Three of 6 TCCs expressed Vbeta 16. TCC stimulation was HLA-DP restricted, and TCCs secreted IL-4, IL-5, and marginal levels of IFN-gamma. TCCs reacted to both PPD and BB. Presentation of BB to TCCs was dependent on viable antigen-presenting cells (APCs) pulsed for 4 hours, and fixed APCs failed to stimulate TCCs. Moreover, polyclonal responses to BB were enhanced by metabolically active enzymes, such as cytochrome P450 enzymes. BB has to be metabolized and processed. In contrast, fixation of APCs did not impair their ability to present PPD to TCC, whereas pulsing of APCs with PPD failed to stimulate TCCs. Thus PPD had to be present during the process, and polyclonal stimulation was not enhanced by cytochromes. CONCLUSION: These results suggest that PPD itself can be recognized by T cells through a processing-independent pathway, whereas its autoxidation product, BB, required processing and possibly metabolism to stimulate the same TCC. Our data demonstrate that 2 distinct pathways of antigen presentation to activate specific TCCs are involved in the immune response to PPD.

Antigen Presentation↗

PubMedDate not supplied

Anaphylaxis induced by glucocorticoids.

Glucocorticoids are frequently used to treat allergic reactions. Therefore, allergic reactions to systemic glucocorticoids in particular are considered most unlikely and are not well known. We report on a 23-year-old woman with atopic dermatitis who had an anaphylactic reaction after oral administration of prednisolone. On treatment with epinephrine, antihistamines and volume symptoms resolved. Skin testing with a panel of glucocorticoids showed immediate type reactions to prednisolone, prednisolone hydrogen succinate, prednisone, and betamethasone dihydrogen phosphate. In challenge testing the patient tolerated methyl prednisolone and dexamethasone. There is increasing evidence that true allergic immediate type reactions to glucocorticoids exist. The severity of the reaction can vary from a rash to anaphylaxis. However, a patient sensitized to one or a group of glucocorticoids does not have to refrain from all types of glucocorticoids. Careful challenge testing is by far the best way to select glucocorticoids that are safe for future treatment. Clinicians should be aware that allergic reactions to glucocorticoids can occur and that worsening of symptoms does not always mean treatment failure.

Adrenergic alpha-Agonists↗

PubMedDate not supplied

Intratumoral induction of thymidylate synthase mRNA by 5-FU in colorectal cancer patients: association with survival.

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in 5-fluorouracil (5-FU) catabolism. Thymidylate synthase (TS) is inhibited to form an inactive ternary complex by 5-fluoro-dUMP and is considered to be a target enzyme of 5-FU treatment. Two enzymes, DPD and TS, have been reported to be major determinants of individual sensitivity to 5-FU, and it has been reported that TS mRNA levels are modified by 5-FU treatment. We investigated their impact on treatment efficacy in colorectal cancer patients. TS and DPD mRNA levels, which correlated to the corresponding enzyme activities, were quantified in tumor tissues before and after treatment in 40 advanced colorectal cancer patients who had been treated with Doxifluridine (5'-DFUR) for 14 days before surgery. Furthermore inter-individual variations of TS mRNA levels after 5-FU treatment were found, and the individual TS induction varied between patients (0.2-2.4). Increased TS mRNA levels were found in 19 out of 40 cases. The samples were divided into two groups according to their TS mRNA induction (< or >1; TS/beta-actin ratio after treatment divided by values prior treatment) and compared with tumor reduction and survival. TS and DPD mRNA levels in tumor biopsies before treatment were not related to 5-FU responses by histological evaluations in this study. However the efficacy of 5-FU treatment was enhanced in patients with no or low TS mRNA induction (odds ratio: 6.2, p<0.05). Furthermore, longer periods of survival were observed in the group without increased TS mRNA levels. These findings suggest that TS mRNA was induced by 5-FU treatment, and the overall induction level varied between individuals. Therefore, the estimation of TS mRNA induction may be useful to predict the efficacy of 5-FU treatment.

Aged↗

PubMedDate not supplied

Unilateral facial telangiectases suggest type 1 segmental manifestation of Osler-Rendu-Weber syndrome in an 11-year-old boy.

An 11-year-old boy revealed multiple telangiectases confined to the left cheek and the left side of the lips. Additionally, unilateral epistaxis was present. Radiological examinations of the brain, lungs and abdomen were normal and bleeding of the gastrointestinal tract was excluded. In this case, we propose a probable segmental type 1 manifestation of the autosomal dominantly inherited Osler-Weber-Rendu syndrome.

Child↗