Anti-FcαRI Monoclonal Antibodies Resolve IgA Autoantibody-Mediated Disease.

Immunoglobulin A (IgA) is generally considered as a non-inflammatory regulator of mucosal immunity, and its importance in diversifying the gut microbiota is increasingly appreciated. IgA autoantibodies have been found in several autoimmune or chronic inflammatory diseases, but their role in pathophysiology is ill-understood. IgA can interact with the Fc receptor FcαRI on immune cells. We now established a novel IgA autoimmune blistering model, which closely resembles the human disease linear IgA bullous disease (LABD) by using genetically modified mice that produce human IgA and express human FcαRI. Intravital microscopy demonstrated that presence of IgA anti-collagen XVII, - the auto-antigen in LABD-, resulted in neutrophil activation and extravasation from blood vessels into skin tissue. Continued exposure to anti-collagen XVII IgA led to massive neutrophil accumulation, severe tissue damage and blister formation. Importantly, treatment with anti-FcαRI monoclonal antibodies not only prevented disease, but was also able to resolve existing inflammation and tissue damage. Collectively, our data reveal a novel role of neutrophil FcαRI in IgA autoantibody-mediated disease and identify FcαRI as promising new therapeutic target to resolve chronic inflammation and tissue damage.

Silver Sulfadiazine Cream Treatment Results in More Wound Contraction and More Itch in a Standardized Porcine Scald Model.

A variety of dressings is available for the treatment of partial-thickness wounds, but none has strong evidence supporting their beneficial effect on healing. This may be due to variation in the type and depth of wounds in clinical studies. The aim of this study was to use a standardized porcine wound model to compare three dressings commonly used in burn centers for partial-thickness burns. Partial-thickness scalds were made on the flanks of pigs. Wounds were treated with silver sulfadiazine (SSD, flammazine), a hydrofiber dressing, or glycerol-preserved allogeneic (pig) skin. The healing process was monitored for 8 weeks. Macroscopic parameters were the itching behavior, the cosmetic appearance of the scars, and contraction. Microscopic parameters were the inflammatory response, myofibroblast influx, and the numbers of nerves. All wounds were closed on day 14 and wound infection did not occur. Treatment with SSD resulted in significantly more wound contraction compared to treatment with glycerol-preserved pig skin. Animals treated with SSD suffered more from itching (scratching) during the first 2 weeks after wounding. The number of nerves in healing wounds of these animals was significantly higher compared to wounds treated with hydrofiber dressing or allogeneic skin. In our standardized porcine partial-thickness wound model, treatment with SSD resulted in less favorable wound healing. Compared to treatment with glycerol-preserved allogeneic skin, SSD resulted in more contraction.

Peptide mimetics of immunoglobulin A (IgA) and FcαRI block IgA-induced human neutrophil activation and migration.

The cross-linking of the IgA Fc receptor (FcαRI) by IgA induces release of the chemoattractant LTB4, thereby recruiting neutrophils in a positive feedback loop. IgA autoantibodies of patients with autoimmune blistering skin diseases therefore induce massive recruitment of neutrophils, resulting in severe tissue damage. To interfere with neutrophil mobilization and reduce disease morbidity, we developed a panel of specific peptides mimicking either IgA or FcαRI sequences. CLIPS technology was used to stabilize three-dimensional structures and to increase peptides' half-life. IgA and FcαRI peptides reduced phagocytosis of IgA-coated beads, as well as IgA-induced ROS production and neutrophil migration in in vitro and ex vivo (human skin) experiments. Since topical application would be the preferential route of administration, Cetomacrogol cream containing an IgA CLIPS peptide was developed. In the presence of a skin permeation enhancer, peptides in this cream were shown to penetrate the skin, while not diffusing systemically. Finally, epitope mapping was used to discover sequences important for binding between IgA and FcαRI. In conclusion, a cream containing IgA or FcαRI peptide mimetics, which block IgA-induced neutrophil activation and migration in the skin may have therapeutic potential for patients with IgA-mediated blistering skin diseases.

Locking, jamming, and ratchet mechanisms of sliding surgical knots topologically revisited.

BACKGROUND: The geometry of lockable, ratchet, or jamming sliding surgical knots was assessed to enhance practical and topological understanding of knots among surgeons. METHODS: Using a database of more than 100 surgical knots, 29 knots that reportedly feature locking, ratchet, or jamming mechanisms were topologically assessed for their ability to lock antegradely or retrogradely, to lock by assuming their flat geometry, or to jam. RESULTS: Eighteen of the 29 investigated surgical knots have previously been mistakenly categorized. Topologically, the concept of a true ratchet knot is a fallacy. CONCLUSIONS: Surgical knots may be consistently classified on the basis of precise and detailed definition of various anti-backsliding geometrical characteristics of knots.

