Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation

Acne is a chronic disease hallmarked by sebaceous hyperplasia, follicular hyperkeratosis, and inflammation. Parallel targeting of these factors is required to treat acne effectively. Inhibitors of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) show strong anti-inflammatory effects on immune cells and therapeutic efficacy in autoimmune disorders. Our investigation focused on the expression and functional relevance of these ectopeptidases in three cell types which exhibit an altered phenotype in early acne lesions. We showed for the first time expression of DP IV and APN on human sebocytes. In the SZ95 sebocyte cell line, the DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide and the APN inhibitors actinonin and bestatin suppressed proliferation, enhanced terminal differentiation, and slightly decreased total neutral lipid production. The anti-inflammatory and differentiation-restoring cytokine IL-1 receptor antagonist was significantly upregulated in SZ95 sebocytes and the HaCaT keratinocyte cell line in the presence of inhibitors. Furthermore, the inhibitors suppressed proliferation and IL-2 production of Propionibacterium acnes-stimulated T cells ex vivo and enhanced the expression of the immunosuppressive cytokine transforming growth factor-beta1. Our data provide first evidence for a functional role of DP IV and APN in the sebaceous gland apparatus and for their inhibitors, used alone or in combination, as completely new substances possibly affecting acne pathogenesis in a therapeutic manner.     

Morphological skin ageing criteria by multiphoton laser scanning tomography: non-invasive in vivo scoring of the dermal fibre network

Background: Morphological changes in the dermal collagen and elastin fibre network are characteristic for skin ageing and for pathological skin conditions of the dermis. Objectives: To characterize pathological and physiological conditions by multiphoton laser scanning tomography (MLT) in vivo, it is necessary to investigate and identify morphological alterations related to ageing. Methods: In vivo MLT was used to image two‐photon excited autofluorescence (AF) and second harmonics generation (SHG) in human dermis of 18 volunteers of different ages. Criteria for the evaluation of age‐dependent morphological changes in MLT images were fibre tension and morphology, network pattern, clot formation and image homogeneity. These criteria were weighted and a score was calculated. Results: The resulting MLT‐based Dermis Morphology Score is correlated with age (R² = ?0.90) and with the previously published SHG to AF Ageing Index of Dermis (R² = 0.66). The two groups of young (age 21–38) and old (age 66–84) volunteers showed a significant difference in MLT score values (P < 0.001). Conclusions: We could demonstrate an in vivo relationship between morphological characteristics of human dermis assessed by MLT and age. The present score allows the semi‐quantitative evaluation of specific morphological changes of the dermal fibre network in ageing skin by in vivo AF and SHG imaging. This method will be useful for diagnostics of pathological conditions and their differentiation from ageing effects.     

Similar appearance,different mechanisms: xerosis in HIV,atopic dermatitis and ageing

Xerosis is one of the most common dermatologic disorders occurring in the elderly and in patients with atopic dermatitis (AD) and human immunodeficiency virus (HIV) infection. Xerosis has been linked to an impaired skin barrier function of the stratum corneum. Using Raman microspectroscopy, we concentrated on deeper skin layers, viable epidermis and dermis of 47 volunteers and associated molecular alterations to the evolution of xerosis and the skin barrier, for example, lipid, water and antioxidant content. A decrease in lipids within the viable epidermis is found for elderly and HIV‐patients. Lipid and water values of AD patients and their healthy reference group are similar. Decreases in lipids and simultaneous increases in water are found in the dermis for HIV and AD patients in comparison to their healthy reference groups. Excessive levels of epidermal carotenoids, mainly lycopene, in HIV‐patients were found potentially leading to adverse effects such as premature skin ageing.     

Genomic distribution of beta papillomaviruses in single eyebrow hair samples and pools of eyebrow hair samples

