The prenatal diagnosis, natural history and management of mainstem bronchial atresia have not been described previously. We report two cases of prenatally diagnosed proximal bronchial atresia. The ...first patient presented at 18 weeks with sonographic and MRI findings consistent with bronchial atresia with fetal hydrops. The mother developed the mirror syndrome and labor was induced. A non-viable fetus was delivered at 25 weeks. The second patient presented at 16 weeks gestation with evidence of an intrathoracic mass that was subsequently prenatally diagnosed as a right mainstem bronchial atresia. The right lung increased rapidly in size and was associated with the onset of fetal hydrops. At 24 weeks, fetal pneumonectomy was performed but the fetus expired intraoperatively due to cardiovascular collapse. Post-mortem findings in both cases confirmed the presence of an atretic mainstem bronchus with massive enlargement of the lung. Bronchial atresia involving the mainstem bronchus is associated with a poor prognosis.
Cutaneous scarring affects millions of patients worldwide and results in significant financial and psychosocial burdens. Given the immune system's intricate involvement in the initiation and ...progression of wound healing, it is no surprise that the scarring outcome can be affected by the actions of various immune cells and the cytokines and growth factors they produce. Understanding the role of T cells in regulating immune responses and directing the action of wound mesenchymal cells is essential to developing antifibrotic therapies to reduce the burden of scarring.
As the immune system is intimately involved in wound healing, much work has examined the impact of T cells and their cytokines on the final wound outcome. New innovative tools for studying T cells have resulted in more sophisticated immunophenotyping capabilities and the ability to examine effects of individual cytokines in the wound environment.
Despite continued advances in the study of specific immune cells and their effects on dermal fibrosis, minimal progress has been made to modulate immune responses to result in improved wound cosmesis.
The actions of T cells represent potential pharmacologic targets that could lead to novel bioengineered or immunoengineered therapies to improve the lives of people with cutaneous scarring.
Although polyp size dictates surveillance intervals, endoscopists often estimate polyp size inaccurately. We hypothesized that an intervention providing didactic instruction and real-time feedback ...could significantly improve polyp size classification.
We conducted a multicenter randomized controlled trial to evaluate the impact of different components of an online educational module on polyp sizing. Participants were randomized to control (no video, no feedback), video only, feedback only, or video + feedback. The primary outcome was accuracy of polyp size classification into clinically relevant categories (diminutive 1-5mm, small 6-9mm, large ≥10mm). Secondary outcomes included accuracy of exact polyp size (inmm), learning curves, and directionality of inaccuracy (over- vs. underestimation).
36 trainees from five training programs provided 1360 polyp size assessments. The feedback only (80.1%,
=0.01) and video + feedback (78.9%, P=0.02) groups had higher accuracy of polyp size classification compared with controls (71.6%). There was no significant difference in accuracy between the video only group (74.4%) and controls (
=0.42). Groups receiving feedback had higher accuracy of exact polyp size (inmm) and higher peak learning curves. Polyps were more likely to be overestimated than underestimated, and 29.3% of size inaccuracies impacted recommended surveillance intervals.
Our online educational module significantly improved polyp size classification. Real-time feedback appeared to be a critical component in improving accuracy. This scalable and no-cost educational module could significantly decrease under- and overutilization of colonoscopy, improving patient outcomes while increasing colonoscopy access.
Background The diabetic phenotype of wound healing is in part characterized by impaired neovascularization and deficient endothelial progenitor cell (EPC) recruitment. Angiopoietin-1 (Ang-1) is a ...potent mobilizer of EPCs from the bone marrow (BM). A suggested mechanism for EPC mobilization from the BM is mediated by matrix metalloproteinase 9 (MMP-9) and stem cell factor (SCF). Taken together, we hypothesized that overexpression of Ang-1 in diabetic wounds will recruit EPCs and improve neovascularization and wound healing. Methods An endothelial lineage BM-labeled murine model of diabetes was developed to track BM-derived EPCs. FVBN mice were lethally irradiated and then reconstituted with BM from syngeneic Tie2/LacZ donor mice. Diabetes was induced with streptozotocin. Dorsal wounds in BM-transplanted mice were treated with Ad-Ang-1, Ad-GFP, or phosphate-buffered saline. At day 7 after injury, wounds were harvested and analyzed. A similar experiment was conducted in EPC mobilization deficient MMP-9 –/– mice to determine whether the effects of Ang-1 were EPC-dependent. Results Overexpression of Ang-1 resulted in greatly improved re-epithelialization, neovascularization, and EPC recruitment in diabetic BM-transplanted wounds at day 7. Ang-1 treatment resulted in increased serum levels of proMMP-9 and SCF but had no effect on vascular endothelial growth factor levels. According to our FACS results, peripheral blood EPC (CD34+ /Cd133+ /Flk1+ ) counts at day 3 after wounding showed impaired EPC mobilization in MMP-9 –/– mice compared with those of wild-type controls. EPC mobilization was rescued by SCF administration, validating this model for EPC-mobilization–deficient mechanistic studies. In MMP-9 –/– mice, Ad-Ang-1 accelerated re-epithelialization in a similar manner, but had no effect on neovascularization. Conclusion Our results show that Ang-1 administration results in improved neovascularization which is dependent on EPC recruitment and has direct effects on wound re-epithelialization. These data may represent a novel strategy to correct the phenotype of impaired diabetic neovascularization and may improve diabetic wound healing.
