Combination therapy of oral propranolol and combined Nd:YAG/pulsed dye laser therapy in infantile hemangiomas: a retrospective analysis of 48 treated hemangiomas in 30 children.

BACKGROUND AND AIMS: Infantile hemangiomas can be successfully treated by both systemic propranolol and neodymium:YAG (Nd:YAG)-dye laser combination therapy. In this retrospective study, the efficacy and safety of sequential and parallel therapy of complicated hemangiomas treated with both methods were evaluated. PATIENTS AND METHODS: 30 children with 48 complicated hemangiomas were treated with propranolol and Nd:YAG-dye laser combination therapy. Using photo comparison, the percentage remission rate was evaluated by three investigators on a four-step scale (I: 0-25 %, II: 26-50 %, III: 51-75 % and IV: 76-100 %). RESULTS: Eleven children received propranolol and laser therapy in parallel (A), twelve children received laser therapy after propranolol (B) and seven children received propranolol after laser therapy (C). Due to emigration abroad, one child was lost to follow-up. A strong improvement (IV) was observed in 23/29 (79.3 %) of all treated children (A: 90.9 %, B 75 %, C 66.7 %). The mean duration of propranolol therapy in all children was 8.6 months (A: 8.9 months, B: 8.2 months, C: 8.9 months). On average, 2.33 laser treatments were performed per hemangioma (A: 1.95, B: 3.2, C: 1.91). Serious side effects caused by propranolol and laser therapy were not observed. CONCLUSIONS: Propranolol and Nd:YAG-dye laser combination therapy can be used sequentially or in parallel safely and effectively. They complement each other in a meaningful manner.

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.

Caspase-1-independent IL-1 release mediates blister formation in autoantibody-induced tissue injury through modulation of endothelial adhesion molecules.

Although reports documented aberrant cytokine expression in autoimmune bullous dermatoses (AIBDs), cytokine-targeting therapies have not been established in these disorders. We showed previously that IL-6 treatment protected against tissue destruction in experimental epidermolysis bullosa acquisita (EBA), an AIBD caused by autoantibodies to type VII collagen (COL7). The anti-inflammatory effects of IL-6 were mediated by induction of IL-1ra, and prophylactic IL-1ra administration prevented blistering. In this article, we demonstrate elevated serum concentrations of IL-1ß in both mice with experimental EBA induced by injection of anti-COL7 IgG and in EBA patients. Increased IL-1α and IL-1ß expression also was observed in the skin of anti-COL7 IgG-injected wild-type mice compared with the significantly less diseased IL-1R-deficient or wild-type mice treated with the IL-1R antagonist anakinra or anti-IL-1ß. These findings suggested that IL-1 contributed to recruitment of inflammatory cells into the skin. Accordingly, the expression of ICAM-1 was decreased in IL-1R-deficient and anakinra-treated mice injected with anti-COL7. This effect appeared to be specifically attributable to IL-1 because anakinra blocked the upregulation of different endothelial adhesion molecules on IL-1-stimulated, but not on TNF-α-stimulated, cultured endothelial cells. Interestingly, injection of caspase-1/11-deficient mice with anti-COL7 IgG led to the same extent of skin lesions as in wild-type mice. Collectively, our data suggest that IL-1, independently of caspase-1, contributes to the pathogenesis of EBA. Because anti-IL-1ß in a prophylactic setting and anakinra in a quasi-therapeutic setting (i.e., when skin lesions had already developed) improved experimental EBA, IL-1 appears to be a potential therapeutic target for EBA and related AIBDs.

Mutually enhancing anti-inflammatory activities of dimethyl fumarate and NF-κB inhibitors--implications for dose-sparing combination therapies.

