Rare Case of Pyoderma Gangrenosum in the Setting of PAPA Syndrome in a 12-Year-Old Child

We report on a 12-year-old boy who presented with an intermittently painful wound present for months without any tendency to heal after a slackline accident two years ago. A biopsy of the ulcer margin revealed epithelial hyperplasia, marked fibrosis, and vascular proliferation without evidence of vasculitis. Pretibial findings on the right side were a 3.8 × 3.1 cm fibrin-covered, flat ulcer with slight reddening of the surrounding area. Other findings were unremarkable with hypermobility of the wrists and finger joints. Local therapy with a foam dressing, topical steroid in the wound margin, and class II compression stockings showed no effect. The pediatric rheumatologist evaluated the ulcer with a camptodactyly of digit 5, subluxation of the wrists on both sides, and symmetric ulnar deviation. Elevated S100 as an isolated autoimmune phenomenon or concomitant with systemic autoimmune disease or autoinflammation (eg, Pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome) was also observed. The therapy with oral steroids, initially 30 mg/day and gradual reduction in the course, only achieved a tissue bridge's formation with the same size extension of the ulcer. Unfortunately, the patient spontaneously developed a second ulcer on the left lateral malleolus, which is why the therapy was changed to dapsone 50 mg/day and tacrolimus in the wound margin after nine weeks. In the absence of success, further treatment with ciclosporin or tumor necrosis factor-alpha antibody therapy is planned in interdisciplinary cooperation.

c-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation

Keratinocyte differentiation dysfunction in diabetic skin is closely related to impaired skin barrier functions. We investigated the effects of c-Myc and S100A6 on Human immortal keratinocyte line (HaCaT) or keratinocyte differentiation and potential mechanisms. The expression levels of differentiation makers such as transglutaminase 1 (TGM1), loricrin (LOR), and keratin 1 (K1) were significantly reduced, while the expression of c-Myc was significantly increased in HaCaT cells cultured in high glucose and wound margin keratinocytes from diabetic rats and human patients. Overexpression of c-Myc caused differentiation dysfunction of HaCaT, while knocking down c-Myc promoted differentiation. High glucose increased the expression of c-Myc and inhibited differentiation in HaCaT cells by activating the WNT/β-catenin pathway. Moreover, inhibition of c-Myc transcriptional activity alleviated the differentiation dysfunction caused by high glucose or overexpression of c-Myc. c-Myc binds to the S100A6 promoter to directly regulate S100A6 expression and high glucose promoted S100A6 transcription. The expression of S100A6 was increased in HaCaT cultured with high glucose and wound margin keratinocytes from diabetic rats and human patients. However, the expression of S100A6 was decreased during normal HaCaT differentiation. HaCaT cells treated with S100A6 recombinant protein showed differentiation dysfunction. The expressions of TGM1, LOR and K1 in knockdown S100A6 HaCaT cells were higher than those in the control group. Overexpression of c-Myc or high glucose caused differentiation dysfunction of HaCaT cells, and was rescued by knocking down S100A6. These findings illustrate a new mechanism by which c-Myc upregulated by high glucose inhibits HaCaT differentiation by directly activating S100A6 transcription. Thus, c-Myc and S100A6 may be potential targets for the treatment of chronic diabetic wounds.

Different therapeutic effects between diabetic and non-diabetic adipose stem cells in diabetic wound healing

Objective: This study aimed to investigate how adipose tissue-derived stem cells (ASCs) from diabetic and from non-diabetic rats affect wound healing in different microenvironments. Method: The two types of ASC-rich cells were distinguished by characteristic surface antigen detection. The ASC-rich cells were transplanted into the wounds of diabetic and non-diabetic rats. Wound healing rates were compared and the healing process in the wound margin sections was used to determine how ASC-rich cells affect wound healing in different microenvironments. Results: ASC density was decreased in diabetic rats. The generation time of ASC-rich cells from diabetic rats (d-ASC-rich cells) was longer than that of ASC-rich cells from non-diabetic rats. The number of pre-apoptotic cells in the third generation (passage 3) of d-ASC-rich cells was higher than that among the ASC-rich cells from non-diabetic rats. CD31 and CD34 expression was higher in d-ASC-rich cells than in ASC-rich cells from non-diabetic rats, whereas CD44 and CD105 expression was lower than that in ASC-rich cells from non-diabetic rats. Transplantation of ASC-rich cells from non-diabetic rats promoted wound healing in both non-diabetic and diabetic rats. In contrast, d-ASC-rich cells and enriched nuclear cells only promoted wound healing in non-diabetic rats. ASC-rich cell transplantation promoted greater tissue regeneration than d-ASC-rich cell transplantation. Conclusion: ASC-rich cells promoted wound healing in diabetic and non-diabetic rats. ASC density was lower in the adipose tissue of diabetic rats compared with non-diabetic rats. d-ASC-rich cells did not promote wound healing in diabetic rats, suggesting that caution is warranted regarding the clinical use of diabetic adipose stem cell transplantation for the treatment of diabetic wounds.

Cosmetic results of circumcision and scar wrinkling: Do we exaggerate in terms of hemostasis and sutures?

