Long-term quality of life and cost-effectiveness of treatment of partial thickness burns: A randomized controlled trial comparing enzyme alginogel vs silver sulfadiazine (FLAM study)

The clinical effectiveness and scar quality of the randomized controlled trial comparing enzyme alginogel with silver sulfadiazine (SSD) for treatment of partial thickness burns were previously reported. Enzyme alginogel did not lead to faster wound healing (primary outcome) or less scar formation. In the current study, the health-related quality of life (HRQoL), costs, and cost-effectiveness of enzyme alginogel compared with SSD in the treatment of partial thickness burns were studied. HRQoL was evaluated using the Burn Specific Health Scale-Brief (BSHS-B) and the EQ-5D-5L questionnaire 1 week before discharge and at 3, 6, and 12 months postburn. Costs were studied from a societal perspective (health care and nonhealth-care costs) for a follow-up period of 1 year. A cost-effectiveness analysis was performed using cost-effectiveness acceptability curves and comparing differences in societal costs and Quality Adjusted Life Years (QALYs) at 1 year postburn. Forty-one patients were analyzed in the enzyme alginogel group and 48 patients in the SSD group. None o

Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal

The canonical Wnt/β-catenin signaling pathway governs diverse developmental, homeostatic and pathologic processes. Palmitoylated Wnt ligands engage cell surface Frizzled (Fzd) receptors and Lrp5/6 co-receptors enabling β-catenin nuclear translocation and Tcf/Lef-dependent gene transactivation1–3. Mutations in Wnt downstream signaling components have revealed diverse functions presumptively attributed to Wnt ligands themselves, although direct attribution remains elusive, as complicated by redundancy between 19 mammalian Wnts and 10 Fzds1 and Wnt hydrophobicity2,3. For example, individual Wnt ligand mutations have not revealed homeostatic phenotypes in the intestinal epithelium4, an archetypal canonical Wnt pathway-dependent rapidly self-renewing tissue whose regeneration is fueled by proliferative crypt Lgr5+ intestinal stem cells (ISCs)5–9. R-spondin ligands (Rspo1–4) engage distinct Lgr4-6 and Rnf43/Znrf3 receptor classes10–13, markedly potentiate canonical Wnt/β-catenin signaling and induce intestinal organoid growth in vitro and Lgr5+ ISCs in vivo8,14–17. However, the interchangeability, functional cooperation and relative contributions of Wnt versus Rspo ligands to in vivo canonical Wnt signaling and ISC biology remain unknown. Here, we deconstructed functional roles of Wnt versus Rspo ligands in the intestinal crypt stem cell niche. We demonstrate that the default fate of Lgr5+ ISCs is lineage commitment, escape from which requires both Rspo and Wnt ligands. However, gain-of-function studies using Rspo versus a novel non-lipidated Wnt analog reveal qualitatively distinct, non-interchangeable roles for these ligands in ISCs. Wnts are insufficient to induce Lgr5+ ISC self-renewal, but rather confer a basal competency by maintaining Rspo receptor expression that enables Rspo to actively drive and specify the extent of stem cell expansion. This functionally non-equivalent yet cooperative interplay between Wnt and Rspo ligands establishes a molecular precedent for regulation of mammalian stem cells by distinct priming and self-renewal factors, with broad implications for precision control of tissue regeneration

Molecular imaging of inflammation and intraplaque vasa vasorum: A step forward to identification of vulnerable plaques?

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed

Course and Predictors of Pruritus Following Burns: A Multilevel Analysis

Itch is a common problem after burns. Although the topic receives increasing attention, the number of prospective studies is limited. The aim of this study was to assess the influence of acute traumatic stress symptoms, controlled for injury characteristics, age and sex, on itch over a period of 18 months using multilevel analysis. A total of 226 respondents provided itch scores. Participants completed the Burn Itch Questionnaire during admission (n = 208) and at 3 (n =179), 12 (n =143) and 18 (n =99) months post-burn. They completed the Impact of Event Scale to assess acute traumatic stress symptoms during admission. Skin graft requirement, a higher level of acute traumatic stress symptoms and younger age were statistically significant predictors of a higher itch score. Younger age was particularly associated with higher itch scores during admission, whereas the effect of skin grafting was particularly observed at 3 months post-burn. This study replicates the predictive role of traumatic stress symptoms, which warrants further research