Fumaric acid esters, dimethyl fumarate (DMF) in particular, have been established for the therapy of psoriasis and, more recently, multiple sclerosis. In the light of therapy-limiting dose-dependent side effects, such as gastrointestinal irritation, reducing the effective doses of FAE is a worthwhile goal. In search of strategies to maintain the anti-inflammatory activity of DMF at reduced concentrations, we found that NF-κB inhibition augmented key anti-inflammatory effects of DMF in two complementary experimental settings in vitro. At non-toxic concentrations, both proteasome inhibition with bortezomib as well as blocking NF-κB activation through KINK-1, a small molecule inhibitor of IKKß-profoundly enhanced DMF-dependent inhibition of nuclear NF-κB translocation in TNFα-stimulated human endothelial cells. This resulted in significant and selective co-operative down-regulation of endothelial adhesion molecules crucial for leucocyte extravasation, namely E-selectin (CD62E), VCAM-1 (CD106) and ICAM-1 (CD54), on both mRNA and protein levels. Functionally, these molecular changes led to synergistically decreased rolling and firm adhesion of human lymphocytes on TNF-activated endothelial cells, as demonstrated in a dynamic flow chamber system. If our in vitro findings can be translated into clinical settings, it is conceivable that anti-inflammatory effects of DMF can be achieved with lower doses than currently used, thus potentially reducing unwanted side effects.

Repetitive injections of botulinum toxin A continuously increase the duration of efficacy in primary axillary hyperhidrosis: a retrospective analysis in 101 patients.

BACKGROUND AND OBJECTIVES: Botulinum toxin type A is an effective, well-tolerated, albeit temporary treatment for primary axillary hyperhidrosis. However, little is known about the influence of repetitive injections on the duration of efficacy. PATIENTS AND METHODS: 139 patients with primary axillary hyperhidrosis were injected with 50 units of botulinum toxin per axilla. In 101 patients, who received at least three treatments, the duration of efficacy after the first, second, and last treatment was evaluated. RESULTS: The median duration of efficacy was 4.0 months, 4.5 months, and 5.0 months after the first, second, and last injection, respectively. Overall, the duration of efficacy was significantly longer after the last injection compared to the duration of efficacy after the first injection (p = 0.0055, Wilcoxon matched-pairs signed-rank test). Likewise, the difference between the first and second injection (p = 0.0302) as well as the difference between the second and the last injection (p = 0.0381) were significant. In 25.7 % of patients, the duration of efficacy remained unchanged over the entire treatment period. CONCLUSIONS: Repetitive botulinum toxin treatments led to a significantly increased duration of efficacy in axillary hyperhidrosis. While the average duration of efficacy continued to increase with each treatment, there were considerable interindividual differences.

TNF α-induced leukocyte-endothelial cell interactions show marked interindividual differences independent of the clinical response to adalimumab.

The responses of patients with psoriasis to TNFα-antagonists show interindividual differences. Here, TNFα-incubation induced endothelial adhesion molecules, a prerequisite for leucocyte recruitment to inflamed tissues. Using a standardized flow chamber system equipped with near-confluent endothelial cells and a mobile phase containing human leucocytes, proportions of leucocytes interacting with endothelial cells were remarkably different between individual donors (up to 3.5-fold), regardless of whether the leucocytes originated from patients with psoriasis (n = 10) or healthy donors (n = 10). Adalimumab abrogated adhesion molecule induction and interactions with leucocytes when present prior to or simultaneously with, but not after exposure of the cultures to TNFα. This pattern was seen similarly with leucocytes from healthy donors (n = 4), and patients whose psoriasis responded well to adalimumab (n = 5) and non-responders (n = 5). Thus, although considerable interindividual differences of leucocyte-endothelial cell interactions were demonstrated ex vivo in a TNFα-governed microenvironment, such differences are not associated with individual responses to treatment with adalimumab in vivo.

Phenotypic and functional traits of peripheral blood mononuclear cells retained by controlled cryopreservation: implications for reliable sequential studies of dynamic interactions with endothelial cells.

Many immunological experiments would be greatly facilitated if peripheral blood mononuclear cells (PBMC) preserved important functional properties over longer periods of time. Regarding adhesive interactions with endothelial cells, a crucial step of inflammatory processes, this had not been investigated yet. We demonstrate that PBMC subsets subjected to controlled cryopreservation retain their phenotypic traits inasmuch as the proportion of viable T cells, monocytes/macrophages and B cells was comparable with their freshly isolated counterparts. More importantly, we demonstrate for the first time that the procedure does not impede crucial adhesion-mediated dynamic interactions with endothelial cells. Using a flow chamber system, freshly isolated and cryopreserved PBMC showed similar rolling and firm adhesion on TNF-α-activated endothelial cells under shear flow as compared to freshly isolated PBMC from the same donors. Thus, our observation is an important prerequisite for functional studies of leucocyte recruitment when sequential investigations with material from the same patients are required.