Medizin - Open Access LMU - Teil 15/22 Archiv

Terbinafine, a synthetic allylamine, exerts fungicidal activity against dermatophytes, the causative pathogens of tinea pedis. As proven in numerous clinical trials, tinea pedis can be effectively and safely treated by topical terbinafine. In fact, a 1-week application of terbinafine 1% cream eradicated fungal pathogens at least as effectively as 4-week treatment courses with topical azole derivative antifungals and showed lower relapse rates. A new innovative single-application formulation of terbinafine 1% in a film-forming solution produces a high concentration gradient on the skin surface and enables a prolonged (up to 13 days) exposure of the skin to terbinafine. High drug penetration into the skin results in an otherwise not obtained drug reservoir in the horny layer, the location of dermatophytes in tinea pedis. Although azole antimycotics can also effectively penetrate into the horny layer of the skin, short-term therapy might not be feasible due to its primarily fungistatic activity against dermatophytes. Thus, we conclude that the high efficacy of short-term treatment with terbinafine in patients with tinea pedis is possible due to its fungicidal activity coupled with a distinct reservoir formation in the upper layers of the epidermis. Copyright (C) 2008 S. Karger AG, Basel.

Introduction: We report on a double-blind, vehicle-controlled, single-center confirmatory study with random assignment. The purpose of the study was to investigate the topical bioavailability of different topical corticosteroid formulations in healthy human beings focussing on desoximetasone (DM). Materials and Methods: Two DM 0.25% formulations {[}ointment (DM-o) and fatty ointment (DM-fo, water-free); class III corticosteroids], the corresponding active ingredient-free vehicles and three comparators of different strength {[}clobetasol propionate 0.05% (CP 0.05%), fatty ointment, class IV; hydrocortisone (HC) 1%, fatty ointment, class I, and betamethasone (BM) 0.05%, fatty ointment, class III] were tested using the vasoconstriction assay. The degree of vasoconstriction (blanching) in the treatment field was compared to the one found in untreated control fields using chromametric measurements and clinical assessment. Results/Conclusion: DM-o 0.25%, DM-fo 0.25% and BM 0.05% showed similar vasoconstrictive potential, i.e., clear blanching. In fact, both DM preparations were proven to be non-inferior to BM 0.05%, while CP 0.05% was found a little less active. HC 1.0% and the DM vehicles showed no clear-cut vasoconstrictive effect. No adverse events related to the study medications were observed. Good topical bioavailability of both DM formulations was detected by chromametric measurement and clinical assessment. Copyright (C) 2008 S. Karger AG, Basel.

Objective: To validate the prognostic value of preoperative levels of CYFRA 21-1, CEA and the corresponding tumor marker index (TMI) in patients with stage I non-small cell lung cancer (NSCLC). Methods: Two hundred forty stage I NSCLC patients (80 in pT1 and 160 in pT2; 100 squamous cell carcinomas, 91 adenocarcinomas, 32 large-cell carcinomas, 17 with other histologies; 171 males and 69 females) who had complete resection (R0) between 1986 and 2004 were included in the analysis. CYFRA 21-1 and CEA were measured using the Elecsys system (Roche) and AxSym-System (Abbott), respectively. Univariate analysis was performed using the Kaplan-Meier method to identify potential associations between survival and age, gender, CYFRA 21-1, CEA and TMI. Results: Overall 3- and 5-year survival rates were 74 and 64%, respectively. Male gender (p = 0.0009) and age 1 70 years (p = 0.0041) were associated with a worse prognosis; there were no differences between pT1 and pT2 nor between histological subtypes. Three- year survival was 72% for CYFRA 21-1 levels > 3.3 ng/ml versus 75% for levels 6.7 ng/ ml versus 75% for CEA 70 years were associated with a worse outcome, but elevated levels of CEA and CYFRA 21-1, and TMI risk were not. Copyright (C) 2008 S. Karger AG, Basel.

