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Background In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off‐label treatment options. To avoid claims, physicians in Germany can file a cost‐coverage request (off‐label application, OL‐A). Objectives Our aim was to investigate the extent to which the current regulations affect patient care. Material and methods Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL‐As (05/2019–09/2020) and assessing the follow‐up correspondence. We modelled regressions to assess factors associated with cost‐coverage decisions and the time needed by health insurers to process the OL‐As. Results Thirteen clinics provided data on 121 OL‐As, two of which applied for on‐label treatments. Of the remaining 119 OL‐As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL‐As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%‐CI: 0.03–0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%‐CI 0.12–0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22–38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL‐A to the actual initiation of the treatment was 65.5 days (IQR 51–92). Conclusions Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.

Journal of cancer research and clinical oncology 149(7), 3575-3586 (2023). doi:10.1007/s00432-022-04263-z, Published by Springer, Berlin

Agonists and antagonists of the canonical Wnt signaling pathway are modulators of pathological aspects of rheumatoid arthritis (RA). Their activity is primarily modifying bone loss and bone formation, as shown in animal models of RA. More recently, modulation of Wnt signaling by the antagonist Sclerostin has also been shown to influence soft-tissue-associated inflammatory aspects of the disease pointing towards a role of Wnt signaling in soft-tissue inflammation as well. Yet, nothing is known experimentally about the role of Wnt ligands in RA. Here we provide evidence that altering Wnt signaling at the level of a ligand affects all aspects of the rheumatoid arthritic disease. WNT9a levels are increased in the pannus tissue of RA patients, and stimulation of synovial fibroblasts (SFB) with tumor necrosis factor (TNF) leads to increased transcription of Wnt9a. Loss of Wnt9a in a chronic TNF-dependent RA mouse model results in an aggravation of disease progression with enhanced pannus formation and joint destruction. Yet, loss of its activity in the acute K/BxN serum-transfer induced arthritis (STIA) mouse model, which is independent of TNF signaling, has no effect on disease severity or progression. Thus, suggesting a specific role for WNT9a in TNF-triggered RA. In synovial fibroblasts, WNT9a can activate the canonical Wnt/β-catenin pathway, but it can also activate P38- and downregulate NFκB signaling. Based on in vitro data, we propose that loss of Wnt9a creates a slight proinflammatory and procatabolic environment that boosts the TNF-mediated inflammatory response.

The goal of the review is to summarize the current knowledge on the process of chondrocyte-to-osteoblast transdifferentiation during endochondral bone formation and its potential implications in fracture healing and disease. Lineage tracing experiments confirmed the transdifferentiation of chondrocytes into osteoblasts. More recent studies lead to the discovery of molecules involved in this process, as well as to the hypothesis that these cells may re-enter a stem cell-like phase prior to their osteoblastic differentiation. This review recapitulates the current knowledge regarding chondrocyte transdifferentiating into osteoblasts, the developmental and postnatal events where transdifferentiation appears to be relevant, and the molecules implicated in this process.

Mutations in the human receptor tyrosine kinase ROR2 are associated with Robinow syndrome (RRS) and brachydactyly type B1. Amongst others, the shortened limb phenotype associated with RRS is recapitulated in Ror2(−/−) mutant mice. In contrast, Ror1(−/−) mutant mice are viable and show no limb phenotype. Ror1(−/−);Ror2(−/−) double mutants are embryonic lethal, whereas double mutants containing a hypomorphic Ror1 allele (Ror1(hyp)) survive up to birth and display a more severe shortened limb phenotype. Both orphan receptors have been shown to act as possible Wnt coreceptors and to mediate the Wnt5a signal. Here, we analyzed genetic interactions between the Wnt ligand, Wnt9a, and Ror2 or Ror1, as Wnt9a has also been implicated in skeletal development. Wnt9a(−/−) single mutants display a mild shortening of the long bones, whereas these are severely shortened in Ror2(−/−) mutants. Ror2(−/−);Wnt9a(−/−) double mutants displayed even more severely shortened long bones, and intermediate phenotypes were observed in compound Ror2;Wnt9a mutants. Long bones were also shorter in Ror1(hyp/hyp);Wnt9a(−/−) double mutants. In addition, Ror1(hyp/hyp);Wnt9a(−/−) double mutants displayed a secondary palate cleft phenotype, which was not present in the respective single mutants. Interestingly, 50% of compound mutant pups heterozygous for Ror2 and homozygous mutant for Ror1 also developed a secondary palate cleft phenotype.

