Coins occasionally cause health problems. These have a wide range of presentations and can affect multiple organ systems. This article presents a review of the medical literature addressing health problems caused by coins. These problems can be categorized as follows: (1) respiratory manifestations of ingested coins, (2) gastrointestinal manifestations of swallowed coins, (3) systemic effects of swallowed coins, (4) clinical management of swallowed coins, (5) allergic manifestations of coin exposure, and (6) miscellaneous health issues related to swallowed coins.

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The dermal filler Sculptra® has been employed to treat facial volume loss and age-related wrinkles in Europe since 1999. Sculptra® injections were administered 87,946 times (increase of 25.7% to 2012) in the USA in 2013. Except for histological analysis and clinical reports, data based on molecular biology or biochemistry, enlightening the mechanisms of action, do not exist to date. In contrast, such data are available for cross-linked hyaluronic acid, which is also administered for facial augmentation. To overcome this gap of knowledge, a comprehensive study about macroscopic to microscopic events occurring after Sculptra® injections was conducted. The augmentation of facial tissue with Sculptra® is approved; however, as the required repetitive biopsies could not be taken from the face, Sculptra® was injected to the inner side of the upper arms of 21 volunteers. Furthermore, this “off label use” was documented: The effect of the injections on the volunteer’s subjective quality of life was investigated using a questionnaire. For objective evaluation, the upper arms were photographed and sonographic measurements were applied. Photos of the treated upper arms revealed no changes in their shape during the study course. The amount of Sculptra® administered was not sufficient to augment the upper arms of postmenopausal women. Furthermore, these applied Sculptra® treatments of the upper arm did not improve the volunteers’ quality of life significantly. Upon sonographic measurement, however, a highly significant decrease in echogenicity was retrieved by comparing baseline subepidermal tissue values (t0) with 20 month (t2) values from either arm. Upon comparison of both treated sides, echogenicity was comparable; therefore 22 MHz sonography is an objective non-invasive measure to document the subcutaneous effect of Sculptra®. Immunofluorescence staining of sections from biopsies characterised the cell infiltrate and collagen type. CD68+ macrophages were found in direct proximity to PLLA, CD90+ fibroblasts aligned adjacently, while αSMA positive structures indicated myofibroblasts and neovascularisation. Substantial collagen type III deposition was detected right next to PLLA particles and collagen type I in the periphery of a given PLLA encapsulation. mRNA expression was strongly up-regulated for collagen type I and III transcripts, as well as for TGFß1 and TIMP1. PLLA particles were still retrievable 28 months after subcutaneous application. The augmenting effect of Sculptra® is generated by a complex reaction, comprised of various cells, chemokines and cytokines, leading to the proliferation of fibroblasts and their differentiation into myofibroblasts, synthesising a substantial amount of collagen in order to restore subcutaneous volume deficiencies. Degradation of facial and extra facial PLLA particles is considerably slower than described previously. The augmenting effect of Sculptra® diminishes over a period of 18-20 months in the face, but the degradation of PLLA particles seems to be much slower. Whether Sculptra® stimulates the synthesis of other ECM components, such as HA, or rationalises a continuous stimulus for collagen production, at least as long as it is not synthesised, should be analysed in further studies.