Demonstrate the impact of IL-10 producing T lymphocytes on mediating dermal scarring.
We demonstrated that CD4+ cells are essential to improving postinjury wound healing and preventing fibrosis. CD4+ ...subsets secrete differential cytokine and growth factor profiles, though their role in fibrosis is not known. IL-10, a key anti-inflammatory cytokine shown to promote regenerative wound healing, is secreted by some CD4+ subsets. We, therefore, hypothesize that IL-10 producing CD4+ T lymphocyte subsets selectively attenuate dermal wound fibrosis.
IL-10-/- and wild-type murine splenocytes were enriched for CD4+ lymphocytes and adoptively transferred into severe combined immunodeficient (SCID) mice that received full-thickness wounds which were analyzed at days 7 and 28 for inflammation and collagen content. We then sorted CD4+CD44int/lowFoxP3-CD62L+ T cells (Tnaive) or CD4+CD44HiFoxP3- type 1 regulatory (Tr1) T cell subsets from 10BiT murine splenocytes, activated them, and transferred them into wounds. In vitro, dermal fibroblasts were cocultured with Tnaive or Tr1 and the effect on extracellular matrix (ECM) regulation was analyzed.
The anti-inflammatory and antifibrotic effects of CD4+ cells on SCID wounds were lost with cells from IL-10-/- mice. Adoptive transfer of Tr1 into SCID mice resulted in accelerated wound closure at d7 with reduced fibrosis at d28, with Tr1 favoring hyaluronan production by fibroblasts, an ECM molecule implicated in IL-10-induced regenerative healing.
IL-10 producing T-lymphocytes, specifically Tr1, regulate inflammatory cell cytokine expression to promote HA-rich ECM deposition and attenuate fibrosis. Promoting IL-10 producing lymphocytes in wounds may be a therapeutic target to promote regenerative wound healing.
The most vital part of a grant is the specific-aims section. As the leading section of the proposal, the specific-aims section serves as a 1-page synopsis that needs to gain the attention and ...interest of the reviewers. It must present a compelling case for the importance of the proposed work and provide a convincing rationale and evidence that you and your team are the best people to carry out the project. Developing the specific-aims page is usually the first stage of the grant writing process, as it provides an overview of the proposal and research directions. Furthermore, it can be instrumental in getting external feedback from program officers, collaborators, and others as the grant develops. The process of writing the Specific Aims page requires that one touch on each of the elements that comprise the scoring criteria of the proposal (eg, significance, innovation, investigator(s), approach, and environment) and succinctly introduce all the main topics that will be addressed in the application, but focus especially on the knowledge gap and the importance of filling it, the central hypothesis and the aims that will address it, and the overall impact of the work. This page sets a clear framework for writing the rest of the grant. In this article, we present a set of recommendations and guidelines on how to utilize an algorithmic approach to develop the specific-aims page, what elements to include, and how to maximize its value to create a competitive grant.
Precision agriculture involves manipulation of variations in field productivity, maximization of income, scale backing of wastes, and minimizing of the impact on surroundings using automated ...machine-controlled information assortment and documentation. This work focuses on the efficient control of farm irrigation by exploiting the capabilities of Internet of Things (IoT) and Big Data-based Decision Support System (DSS) to generate adequate valve control commands. Three varieties of prediction techniques such as Deep Neural Network (DNN), Random Forest (RF) and Resilient Back-Propagation Neural Network model are tested to predict soil Moisture Content (MC) in one hour advance by considering 6 numbers of different sensors. The real-time data collection is performed using the proposed IoT node deployment strategy tested in the field. An integrated IoT-based DSS framework is proposed to accumulate 17 numbers of soil and environmental parameters to predict future variation of soil MC in 1 h advance. Further, Structural Similarity (SSIM) Index is used to visualize and maintain uniform MC all over the agriculture area during the entire cropping period. Site and zone specific irrigation control scheme is tested in the test site using fuzzy logic-based weather dependent model. The complete system architecture, deployment strategy and performance of the proposed IoT-based DSS mechanism is discussed in this article.
