Atopic skin diathesis rather than atopic dermatitis is associated with specific contact allergies.

BACKGROUND: The association of atopic dermatitis (AD) and allergic contact dermatitis has been a matter of considerable uncertainty. Study results range from lack of any association to increased sensitization for multiple allergens, but fail to identify consistent allergen associations. OBJECTIVE: We studied a large patch test cohort of patients stratified by their atopic skin diathesis using the Erlangen Atopy Score (EAS), independent of active skin disease. METHODS: Retrospective multi-center data analysis from five departments of dermatology in Germany with 4,509 patients. Patients were grouped as "no atopic skin diathesis" (n = 2,165) and "atopic skin diathesis" (n = 1,743), according to EAS. RESULTS: Significantly more individuals with atopic skin diathesis showed at least one positive patch test reaction to the baseline series compared to individuals without atopic skin diathesis (49.1 % vs. 38.3 %). In logistic regression analyses, atopic skin diathesis was associated with a significantly higher risk of sensitization to methylchloroisothiazolinone/methylisothiazolinone (OR 2.383) and methylisothiazolinone (OR 1.891), thiuram mix (OR 1.614), as well as nickel (OR 1.530), cobalt (OR 1.683), and chromium (OR 2.089). CONCLUSIONS: Atopic skin diathesis proved to be the most important intrinsic risk factor for contact sensitization to few, specific allergens. Past or present AD was a less relevant variable.

Testing Elevated Protease Activity: Prospective Analysis of 160 Wounds.

OBJECTIVE: Given that local elevated protease activity (EPA) has been implicated in impaired wound healing, a prospective single-center study was conducted to assess protease activity in various wound types. METHODS: Protease activity was determined using an easy-to-use test system (Woundchek Protease Status Test Kit; Systagenix, Gatwick, United Kingdom) in 160 wounds in 143 patients. The assay detects the combined activity of inflammatory proteases, mainly matrix metalloproteinases 8 and 9 and human neutrophil elastase. RESULTS: Local EPA was detected in 29 of 153 validly tested wounds (18.95%). No difference was detected between acute and chronic wounds, regardless of associated or causative conditions, with the sole exception of surgical wounds. Surgical wounds showed EPA significantly less frequently than nonsurgical wounds. Among nonsurgical wounds, EPA was detected more frequently in acute compared with chronic wounds. Wounds with signs of unimpeded healing (granulation or epithelialization) showed EPA less often than wounds covered with necrotic tissue or a fibrin layer. However, 14% of wounds with epithelialization or granulation exhibited EPA potentially impeding wound healing. Wounds treated with moisture-retentive wound dressings showed EPA significantly less frequently compared with wounds bandaged with dressings with less moisture-retentive properties. Remarkably, none of the wounds treated with collagen/oxidized regenerated cellulose/silver, which is a protease-modulating dressing, showed EPA. CONCLUSIONS: To the study authors' knowledge, this is the largest study assessing EPA in various wound types. The convenient applicability of the test system provides a basis for future studies assessing the pathophysiologic relevance of EPA. In some unsuspicious wounds, early detection of EPA might precede impaired healing and prompt protease-modulating treatment before failure to heal becomes apparent.

Palmoplantar pustulosis - a cross-sectional analysis in Germany.