Background: Tissue inhibitor of metalloproteinases-1 (TIMP-1) in blood might be a helpful biomarker in various diseases. However, various authors report that TIMP-1 is dependent on preanalytical procedures. Our study was performed to determine how storage conditions and time to centrifugation influence TIMP-1. Materials and Methods: Twenty-six blood specimens were collected from each of 20 volunteers. Two specimens from each person were centrifuged/measured within 1 h after venipuncture and frozen at -80 degrees C. They were thawed once or twice within 72 h. Eight specimens were stored at 20 degrees C in daylight, 8 at 20 degrees C covered and 8 at 4 C in daylight. Four of each of these 8 specimens were mixed once a day until centrifugation. A mixed and an unmixed specimen of each group was centrifuged/measured after 3, 6, 24 and 72 h. Results: TIMP-1 increased after freeze/ thaw (p < 0.001). Mixing blood specimens more than once caused increased TIMP-1 (p < 0.001). TIMP-1 increased within 3 h of storage (p < 0.001). The increase was lower in specimens covered and refrigerated (p < 0.001). Conclusion: TIMP-1 is unstable and has to be evaluated carefully. Blood should be centrifuged directly after venipuncture. For routine application, specimen handling must be standardized and carefully followed. Research should be done on specimens handled identically. Copyright (C) 2008 S. Karger AG, Basel.

Background: New methods of internet-based real-time monitoring of psychotherapy processes allow for the documentation, analysis, and data-driven control of behaviour therapy. Daily ratings of the patient result in highly resolved time series of the change dynamics. Method and Patient: The Synergetic Navigation System was used in the treatment setting of a day hospital. This method is specialized in the representation of critical instabilities and pattern transitions of the process. The patient of this case report had the combined diagnosis of obsessive-compulsive disorder and depressive episodes. Result: Quantitative time-series and qualitative data from the internet-assisted diaries mirror important features of the change process. Conclusion: The method could help optimise treatment effects of behavioural interventions by using the feedback on necessary conditions, appropriate timing, and short-term effects of these interventions. Patients' motivation for change can be enhanced and the navigation system realises the continuous documentation of treatment processes and effects.

Introduction: A lack of studies on the effects of continuous blood pressure biofeedback led to the development of a screening and feedback software allowing for a `beat-to-beat' representation of arterial blood pressure. Through this method patients find that they can exert some control of their blood pressure. Patients and Methods: For evaluation purposes a pilot study was conducted with 84 hypertensive patients at the Klinik Hohenried, Germany. Two experimental groups which received the normal treatment program of the hospital and an additional 2 (20 patients) or 3-6 (22 patients) biofeedback sessions, respectively, were compared with one control group treated additionally with pseudo biofeedback (20 patients) and another control group (22 patients) which underwent the clinic program without biofeedback. Results: Both experimental groups yielded significantly more markedly blood pressure reductions (MAP) than the controls (p = 0.001), but patients who received 3-6 feedback sessions did not perform significantly better than patients who received only 2 sessions (p = 0.517). Conclusions: 2 sessions of feedback treatment can already have clinically relevant effects. This suggests a major influence of cognitive processes such as self-effectiveness and self-control.

Background: DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case–control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male–female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD. Methods: DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male–female frequency differences in controls and for case–control frequency differences in men and in women. Results: The data showed no male–female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p=0.049, OR=0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p=0.058, OR=0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p=0.010, OR=0.86, 95% CI 0.76 to 0.97), but not in men. Conclusion: DLG5 30Q is associated with a small reduction in risk of CD in women.

Background: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. Objective: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype– phenotype correlations in ICF patients. Methods: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. Results and conclusions: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n=41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n=39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype–phenotype correlation was found between patients with and without DNMT3B mutations.

Acute unilateral peripheral and central vestibular lesions can cause similar signs and symptoms, but they require different diagnostics and management. We therefore correlated clinical signs to differentiate vestibular neuritis (40 patients) from central ‘‘vestibular pseudoneuritis’’ (43 patients) in the acute situation with the final diagnosis assessed by neuroimaging. Skew deviation was the only specific but non-sensitive (40%) sign for pseudoneuritis. None of the other isolated signs (head thrust test, saccadic pursuit, gaze evoked nystagmus, subjective visual vertical) were reliable; however, multivariate logistic regression increased their sensitivity and specificity to 92%.