For a lay summary of the thesis presented in a 1-minute video format, visit the following link: https://www.youtube.com/watch?v=VhLzt_tEz-s / It is projected that, by 2030, 8% of all adults in the world will have diabetes mellitus and treatment will account for 10% of the total healthcare budget in many countries. Polymeric biomaterial research has led to the design of robust polymer hydrogel capsules to develop curative cell-based therapies for chronic disorders such as diabetes mellitus. Encapsulation of insulin-producing beta cells within synthetic, semi-permeable polymer hydrogels can avoid host immune rejection including fibrotic responses, and thus holds the promise of a long-term curative treatment of this disease. There is a paucity of literature regarding methods available for standardized in vitro screening of synthetic polymer hydrogel capsules to predict host responses in vivo. Thus, the focus of this thesis was to design in vitro assays able to screen for subsequent in vivo fibrotic responses. Two dimensional (‘2D’) (cell attachment to thin film hydrogel coatings) and three dimensional (‘3D’) (cell attachment and protein adsorption to hydrogel capsules) in vitro experiments were designed and tested in an iterative process to assess fibrotic responses to a diverse group of polymer hydrogels. Cell attachment assays included fibroblast (NIH 3T3) and macrophage (RAW 264.7) cell lines, and protein adsorption assays included proteins used to model fibrosis including fibrinogen and lysozyme. For some formulations, in vitro assays were compared with in vivo data on pericapsular cellular overgrowth (PCO) after being implanted into mice. A binomial logistic regression model was designed and validated to assess whether the ‘3D’ in vitro assays correlated with in vivo PCO responses. It was found that the RAW 264.7 cell attachment assay was significantly correlated with PCO outcomes in vivo, demonstrating for the first time a simple, cost-effective, and rapid in vitro cell-based approach to screen and select capsules with lower fibrotic potential to be further tested in animals. / Thesis / Master of Health Sciences (MSc) / In North America, one in eleven adults, or about 415 million people, have diabetes. It is projected that by 2030, around 8% of the world population will be diagnosed with this disease. A common form of treatment is through the frequent injection of insulin, but this is costly, requires multiple daily interventions, and cannot prevent regular excursions from the ideal blood glucose range. Cell-based therapies have a lot of promise in treating several chronic diseases including diabetes. Donor and stem-cell derived islets can be implanted into patients with type 1 diabetes and have been shown to function for over a year, albeit at the price of systematic immune suppression. Alternatively, cells that produce insulin can be placed inside immune-evasive capsules and implanted, potentially providing continuous blood glucose regulation without the need for daily insulin injections. However, this novel form of treatment is limited by the encapsulated cells’ survival once implanted. Cell survival can be affected by the body’s response to a foreign body (the capsule), causing deposition of protein or cells on the capsule surface which can limit the oxygen supply to cells in the capsule and the ability of insulin to leave the capsule in a timely fashion. The goal of this project is to develop assays to screen new capsule formulations. This can advance research by using capsules more readily accepted by the body, leading to a more promising and long-term treatment of diabetes.

<p><strong>A compatible interface between a biomedical material and host tissue is paramount to the continual function and life-span of medical devices that reside in the body. However, the unfavourable host response that ensues when foreign materials inhabit the body must be overcome for sophisticated medical devices, such as artificial organs and real-time biosensors, to be used clinically. My thesis research commenced with a search to find a pharmaceutical compound that could be incorporated into a medical device to suppress the accumulation of fibrous tissue. A prolyl hydroxylase inhibitor, a drug developed to inhibit collagen synthesis, was found to be effective at inhibiting collagen deposition within and on the outer surface of a poly(lactic-glycolic acid) disc, and also limited connective tissue ingrowth. Furthermore, the drug suppressed Scavenger Receptor A (SRA) expression on a macrophage-like cell culture, a receptor known to contain a collagenous domain. The latter finding prompted a review of the literature, upon which it was discovered that SRA mediates leukocyte adhesion and binding to an assortment of materials, such as silica, modified polystyrene, titanium, and iron(III) oxide. As a result, a series of studies were initiated to investigate whether leukocytes use SRA to detect a range of different biomedical materials. Consequently, we found that SRA contributes very little to leukocyte binding of two common medical polymers, polystyrene and poly(lactic-co-glycolic acid), but may interact with the materials to affect the cytokine profile in the local environment. In a subsequent study, SRA was found to be crucial to the leukocyte binding of polyanionic hydrogels. In summary, we have identified a unique pharmaceutical strategy for suppressing the accumulation of fibrous tissue on medical devices in vivo, and uncovered a mechanism of leukocyte stimulation in response to incubation with biomedical materials that the material science research community was not previously aware of. </strong></p> / Doctor of Philosophy (PhD)