In hypertrophic chondrocytes, β-catenin has two roles. First, it locally suppresses the differentiation of osteoclasts at the chondro-osseous junction by maintaining the pro-osteoclastic factor receptor activator of NF-κB ligand (RANKL) at low levels. Second, it promotes the differentiation of osteoblast-precursors from chondrocytes. Yet, β-catenin is a dual-function protein, which can either participate in cell-cell adherens junctions or serve as a transcriptional co-activator in canonical Wnt signaling interacting with T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors. Hence, whenever studying tissue-specific requirements of β-catenin using a conventional conditional knockout approach, the functional mechanisms underlying the defects in the conditional mutants remain ambiguous. To decipher mechanistically which of the two molecular functions of β-catenin is required in hypertrophic chondrocytes, we used different approaches. We analyzed the long bones of newborn mice carrying either the null-alleles of Lef1 or Tcf7, or mice in which Tcf7l2 was conditionally deleted in the hypertrophic chondrocytes, as well as double mutants for Lef1 and Tcf7l2, and Tcf7 and Tcf7l2. Furthermore, we analyzed Ctnnb1 mutant newborns expressing a signaling-defective allele that retains the cell adhesion function in hypertrophic chondrocytes. None of the analyzed Tcf/Lef single or double mutants recapitulated the previously published phenotype upon loss of β-catenin in hypertrophic chondrocytes. However, using this particular Ctnnb1 allele, maintaining cell adhesion function, we show that it is the co-transcriptional activity of β-catenin, which is required in hypertrophic chondrocytes to suppress osteoclastogenesis and to promote chondrocyte-derived osteoblast differentiation. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Ulcera duodeni werden am haufigsten durch eine Helicobacter-pylori-Infektion ausgelost, gefolgt von nichtsteroidalen Antirheumatika und einer Minderdurchblutung der Schleimhaut. Die posttransplantationslymphoproliferative Erkrankung (PTLD) kommt bei etwa 1–6,3 % der Patienten nach einer Herztransplantation unter immunsuppressiver Therapie vor. Bis zu 25 % der Falle der PTLD haben eine gastrointestinale Beteiligung. Aufgrund eines breiten Spektrums klinischer Symptome und pathologischer Entitaten kann die Diagnosestellung eine Herausforderung sein. Wir berichten uber einen 55-jahrigen Patienten nach einer Herztransplantation vor 12 Jahren unter Tacrolimus, der sich mit rezidivierenden Blutungen aus einem Ulcus duodeni vorstellte. Immunhistologisch zeigte sich erst im weiteren Verlauf eine seltene Epstein-Barr-Virus(EBV)-assoziierte polymorphe PTLD. Selten war die erste Manifestation einer PTLD nur ein isoliertes Ulkus im Bereich des Bulbus duodeni. Der Verlauf war progredient, von einem Zufallsbefund mit einer transfusionspflichtigen Anamie bis zur gedeckten Perforation verging nur ein Monat. Wiederholte endoskopische Interventionen waren erfolglos. Trotz chirurgischer Ubernahung des Ulkus verstarb der Patient im Rahmen eines Multiorganversagens. Retrospektiv ware eine Reduktion der Immunsuppression eine Erfolg versprechende Therapieoption bei polymorpher PTLD gewesen.