Effective enzymatic debridement of burn wounds depends on the denaturation status of collagen

The treatment of burn wounds by enzymatic debridement using bromelain has shown promising results in our burn center. However, inadequate debridement occurred in a few cases in which the etiology of the burn was attributed to relatively low temperature burns. We hypothesized that bromelain is ineffective in burns in which collagen denaturation, which occurs approximately at 65°C, has not taken place. Our objective was to assess whether there is a relationship between the denaturation of collagen and the ability of bromelain to debride acute scald burn wounds of different temperatures. Ex vivo human skin from four different donors was cut into 1x1 cm samples, and scald burns were produced by immersion in water at temperatures of 40°C, 50°C, 60°C, 70°C, and 100°C for 20 minutes. Denaturation of collagen was assessed with histology, using hematoxylin and eosin (H&E) staining and a fluorescently labeled collagen hybridizing peptide (CHP), and with second harmonic generation (SHG) microscopy. Burned samples and one control sample (room temperature) were weighed before and after application of enzymatic debridement to assess the efficacy of enzymatic debridement. After enzymatic debridement, a weight reduction of 80% was seen in the samples heated to 70°C and 100°C, whereas the other samples showed a reduction of 20%. Unfolding of collagen, loss of basket-weave arrangement, and necrosis was seen in samples heated to 60°C or higher. Evident CHP fluorescence, indicative of collagen denaturation, was seen in samples of 60°C, 70°C and 100°C. SHG intensity, signifying intact collagen, was significantly lower in the 70°C and 100°C group (P '.05) compared to the lower temperatures. In conclusion, denaturation of collagen in skin samples occurred between 60°C and 70°C and strongly correlated with the efficacy of enzymatic debridement. Therefore, enzymatic debridement with the use of bromelain is ineffective in scald burns lower than 60°C

Protection against oral and gastrointestinal diseases: Importance of dietary nitrate intake, oral nitrate reduction and enterosalivary nitrate circulation.

Over the last 20 years, dietary nitrate has been implicated in the formation of methemoglobin and carcinogenic nitrosamines in humans. This has led to restrictions of nitrate and nitrite levels in food and drinking water. However, there is no epidemiological evidence for an increased risk of gastric and intestinal cancer in population groups with high dietary vegetable or nitrate intake. A reevaluation of our currently very negative perception of dietary nitrates comes from recent research into the metabolism and enterosalivary circulation of nitrate in mammals. These studies showed that nitrate is converted to nitrite in the oral cavity that then “fuels” an important mammalian resistance mechanism against infectious diseases. Moreover, there is now evidence that the conversion of nitrate into oxides of nitrogen prevents the formation carcinogenic nitrosamines

Intestinal Enteroendocrine Lineage Cells Possess Homeostatic and Injury-Inducible Stem Cell Activity

Several cell populations have been reported to possess intestinal stem cell (ISC) activity during homeostasis and injury-induced regeneration. Here, we explored inter-relationships between putative mouse ISC populations by comparative RNA-sequencing (RNA-seq). The transcriptomes of multiple cycling ISC populations closely resembled Lgr5+ ISCs, the most well-defined ISC pool, but Bmi1-GFP+ cells were distinct and enriched for enteroendocrine (EE) markers, including Prox1. Prox1-GFP+ cells exhibited sustained clonogenic growth in vitro, and lineage-tracing of Prox1+ cells revealed long-lived clones during homeostasis and after radiation-induced injury in vivo. Single-cell mRNA-seq revealed two subsets of Prox1-GFP+ cells, one of which resembled mature EE cells while the other displayed low-level EE gene expression but co-expressed tuft cell markers, Lgr5 and Ascl2, reminiscent of label-retaining secretory progenitors. Our data suggest that the EE lineage, including mature EE cells, comprises a reservoir of homeostatic and injury-inducible ISCs, extending our understanding of cellular plasticity and stemness