Full publication of papers presented at the 1995 through 1999 European Association of Plastic Surgeons annual scientific meetings: a systemic bibliometric analysis.

From the multitude of oral presentations at major medical meetings, the most informative and highest-quality studies make it to full publication in peer-reviewed journals. The rate of publication may be regarded as an indicator of the scientific level of the meeting. Study of the publication rates of consecutive annual meetings allows for the evaluation of the consistency of the scientific level of these meetings and for comparison with publication rates of other meetings in the same field of interest. To grade how useful any publication is to other authors, one can furthermore measure how frequently they cite it in their own publications. Finally, the time lag between oral presentation and full publication is of importance to both its authors and the audience at the meeting. The main objectives of this study were to determine the publication rate of papers of various fields of interest as presented at five consecutive annual meetings of the European Association of Plastic Surgeons (EURAPS) and the time lag between these presentations and their publication. The authors compared their overall findings to those reported for other surgical specialties. Moreover, they identified and classified the journals in which the full publications appeared as an indicator of the scientific value of the meeting. They conclude that a greater than average number of papers presented at the 1995 through 1999 annual EURAPS meetings went on to full publication in peer-reviewed journals. Among these journals, Plastic and Reconstructive Surgery was the best source for information presented at the meetings. Although approximately 90 percent of the publications appeared before 3 years had passed after a meeting, additional publications may be expected to appear even more than 6 years after the meeting. Given the high publication rate and the high average normalized impact factor of the journals in which the presentations appeared, the five studied EURAPS meetings overall had high scientific value.

Validity of a structured method of selecting abstracts for a plastic surgical scientific meeting.

In 1999, the European Association of Plastic Surgeons accepted a structured method to assess and select the abstracts that are submitted for its yearly scientific meeting. The two criteria used to evaluate whether such a selection method is accurate were reliability and validity. The authors previously established this method to be reliable on the basis of a prospective evaluation of the selection process used for the 2000 meeting of the European Association of Plastic Surgeons. It is more difficult to assess the validity of this method because there is no objective standard of quality of a scientific abstract against which the accuracy of selection can be assessed. This study statistically evaluated the accuracy of the meeting participants' assessment of presentations made during the meeting as the criterion standard for abstract selection on the basis of data obtained from the 2002 selection process. The authors evaluated the interobserver repeatability among five meeting participants of selecting the best presentations, the validity of the method of abstract selection after this criterion standard had been established, and the validity of reviewers' rating of abstracts as indicators of the scientific value of the actual presentations. The authors conclude that the assessment of platform presentations at a plastic surgical meeting is reliable. Accepting this assessment as the criterion standard, however, they could not prove the validity of their selection method or the validity of the reviewers' rating of abstracts as an indicator of the scientific value of the actual presentations.

Reliability of a structured method of selecting abstracts for a plastic surgical scientific meeting.

There is no generally accepted method for assessing abstracts that are submitted for a medical scientific meeting. This article describes the development and prospective evaluation of such a method applied to the 220 abstracts submitted for the 2000 Annual Meeting of the European Association of Plastic Surgeons. Structured abstracts were evaluated in three categories: aesthetic surgery, basic research, and clinical study. Each anonymous abstract was assessed separately by 10 reputable European plastic surgeons. These reviewers used a structured rating questionnaire which resulted in a score given by each reviewer to each abstract between -6 and +6. The scores of all 10 reviewers were added for each abstract, and the papers were accepted in each of the three categories on the basis of this abridged score. To evaluate the reliability of this structured method of selection, the interrater agreement among the reviewers was tested by means of kappa analysis and the Cronbach alpha coefficient. The kappa values for agreement among reviewers regarding acceptability of abstracts were low, but the alpha coefficient indicated an acceptable degree of reliability of the average reviewers' ratings for all categories. Using a structured questionnaire can be helpful in the objective assessment of abstracts for a scientific meeting and may facilitate comparison of abstracts. Meritocratic dichotomy of abstracts by the reviewers is advocated to further improve reliability of the rating. Even though reliability generally increases with the number of reviewers, the annual increase of submitted abstracts may necessitate a decrease in the number of reviewers for each abstract.