Attending physicians (AP) in urology represent a very heterogeneous group covering various clinical priorities and career objectives. To date, there are no reliable data on professional, personal and position-linked aspects of AP in urology working in university centers (univ-AP) opposed to those working in non-university centers (n-univ-AP).The objective of this study was to analyze individual professional perspectives, professional and personal settings, specific job-related activities and individual professional goals of univ-AP opposed to n‑univ-AP. Thus, a web-based survey containing 55 items was designed to perform a cross-sectional study that was then forwarded using a link which was sent via a mailing list of the German Society of Urology. The survey was available for completion by AP at German urological centers from February to April 2019. Group-specific differences were evaluated using bootstrap-adjusted multivariate logistic regression models.Of the 192 evaluable surveys, 61 (31.8%) and 131 (68.2%) were part of the univ-AP and n‑univ-AP study group, respectively. Participating n‑univ-AP compared to univ-AP held the position of AP (p = 0.022) significantly longer and were on call significantly more frequently (p 0.001). AP in urology (self)-assessed themselves as autonomously confident in performing robotic, laparoscopic, open, endo-urologic, and plastic-reconstructive surgery in 12.4%, 25%, 59.6%, 92.1%, and 25.7%, respectively, with no significant differences between the two groups among all above mentioned surgical subdomains based on multivariate analysis. AP in urology were (very) content in 92% concerning the choice of their discipline, in 73.9% concerning their actual working circumstances, and in 60.2% concerning their level of surgical expertise. Only 27.1% and 19.9% were (very) content with the amount of available time for their personal professional development and for private affairs, respectively. As opposed to n‑univ-AP, univ-AP would choose a career in clinical centers once again significantly more frequently (OR 2.87; pIn this first survey study world-wide on AP in urology divided according to their academic background, similarities and variances were analyzed, baring the potential to further improve identification of AP for a career in clinical centers.

Duodenal ulcers are most often caused by Helicobacter pylori (HP) infection, followed by nonsteroidal anti-inflammatory drugs and hypoperfusion. Posttransplant lymphoproliferative disorder (PTLD) occurs in about 1-6.3% of patients with a heart transplant under immunosuppression therapy. Up to 25% of cases of PTLD have gastrointestinal involvement. Due to a wide spectrum of clinical symptoms and pathological entities, the diagnosis can be challenging. We report the case of a 55-year-old man 12 years after receiving a heart transplant being treated with immunosuppressive agents (tacrolimus) who presented with recurrent bleeding from peptic duodeni. Immunohistochemistry revealed a rare Epstein-Barr-virus-associated polymorphic PTLD. Rarely, PTLD can manifest only with isolated lesions of the duodenal bulb. The course was progressive, going from an incidental finding requiring transfusion anemia to a perforation within 1 month. Repeated endoscopic interventions were unsuccessful. After a surgical intervention the patient died in the course of multiple organ failure. Retrospectively, a reduction of immunosuppression in polymorphic PTLD would have been a treatment option.

Members of Polygordiidae Czerniavsky, 1881 are distributed worldwide and are typical inhabitants of coarse grained, marine sublittoral sediments. Species in Polygordiidae are unusual among polychaetes because they lack external segmentation, parapodia, and chaetae as well as external ciliation. Morphological characters for species distinction are thus limited to the shape and minute structures of the prostomium and pygidium. As a result, morphological identification and description of the Polygordius species is difficult. In the present study, we provide new data for species distinction using molecular and morphological methods, i.e., DNA-sequencing (COI gene), transmission electron microscopy (TEM), and confocal laser scanning microscopy (cLSM). Specifically, we investigated whether the photoreceptor-like sense organs, previously described for Polygordius appendiculatus Fraipont, 1887, could provide additional characters of taxonomic value by examining the ultrastructure of these organs in two additional species, Polygordius erythrophthalmus Giard, 1880 and Polygordius lacteus Schneider, 1868. These organs were found to occur in comparatively large numbers and comprise different types of sensory cells including one rhabdomeric and two ciliary, which are variously combined to form small sensory organs. Structural differences in sensory organs were negligible between P. erythrophthalmus and P. lacteus; however, major differences were observed when compared to P. appendiculatus. These results are in accordance with our molecular data which indicated that P. erythrophthalmus and P. lacteus represent the same species. Thus P. erythrophthalmus is an invalid species and represents a junior synonym of P. lacteus. Furthermore, this study shows that ultrastructural data can significantly contribute to species distinction, especially in morphologically similar species.