Endothelial progenitor cells (EPCs) contribute to de novo angiogenesis, tissue regeneration, and remodeling. Interleukin 10 (IL‐10), an anti‐inflammatory cytokine that primarily signals via STAT3, ...has been shown to drive EPC recruitment to injured tissues. Our previous work demonstrated that overexpression of IL‐10 in dermal wounds promotes regenerative tissue repair via STAT3‐dependent regulation of fibroblast‐specific hyaluronan synthesis. However, IL‐10's role and specific mode of action on EPC recruitment, particularly in dermal wound healing and neovascularization in both normal and diabetic wounds, remain to be defined. Therefore, inducible skin‐specific STAT3 knockdown mice were studied to determine IL‐10's impact on EPCs, dermal wound neovascularization and healing, and whether it is STAT3‐dependent. We show that IL‐10 overexpression significantly elevated EPC counts in the granulating wound bed, which was associated with robust capillary lumen density and enhanced re‐epithelialization of both control and diabetic (db/db) wounds at day 7. We noted increased VEGF and high C‐X‐C motif chemokine 12 (CXCL12) levels in wounds and a favorable CXCL12 gradient at day 3 that may support EPC mobilization and infiltration from bone marrow to wounds, an effect that was abrogated in STAT3 knockdown wounds. These findings were supported in vitro. IL‐10 promoted VEGF and CXCL12 synthesis in primary murine dermal fibroblasts, with blunted VEGF expression upon blocking CXCL12 in the media by antibody binding. IL‐10‐conditioned fibroblast media also significantly promoted endothelial sprouting and network formation. In conclusion, these studies demonstrate that overexpression of IL‐10 in dermal wounds recruits EPCs and leads to increased vascular structures and faster re‐epithelialization.
Scar formation is the typical endpoint of postnatal dermal wound healing, which affects more than 100 million individuals annually. Not only do scars cause a functional burden by reducing the ...biomechanical strength of skin at the site of injury, but they also significantly increase healthcare costs and impose psychosocial challenges. Though the mechanisms that dictate how dermal wounds heal are still not completely understood, they are regulated by extracellular matrix (ECM) remodeling, neovascularization, and inflammatory responses. The cytokine interleukin (IL)-10 has emerged as a key mediator of the pro- to anti-inflammatory transition that counters collagen deposition in scarring. In parallel, the high molecular weight (HMW) glycosaminoglycan hyaluronan (HA) is present in the ECM and acts in concert with IL-10 to block pro-inflammatory signals and attenuate fibrotic responses. Notably, high concentrations of both IL-10 and HMW HA are produced in early gestational fetal skin, which heals scarlessly. Since fibroblasts are responsible for collagen deposition, it is critical to determine how the concerted actions of IL-10 and HA drive their function to potentially control fibrogenesis. Beyond their independent actions, an auto-regulatory IL-10/HA axis may exist to modulate the magnitude of CD4
effector T lymphocyte activation and enhance T regulatory cell function in order to reduce scarring. This review underscores the pathophysiological impact of the IL-10/HA axis as a multifaceted molecular mechanism to direct primary cell responders and regulators toward either regenerative dermal tissue repair or scarring.
In the scheme of developing an application for funding from any federal or foundation source, it is reasonable to place significant attention on the science. However, it is also imperative to ...remember that your budget is what will provide the resources to make sure you can complete your proposed investigations and, as such, deserves appropriate consideration. In the competitive arena of extramural funding, funding agencies are incentivized to ensure that the funds committed to research will yield maximum impact. A well-thought-out budget demonstrates to the funding agency 2 key factors: (1) that you understand the needs of the project and (2) you have a realistic expectation of the project costs. When these 2 things are communicated to the funding agency, in addition to the significance of your science, it is more likely that you will receive the budget you request. Herein, we put forth the fundamentals for preparing your budget and the nuances that may help you not only be in compliance but also improve your chances of success. This article will discuss issues to consider when designing a budget for large research grants, using the NIH R&R Budget as a prototype.
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