Objective: To objective of this study was to investigate poor scar appearance of the circumcision line and scar wrinkling caused by the sutures placed during the circumcision in primary school age circumcised children. Methods: A total of 455 children aged between 6 and 9 years, circumcised by four different specialists in our hospital between 2009 and 2018 were evaluated. Circumcisions performed due to balanitis, phimosis, secondary phimosis, and paraphimosis were excluded from the study. Only routine religious circumcisions performed on request of the family were included in the study. Children underwent a second procedure and those receiving treatment after the circumcision due to infection were excluded from the study. About 363 patients included the study. Patients were evaluated according to the Fitzpatrick skin type classification, independent observer scale, Stony Brook Scar Evaluation Scale, and Dunn-Bonferroni test. Results: No statistically significant difference was found between distributions of scar wrinkling levels in children according to the circumcision ( p > 0.05). There was a statistically significant difference between age of circumcision according to scare wrinkling levels ( p = 0.001). According to the Dunn-Bonferroni test; the circumcision age was found to be significantly lower in children with severe scar wrinkling compared to the children with no or mild scar wrinkling ( p = 0.001; p = 0.011). Conclusion: The tense, short-interval sutures placed away from the wound margin during circumcision in order to control subcutaneous bleeding lead to scar wrinkling and a poor cosmetic appearance. Knowing the risk factors leading to scar wrinkling and taking appropriate measures will provide acceptable cosmetic outcomes after the circumcision.

Repatterning of the inflorescence meristem in Gerbera hybrida after wounding

The Asteraceae plant family is characterized by inflorescences, called flower heads or capitula that may combine hundreds of individual florets into a single flower-like structure. The florets are arranged in a regular phyllotactic pattern with Fibonacci numbers of left- and right-winding spirals. Such a pattern may be disrupted due to physical constraints or by wounding occurring during the early meristem development. Recovery from wounding re-establishes patterning although the mechanisms have remained elusive. In this study, we applied Gerbera hybrida as a model system and established methods to conduct wounding experiments either with syringe needles or using laser ablation combined with live imaging of head meristems. By revisiting the historical experiments in sunflower, we conducted wounding to transgenic auxin reporter lines of gerbera and followed the recovery of cellular growth and meristem patterning. We show that wounding disrupted the expression of the gerbera CLAVATA3 (GhCLV3) gene that marks the undifferentiated meristematic region and led to de novo re-initiation of patterning at the wound margin. During the recovery growth, three to five layers of elongated cells showing periclinal cell division planes and lacking auxin signal were formed at the wound rim. DR5 auxin signal was shown to localize and form regularly spaced maxima in a distance from the wound rim. Consequently, spiral pattern of contact parastichies was re-established by stacking of new auxin maxima on top of the previous ones. The developed methods facilitate future studies on understanding the molecular mechanisms of de novo patterning of meristems.

Assessing seal carcasses potentially subjected to grey seal predation

In order to conduct an objective evaluation of potential ecological effects of grey seal predation on marine mammals, it is essential to establish a broad knowledge base helping in the thorough identification of such cases during post-mortem examination. The aim of this work is to report and discuss outcomes resulting from a retrospective evaluation of harbour (Phoca vitulina) and grey seal (Halichoerus grypus) stranding and necropsy data (n = 3274). In addition, the results are compared to a recent case of definite grey seal predation from Germany as well as reports from other countries. Carcasses potentially subjected to grey seal predation show severe lacerations with a circular pattern leaving a smooth, linear and cut-like wound margin. Large parts of skin and underlying tissue are detached from the body and loss of blubber is common. Occurrence frequencies of encountered lesions are presented and a list of parameters to be used for the assessment of similar cases as well as a complementary decision tree are suggested. With the proposed parameters, categories and tools, a baseline can be built in order to facilitate the standardised recognition of predation cases during post-mortem examinations of seals between groups working with populations across several geographic ranges.

Dynamic heterogeneity influences the leader–follower dynamics during epithelial wound closure

Cells of epithelial tissue proliferate and pack together to attain an eventual density homeostasis. As the cell density increases, spatial distribution of velocity and force show striking similarity to the dynamic heterogeneity observed elsewhere in dense granular matter. While the physical nature of this heterogeneity is somewhat known in the epithelial cell monolayer, its biological relevance and precise connection to cell density remain elusive. Relevantly, we had demonstrated how large-scale dynamic heterogeneity in the monolayer stress field in the bulk could critically influence the emergence of leader cells at the wound margin during wound closure, but did not connect the observation to the corresponding cell density. In fact, numerous previous reports had essentially associated long-range force and velocity correlation with either cell density or dynamic heterogeneity, without any generalization. Here, we attempted to unify these two parameters under a single framework and explored their consequence on the dynamics of leader cells, which eventually affected the efficacy of collective migration and wound closure. To this end, we first quantified the dynamic heterogeneity by the peak height of four-point susceptibility. Remarkably, this quantity showed a linear relationship with cell density over many experimental samples. We then varied the heterogeneity, by changing cell density, and found this change altered the number of leader cells at the wound margin. At low heterogeneity, wound closure was slower, with decreased persistence, reduced coordination and disruptive leader–follower interactions. Finally, microscopic characterization of cell–substrate adhesions illustrated how heterogeneity influenced orientations of focal adhesions, affecting coordinated cell movements. Together, these results demonstrate the importance of dynamic heterogeneity in epithelial wound healing. This article is part of the theme issue ‘Multi-scale analysis and modelling of collective migration in biological systems'.

Actin and myosin dynamics are independent during Drosophila embryonic wound repair

Collective cell movements play a central role in embryonic development, tissue repair, and metastatic disease. Cell movements are often coordinated by supracellular networks formed by the cytoskeletal protein actin and the molecular motor nonmuscle myosin II. During wound closure in the embryonic epidermis, the cells around the wound migrate collectively into the damaged region. In Drosophila embryos, mechanical tension stabilizes myosin at the wound edge, facilitating the assembly of a supracellular myosin cable around the wound that coordinates cell migration. Here, we show that actin is also stabilized at the wound edge. However, loss of tension or myosin activity does not affect the dynamics of actin at the wound margin. Conversely, pharmacological stabilization of actin does not affect myosin levels or dynamics around the wound. Together, our data suggest that actin and myosin are independently regulated during embryonic wound closure, thus conferring robustness to the embryonic wound healing response.