The Post-ureteroscopic Lesion Scale (PULS) was designed as a standardized classification system for ureteral lesions after uretero(reno)scopy (URS). This study evaluates its routine use and a possible clinical impact based on a representative patient cohort.Data of 307 patients in 14 German centers within the BUSTER project were used to test 3 hypotheses (H): PULS score shows a high interrater reliability (IRR) after independent assessment by urologic surgeon and assistance personnel (H1); PULS score is correlated with the frequency of postoperative complications during hospital stay (H2); post-URS stenting of the ureter is associated with higher PULS scores (H3).Median age of patients was 54.4 years (interquartile range [IQR] 44.4-65.8; 65.5% male). Median diameter of index stones was 6 mm (IQR 4-8) with 117 (38.4%) pyelo-caliceal and 188 (61.6%) ureteral stones. Overall, 70 and 82.4% of patients had pre-stenting and post-URS stenting, respectively. Stone-free status was achieved in 68.7% after one URS procedure with a complication rate of 10.8% (mostly grade 1-2 according to Clavien-Dindo). PULS scores 0, 1, 2 and 3 were assessed in 40%, 52.1%, 6.9% and 1% of patients, respectively, when estimated by urologic surgeons. PULS score showed a high IRR between the urologic surgeon and assistance personnel (κ = 0.883, p 0.001), but was not significantly correlated with complications (ρ = 0.09, p = 0.881). In contrast, a significant positive correlation was found between PULS score and post-URS stenting (ρ = 0.287, p 0.001). A PULS score of 1 multiplied the likelihood of post-URS stenting by 3.24 (95% confidence interval 1.43-7.34; p = 0.005) as opposed to PULS score 0.Removal of upper urinary tract stones using URS is safe and efficacious. Real-world data provided by this study confirm a high IRR of the PULS score and its clinical impact on the indication for post-URS stenting. A future prospective randomized trial should evaluate a possible standardization of post-URS stenting based on PULS score assessment.

Hanseniaspora uvarum (anamorph Kloeckera apiculata ) is a predominant yeast on wine grapes and other fruits and has a strong influence on wine quality, even when Saccharomyces cerevisiae starter cultures are employed. In this work, we sequenced and annotated approximately 93% of the H. uvarum genome. Southern and synteny analyses were employed to construct a map of the seven chromosomes present in a type strain. Comparative determinations of specific enzyme activities within the fermentative pathway in H. uvarum and S. cerevisiae indicated that the reduced capacity of the former yeast for ethanol production is caused primarily by an ∼10-fold-lower activity of the key glycolytic enzyme pyruvate kinase. The heterologous expression of the encoding gene, H. uvarum PYK1 ( HuPYK1 ), and two genes encoding the phosphofructokinase subunits, HuPFK1 and HuPFK2 , in the respective deletion mutants of S. cerevisiae confirmed their functional homology. IMPORTANCE Hanseniaspora uvarum is a predominant yeast species on grapes and other fruits. It contributes significantly to the production of desired as well as unfavorable aroma compounds and thus determines the quality of the final product, especially wine. Despite this obvious importance, knowledge on its genetics is scarce. As a basis for targeted metabolic modifications, here we provide the results of a genomic sequencing approach, including the annotation of 3,010 protein-encoding genes, e.g., those encoding the entire sugar fermentation pathway, key components of stress response signaling pathways, and enzymes catalyzing the production of aroma compounds. Comparative analyses suggest that the low fermentative capacity of H. uvarum compared to that of Saccharomyces cerevisiae can be attributed to low pyruvate kinase activity. The data reported here are expected to aid in establishing H. uvarum as a non- Saccharomyces yeast in starter cultures for wine and cider fermentations.