Systemic mastocytoses represent neoplastic proliferations of mast cells. In about 20% of cases systemic mastocytoses are accompanied by clonal haematopoietic non-mast cell-lineage disorders, most commonly myeloid neoplasms. A case of systemic mastocytosis carrying the characteristic mutation at codon 816 (D816V) in the KIT gene of mast cells, with two concurrent accompanying clonal haematopoietic non-mast cell-lineage disorders, chronic myeloproliferative disease, unclassifiable and precursor B lymphoblastic leukaemia is documented. Both accompanying clonal haematopoietic non-mast cell-lineage disorders carried the wild-type KIT gene, but had a novel t(13;13)(q12;q22) involving the FLT3 locus at 13q12. The chronic myeloproliferative disease, unclassifiable and the precursor B lymphoblastic leukaemia were cured by syngenous stem cell transplantation, but the systemic mastocytosis persisted for more than 10 years. The additional impact of molecular techniques on the correct diagnosis in haematological malignancies is highlighted, and evidence is provided that, apart from internal tandem duplications and mutations, FLT3 can be activated by translocations.

Objective: Liver regeneration is mainly based on cellular self-renewal including progenitor cells. Efforts have been made to harness this potential for cell transplantation, but shortage of hepatocytes and premature differentiated progenitor cells from extra-hepatic organs are limiting factors. Histological studies implied that resident cells in adult liver can proliferate, have bipotential character and may be a suitable source for cell transplantation. Methods: Particular cell populations were isolated after adequate tissue dissociation. Single cell suspensions were purified by Thy-1 positivity selection, characterised in vitro and transplanted in immunodeficient Pfp/Rag2 mice. Results: Thy-1+ cells that are mainly found in the portal tract and the surrounding parenchyma, were isolated from surgical liver tissue with high yields from specimens with histological signs of regeneration. Thy-1+ cell populations were positive for progenitor (CD34, c-kit, CK14, M2PK, OV6), biliary (CK19) and hepatic (HepPar1) markers revealing their progenitor as well as hepatic and biliary nature. The potential of Thy-1+ cells for differentiation in vitro was demonstrated by increased mRNA and protein expression for hepatic (CK18, HepPar1) and biliary (CK7) markers during culture while progenitor markers CK14, chromogranin A and nestin were reduced. After transplantation of Thy-1+ cells into livers of immunodeficient mice, engraftment was predominantly seen in the periportal portion of the liver lobule. Analysis of in situ material revealed that transplanted cells express human hepatic markers HepPar1 and albumin, indicating functional engraftment. Conclusion: Bipotential progenitor cells from human adult livers can be isolated using Thy-1 and might be a potential candidate for cell treatment in liver diseases.

Inhibitors of coagulation factors from blood-feeding animals display a wide variety of structural motifs and inhibition mechanisms. We have isolated a novel inhibitor from the cattle tick Boophilus microplus, one of the most widespread parasites of farm animals. The inhibitor, which we have termed boophilin, has been cloned and overexpressed in Escherichia coli. Mature boophilin is composed of two canonical Kunitz-type domains, and inhibits not only the major procoagulant enzyme, thrombin, but in addition, and by contrast to all other previously characterised natural thrombin inhibitors, significantly interferes with the proteolytic activity of other serine proteinases such as trypsin and plasmin. The crystal structure of the bovine alpha-thrombin.boophilin complex, refined at 2.35 A resolution reveals a non-canonical binding mode to the proteinase. The N-terminal region of the mature inhibitor, Q16-R17-N18, binds in a parallel manner across the active site of the proteinase, with the guanidinium group of R17 anchored in the S(1) pocket, while the C-terminal Kunitz domain is negatively charged and docks into the basic exosite I of thrombin. This binding mode resembles the previously characterised thrombin inhibitor, ornithodorin which, unlike boophilin, is composed of two distorted Kunitz modules. Unexpectedly, both boophilin domains adopt markedly different orientations when compared to those of ornithodorin, in its complex with thrombin. The N-terminal boophilin domain rotates 9 degrees and is displaced by 6 A, while the C-terminal domain rotates almost 6 degrees accompanied by a 3 A displacement. The reactive-site loop of the N-terminal Kunitz domain of boophilin with its P(1) residue, K31, is fully solvent exposed and could thus bind a second trypsin-like proteinase without sterical restraints. This finding explains the formation of a ternary thrombin.boophilin.trypsin complex, and suggests a mechanism for prothrombinase inhibition in vivo.