BACKGROUND: Palmoplantar pustulosis (PPP) is a recalcitrant chronic inflammatory skin disease. Data relevant for the medical care of patients with PPP are scarce. Thus, the aim of this work was to investigate the disease burden, clinical characteristics, and comorbidity of PPP patients in Germany. PATIENTS AND METHODS: PPP patients were examined in a crosssectional study at seven specialized psoriasis centers in Germany. RESULTS: Of the 172 included patients with PPP, 79.1% were female and 69.8% were smokers.In addition, 25.0% suffered from psoriasis vulgaris, 28.2% had documented psoriatic arthritis, and 30.2% had a family history of psoriasis. In 77 patients the mean Dermatology Life Quality Index (DLQI) was 12.2 ± 7.7 (mean ± SD). The mean Psoriasis Palmoplantar Pustulosis Area and Severity Index (PPPASI) was 12.6 ± 8.6. Mean body mass index was above average at 27.1 ± 5.5. The PPP patients had previously received an average of 2.6 ± 2.1 different anti-psoriatic systemic drugs or UV-therapies. The systemic drugs that had been used most frequently were corticosteroids in 40.1% of patients, followed by acitretin (37.8%), and methotrexate (27.9%). The PPPASI was 13.4 ± 8.9 in patients without current systemic therapy and 10.4 ± 7.9 in patients with systemic therapy. CONCLUSION: Many PPP patients had a concomitant diagnosis of psoriasis vulgaris and/or psoriatic arthritis or had a family history of psoriasis. Despite the fact that many of the patients were using anti-psoriatic therapies, there was still a high burden of disease within this PPP cohort. This insufficient control of symptoms demonstrates the urgent need for new PPP treatments.

Stimulation of pulmonary immune responses by the TLR2/6 agonist MALP-2 and effect on melanoma metastasis to the lung.

Given that metastasized melanoma is a fatal disease in most cases, it is tempting to develop strategies to a priori prevent metastasis. We have stimulated the pulmonary innate immune system by macrophage-activating lipopeptide-2 (MALP-2), a specific agonist at Toll-like receptor (TLR) 2/6, and investigated its impact on experimental melanoma metastasis. In C57BL/6 mice, intratracheal application of MALP-2 induced a profound influx of neutrophils and macrophages into the lung, which peaked after 24 h (sixfold increase) and returned to baseline within 72 h. Further analysis revealed that MALP-2 also markedly induced VCAM-1 expression on pulmonary blood vessels. In vitro experiments demonstrated that this adhesion molecule mediates binding of B16F10 melanoma cells. Furthermore, in vivo or in vitro treatment with MALP-2 did not significantly affect the ability of immune cells to lyse melanoma cells. As a consequence, notwithstanding the profound pulmonary immune response induction and in contrast to conclusions drawn from some previous publications, the net extent of experimental metastasis did not change significantly, regardless of the application regimen of MALP-2 prior to, concomitant with or after tumor cell inoculation. Melanoma cells stably transfected with green fluorescent protein allowed tracking of early events after tumor cell dissemination and showed that MALP-2-mediated TLR2/6 activation did not interfere with pulmonary melanoma cell arrest. Likewise, boosting the immune induction after establishment of metastases did not change the clinical outcome. These unexpected results vividly counsel caution regarding predictions of immunomodulating therapies, as multiple intertwined effects may influence the net outcome.

Generation and cardiac differentiation of an induced pluripotent stem cell line from a patient with arrhythmia-induced cardiomyopathy.

Arrhythmia-induced cardiomyopathy (AIC) is characterized by left-ventricular systolic dysfunction caused by persistent arrhythmia. To date, genetic or pathological drivers causing AIC remain unknown. Here, we generated induced pluripotent stem cells (iPSCs) from an AIC patient. The AIC-iPSCs exhibited full pluripotency and differentiation characteristics and maintained a normal karyotype after reprogramming. The AIC-iPSCs differentiated into functional beating AIC-iPSC-cardiomyocytes (CMs), which represents the cell-type of interest to study molecular, genetic and functional aspects of AIC.

Flare or foe? - Mycobacterium marinum infection mimicking rheumatoid arthritis tenosynovitis: case report and literature review.