The long bones of vertebrate limbs form by endochondral ossification, whereby mesenchymal cells differentiate into chondrogenic progenitors, which then differentiate into chondrocytes. Chondrocytes undergo further differentiation from proliferating to prehypertrophic, and finally to hypertrophic chondrocytes. Several signaling pathways and transcription factors regulate this process. Previously, we and others have shown in chicken that overexpression of an activated form of Calcium/calmodulin-dependent kinase II (CaMKII) results in ectopic chondrocyte maturation. Here, we show that this is not the case in the mouse. Although, in vitro Mef2c activity was upregulated by about 55-fold in response to expression of an activated form of CaMKII (DACaMKII), transgenic mice that expressed a dominant-active form of CaMKII under the control of the Col2a1 regulatory elements display only a very transient and mild phenotype. Here, only the onset of chondrocyte hypertrophy at E12.5 is accelerated. It is also this early step in chondrocyte differentiation that is temporarily delayed around E13.5 in transgenic mice expressing the peptide inhibitor CaM-KIIN from rat (rKIIN) under the control of the Col2a1 regulatory elements. Yet, ultimately DACaMKII, as well as rKIIN transgenic mice are born with completely normal skeletal elements with regard to their length and growth plate organization. Hence, our in vivo analysis suggests that CaMKII signaling plays a minor role in chondrocyte maturation in mice.

In 2012, Bruce Springsteen delivered the keynote address at the South By Southwest Music Conference and Festival. His task was daunting: reconnect authenticity to a traditional approach to creating art. By bringing together ideas on authenticity, creativity, and culture, Springsteen’s talk joins a lineage of essays that defend poetry, creativity, and culture, including famous works by William Wordsworth and T.S. Eliot. In this article, I connect Springsteen’s ideas to the “folk process,” which leads to considering Wordsworth’s ideas on the voice of the common citizen and Eliot’s ideas on historical tradition. In the end, I consider Springsteen’s legacy as cultural ambassador for the arts.

Anamnese und klinischer Befund: Ein 70-jahriger Patient wurde zur Abklarung von Hamoptysen unter oraler Antikoagulation stationar aufgenommen. An Vorerkrankungen bestand eine chronisch obstruktive Lungenerkrankung (COPD) im GOLD-Stadium D mit einer Heimsauerstofftherapie; vor 6 Jahren war eine Tracheotomie wegen einer Langzeitbeatmung (uber 898 Stunden) erfolgt. Daneben war eine periphere arterielle Verschlusskrankheit (pAVK) mit Bypass und wiederholten Thrombektomien infolge rezidivierender Bypassverschlusse trotz effizienter Antikoagulation bekannt. Der Patient hatte alle kardiovaskularen Risikofaktoren. Untersuchungen: Der klinische Verdacht auf ein Bronchialkarzinom wurde computertomographisch bestatigt. Bronchoskopisch wurde im linken Oberlappenbereich eine etwa 2 cm grose Raumforderung biopsiert. Nebenbefundlich fand sich eine erythematose, blutig tingierte Lasion von etwa 7 mm an der Tracheotomienarbe, die zangenbioptisch abgetragen wurde. Diagnose, Therapie und Verlauf: Die aus der Bronchoskopie gewonnenen Biopsien ergaben ein Adenokarzinom im linken Oberlappen und ein onkozytares Adenom der Trachea – ein auserst seltenes benignes Adenom. Das Staging ergab cT1b cN0 cM0 G2 IASLC Ia. In Zusammenschau der gesamten Konstellation des Patienten bestand keine Operabilitat. Es wurde gemas interdisziplinarer Tumorkonferenz ein individualisiertes Vorgehen mit einer kurativ intendierten Strahlentherapie des Adenokarzinoms beschlossen. Neben dem einzuhaltenden Ziel-INR von 2 soll eine endoskopische Kontrolle des bioptisch abgetragenen onkozytaren Adenoms der Trachea nach einem Jahr stattfinden. Folgerung: Das Onkozytom ist ein sehr seltenes (tracheales) Adenom, das im vorgestellten Fall neben dem Bronchialkarzinom die Hamoptysen verursacht hat. Als Genese kann eine reaktive bzw. hyperplastische Antwort nach Tracheotomie vor 6 Jahren vermutet werden. Aufgrund des moglichen infiltrativen Wachstums ist allgemein eine Resektion die Therapie der Wahl. Aber die Entscheidung zur Behandlung richtet sich immer nach dem individuellen Nutzen.