Human beta papillomaviruses (beta-HPVs) are frequently detected in hairs and the majority of people are infected with multiple beta-HPV genotypes. This study was conducted to investigate for the first time the distribution of beta-HPV genotypes in single hair specimens and to estimate the contribution of a single hair to the beta-HPV profile obtained from a specimen made of multiple hairs pooled together. A total of 85 eyebrow hair specimens, representing 64 single hairs and 21 pools of hairs, obtained from 21 immunocompetent individuals, were tested using a reverse-line blot-based beta-HPV genotyping assay that allows identification of 25 different beta-HPVs. Overall, beta-HPV DNA was detected in 82/84 (97.6%) samples. The great majority of hair pools (19/21; 90.5%) contained multiple beta-HPVs, the mean number of identified beta-HPV genotypes per hair pool was 5.2 (ranging from 1 to 12). In individual hairs, the great majority of individual hairs (43/63; 68.3%) contained multiple beta-HPVs, the mean number of identified beta-HPV genotypes was 4 (ranging from 1 to 12). Overall, HPV-23 was the most prevalent genotype, followed by HPV-24 and HPV-38. A comparison of beta-HPV genotype distribution in pooled hair specimens and in at least one individual hair within a single patient revealed that 5/20 patients had a complete match between the number and profile of identified genotypes, 2/20 patients had the same/similar number of HPV genotypes but different genotype profile, 9/20 patients had more HPV genotypes identified in pools than in the majority of individual hairs and 4/20 patients had at least one individual hair with more HPV genotypes identified than in the corresponding pool. Our results suggest that beta-HPVs are unevenly distributed over the eyebrows and even pools made of several hairs do not necessarily provide information on the whole spectrum of HPV genotypes present in eyebrows.     

Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL)

The best strategy for incorporating imatinib in front-line treatment of Ph+ acute lymphoblastic leukemia (ALL) has not been established. We enrolled 92 patients with newly diagnosed Ph+ ALL in a prospective, multicenter study to investigate sequentially 2 treatment schedules with imatinib administered concurrent to or alternating with a uniform induction and consolidation regimen. Coadministration of imatinib and induction cycle 2 (INDII) resulted in a complete remission (CR) rate of 95% and polymerase chain reaction (PCR) negativity for BCR-ABL in 52% of patients, compared with 19% in patients in the alternating treatment cohort (P = .01). Remarkably, patients with and without a CR after induction cycle 1 (INDI) had similar hematologic and molecular responses after concurrent imatinib and INDII. In the concurrent cohort, grades III and IV cytopenias and transient hepatotoxicity necessitated interruption of induction in 87% and 53% of patients, respectively; however, duration of induction was not prolonged when compared with patients receiving chemotherapy alone. No imatinib-related severe hematologic or nonhematologic toxicities were noted with the alternating schedule. In each cohort, 77% of patients underwent allogeneic stem cell transplantation (SCT) in first CR (CR1). Both schedules of imatinib have acceptable toxicity and facilitate SCT in CR1 in the majority of patients, but concurrent administration of imatinib and chemotherapy has greater antileukemic efficacy.     

Long term iNOS expression in thoracic lymph nodes of silicotic rats

Beside the lung, thoracic lymph nodes are most affected during silicosis. The mechanisms leading to enlargement of the lymph nodes and partial activation of lymph node cells are still unclear. The present study demonstrates an increase in iNOS mRNA expression in the lung draining lymph nodes of rats at 1, 2, and 8 months following silica exposure. Histopathological analysis revealed that iNOS protein was exclusively expressed by macrophages located within the granulomatous areas of the enlarged lymph nodes. In contrast, no differences in mRNA expression and number of iNOS-positive cells were found in the lungs of silica-exposed and non-exposed rats. In vitro experiments showed that silica particles alone did not induce NO release in primary alveolar macrophages (AMs) or the alveolar macrophage cell line NR8383. However, the addition of interferon (IFN)-gamma led to a significant nitric oxide production by primary AMs. NR8383 cells responded only when a combination of IFN-gamma and silica particles was applied. These results indicate that the macrophage activator IFN-gamma, which has already been shown to be expressed at elevated levels by lymphocytes of the silicotic lymph nodes, may be responsible for the long-lasting iNOS expression in thoracic lymph nodes. Our observations support the hypothesis that the mutual activation of lymphocytes and macrophages is a central process in the development of chronic silicosis.     

Scraping or shaking—a comparison of methods for the quantitative determination of Echinococcus multilocularis in fox intestines

A modified sedimentation technique (the shaking in a vessel technique; SVT) to examine intestines for smaller helminths such as Echinococcus multilocularis is described and compared with the intestinal scraping technique (IST). Out of 356 foxes, 26 were E. multilocularis positive, 19 using IST (sensitivity 73.1%) and 25 with SVT (sensitivity 96.2%) after IST. Especially low infection intensities went undetected with IST. The result is comparable to the established sedimentation and counting technique (SCT). SVT is recommended for the routine examination of fox intestines as an alternative to SCT.