BACKGROUND: Rheumatoid arthritis is the most common type of inflammatory arthritis affecting about 1% of the population. With the advent of disease-modifying anti-rheumatic drugs the disease can be well controlled in many cases. Patients, however, are prone to developing infectious complications. In rare cases, these can mimic a flare of the underlying itself. CASE PRESENTATION: We report the case of a 45-year-old female patient with a history of seronegative rheumatoid arthritis (RA) who presented with swelling and tenderness of the third metacarpophalangeal joint of the right hand. A flare of her RA was suspected based on clinical and ultrasound findings which showed a tenosynovitis with intense power doppler activity. Her steroid dose was increased but the clinical response to glucocorticoid therapy was very limited. Subsequently, she developed skin manifestations of 'swimmer's granuloma' over the next 2 weeks after first presentation. Finally, a diagnosis of a Mycobacterium marinum infection was established with the help of tissue biopsy and culture, and the patient received appropriate antibiotic treatment with the desired effect. CONCLUSIONS: This case highlights the difficulty of distinction between infection and inflammation in patients with joint swelling and pain, especially in the age of disease-modifying drugs (DMARDs) and the concomitant risk of atypical infections. A review of the literature identified eight additional published cases, which suggests that Mycobacterium marinum infection is a rare but recognized complication of DMARD therapy. It can mimic a flare of the underlying arthritis potentially leading to diagnostic delays, and requires differential diagnostic methods to identify the pathogen and pave the way for appropriate treatment.

Nanoscale Tuning of VCAM-1 Determines VLA-4-Dependent Melanoma Cell Plasticity on RGD Motifs.

The biophysical fine-tuning of cancer cell plasticity is crucial for tumor progression but remains largely enigmatic. Although vascular cell adhesion molecule-1 (VCAM-1/CD106) has been implicated in melanoma progression, here its presentation on endothelial cells was associated with diminished melanoma cell spreading. Using a specific nanoscale modulation of VCAM-1 (tunable from 70 to 670 ligands/µm²) next to integrin ligands (RGD motifs) in a bifunctional system, reciprocal regulation of integrin α4 (ITGA4/VLA-4/CD49d)-dependent adhesion and spreading of melanoma cells was found. As the VCAM-1/VLA-4 receptor pair facilitated adhesion, while at the same time antagonizing RGD-mediated spreading, melanoma cell morphogenesis on these bifunctional matrices was directly regulated by VCAM-1 in a dichotomic and density-dependent fashion. This was accompanied by concordant regulation of F-actin cytoskeleton remodeling, Rac1-expression, and paxillin-related adhesion formation. The novel function of VCAM-1 was corroborated in vivo using two murine models of pulmonary metastasis. The regulation of melanoma cell plasticity by VCAM-1 highlights the complex regulation of tumor-matrix interactions.Implications: Nanotechnology has revealed a novel dichotomic function of the VCAM-1/VLA-4 interaction on melanoma cell plasticity, as nanoscale tuning of this interaction reciprocally determines adhesion and spreading in a ligand density-dependent manner. Mol Cancer Res; 16(3); 528-42. ©2017 AACR.

Attenuation of cell cycle regulator p27(Kip1) expression in vertebrate epithelial cells mediated by extracellular signals in vivo and in vitro.

Cell cycle arrest in potentially dividing cells is often mediated by inhibitors of G1/S-phase cyclin-dependent kinases. The cyclin E/CDK2-inhibitor p27(Kip1) has been implicated in this context in epithelial cells. We cloned and sequenced p27(Kip1) of ducklings (Anas platyrhynchos) and used an in vitro assay system to study the mechanism of p27(Kip1) downregulation in the nasal gland which precedes an increase in proliferation rate upon initial exposure of the animals to osmotic stress. Western blot studies revealed that p27(Kip1) is downregulated during 24 h of osmotic stress in ducklings with the steepest decline in protein levels between 5 and 8 h. As indicated by the results of Northern blot and semi-quantitative PCR studies, protein downregulation is not accompanied by similar changes in mRNA levels indicating that Kip1 is regulated mainly at the translational (synthesis) or posttranslational level (degradation). Using recombinant duck Kip1 protein expressed in E. coli, we showed that Kip1 is subject to polyubiquitinylation by cytosolic enzymes from nasal gland cells indicating that loss of Kip1 may be regulated, at least in part, by acceleration of protein degradation. In cultured nasal gland tissue, attenuation of Kip1 expression could be induced by activation of the muscarinic acetylcholine receptor indicating that mAChR-receptor signalling may play a role in the re-entry of quiescent gland cells into the cell cycle.