This study asks: what counts as writing in a Web 2.0 environment? How do the vocabularies, functionalities, and organizing structures of Web 2.0 environments impact our understanding of what writing is in these spaces and how that writing is performed? Results suggest that we, as scholars and teachers, need to pay more attention to, first, the interactivity that is embedded in and afforded by Web 2.0 applications and, second, the processes that are invisible to the composer. Successful compositional engagement with Web 2.0 applications requires an evolving interactive set of practices similar to those practiced by gamers, comics, and electronic literature authors and readers. What we learn about these practices has the potential to transform the way we understand writing and the teaching of writing within and outside of a Web 2.0 ecosystem.

The long bones of vertebrate limbs form by endochondral ossification, whereby mesenchymal cells differentiate into chondrogenic progenitors, which then differentiate into chondrocytes. Chondrocytes undergo further differentiation from proliferating to prehypertrophic, and finally to hypertrophic chondrocytes. Several signaling pathways and transcription factors regulate this process. Previously, we and others have shown in chicken that overexpression of an activated form of Calcium/calmodulin-dependent kinase II (CaMKII) results in ectopic chondrocyte maturation. Here, we show that this is not the case in the mouse. Although, in vitro Mef2c activity was upregulated by about 55-fold in response to expression of an activated form of CaMKII (DACaMKII), transgenic mice that expressed a dominant-active form of CaMKII under the control of the Col2a1 regulatory elements display only a very transient and mild phenotype. Here, only the onset of chondrocyte hypertrophy at E12.5 is accelerated. It is also this early step in chondrocyte differentiation that is temporarily delayed around E13.5 in transgenic mice expressing the peptide inhibitor CaM-KIIN from rat (rKIIN) under the control of the Col2a1 regulatory elements. Yet, ultimately DACaMKII, as well as rKIIN transgenic mice are born with completely normal skeletal elements with regard to their length and growth plate organization. Hence, our in vivo analysis suggests that CaMKII signaling plays a minor role in chondrocyte maturation in mice.

This catalogue presents 70 species distributed in two genera for Colombia: Gigantodax with 5 groups, and Simulium with 6 subgenera and 17 groups. Three species are recorded for the first time: Gigantodax vulcanius, G. gracilis, and Simulium pautense, and the distributional range is expanded to S.ochraceum, S. paynei, S. metallicum, and S. callidum.

Despite the prominent role of application forms in the process of composing grant proposals, little attention has been given to the rhetorical and ethical implications of their prompts and instructions. This article analyzes classification systems reified within the cognitive properties of online forms that faculty members use to submit grant proposals. Results suggest that the historicity of proposal forms adds to the complexity of developing models that accurately represent proposal writing in multiple contexts.

Here we revise Eoneria Aczdl, 1951, a small genus of flies in the Neriidae, previously known from two species from Argentina. We describe a new species, E. aczeli SepúlvedaCarvalho from Colombia, provide new records from Brazil, a distribution extension from Argentina and a new genus diagnosis, as well as an identification key based on adult morphology.

The major impediment to understanding how an epithelial tissue executes wound repair is the limited availability of models in which it is possible to follow and manipulate the wound response ex vivo in an environment that closely mimics that of epithelial tissue injury in vivo. This issue was addressed by creating a clinically relevant epithelial ex vivo injury-repair model based on cataract surgery. In this culture model, the response of the lens epithelium to wounding can be followed live in the cells’ native microenvironment, and the molecular mediators of wound repair easily manipulated during the repair process. To prepare the cultures, lenses are removed from the eye and a small incision is made in the anterior of the lens from which the inner mass of lens fiber cells is removed. This procedure creates a circular wound on the posterior lens capsule, the thick basement membrane that surrounds the lens. This wound area where the fiber cells were attached is located just adjacent to a continuous monolayer of lens epithelial cells that remains linked to the lens capsule during the surgical procedure. The wounded epithelium, the cell type from which fiber cells are derived during development, responds to the injury of fiber cell removal by moving collectively across the wound area, led by a population of vimentin-rich repair cells whose mesenchymal progenitors are endogenous to the lens1. These properties are typical of a normal epithelial wound healing response. In this model, as in vivo, wound repair is dependent on signals supplied by the endogenous environment that is uniquely maintained in this ex vivo culture system, providing an ideal opportunity for discovery of the mechanisms that regulate repair of an epithelium following wounding.