As the survival rate increases, the importance of quality of life post-cancer is increasing. This, in conjunction with genetic screening, has increase the number of breast reconstructions 36%. The most common complication causing revision of reconstructive surgery is the formation of a dense scar capsule around the silicone implant called capsular contracture. Nearly all patients will experience this complication, though with different degrees of response, ranging from moderate scarring to major disfigurement and pain at the implant site. Presently, there is no way to predict the degree of contraction capsule formation that individual patients will suffer prospectively, nor is there clinical approach to preventing this complication. Patient information and tissue was collected in a uniform manner to address these lingering problems. Clinical data was used to construct a predictive model which can accurately predict capsular contracture severity in breast reconstruction patients. Histological analysis demonstrated differences in structure and cell composition between different capsule severities. Of particular note, a new region was described which could serve as the communication interface between innate immune cells and fibroblasts. RNA-seq analysis identified 1029 significantly dysregulated genes in severe capsules. Pathway enrichment was then performed which highlights IL4/13 signaling, extracellular matrix organization, antigen presentation, and interferon signaling as importantly dysregulated pathways. These RNA results were also compared to various clinical and histological measurements to evaluate novel correlations. PVT-1, a long non-coding RNA associated with cancer, was strongly correlated to capsules formed after cancer removal. This suggests cancerous transformations of cell types that remain after the tumor is removed. Furthermore, transgelin and caspase 7 correlated to myofibroblasts density, suggesting an abnormal fibroblasts that are resistant to cell death and may have enhanced contractile abilities. Capsule formation is a complex process however, with well controlled clinical models quantitative differences can be found. These results serve as stepping stone for the field to move beyond retrospective clinical trials and pursue treatments and preventative measures. / Ph. D. / As the survival rate increases, the importance of quality of life post-cancer is increasing. This, in conjunction with genetic screening, has increase the number of breast reconstructions 36%. The most common complication causing revision of reconstructive surgery is the formation of a dense scar capsule around the silicone implant called capsular contracture. Nearly all patients will experience this complication, though with different degrees of response, ranging from moderate scarring to major disfigurement and pain at the implant site. Presently, there is no way to predict the degree of contraction capsule formation that individual patients will suffer prospectively, nor is there clinical approach to preventing this complication. Patient information and tissue was collected in a uniform manner to address these lingering problems. Clinical data was used to construct a predictive model which can accurately predict capsular contracture severity in breast reconstruction patients. Histological analysis demonstrated differences in structure and cell composition between different capsule severities. Of particular note, a new region was described which could serve as the communication interface between innate immune cells and fibroblasts. RNA-seq analysis identified 1029 significantly dysregulated genes in severe capsules. Pathway enrichment was then performed which highlights IL4/13 signaling, extracellular matrix organization, antigen presentation, and interferon signaling as importantly dysregulated pathways. These RNA results were also compared to various clinical and histological measurements to evaluate novel correlations. PVT-1, a long non-coding RNA associated with cancer, was strongly correlated to capsules formed after cancer removal. This suggests cancerous transformations of cell types that remain after the tumor is removed. Furthermore, transgelin and caspase 7 correlated to myofibroblasts density, suggesting an abnormal fibroblasts that are resistant to cell death and may have enhanced contractile abilities. Capsule formation is a complex process however, with well controlled clinical models quantitative differences can be found. These results serve as stepping stone for the field to move beyond retrospective clinical trials and pursue treatments and preventative measures.

There is a need to develop novel and effective therapies targeting end-stage peripheral arterial occlusive disease (PAOD). Inducing collateral arteriogenesis is a possible novel treatment that produces a natural bypass for blood flow, a promising solution to the long-term issues seen with current treatments. Regenerative therapies, and progenitor cells specifically, have demonstrated great promise in repair after injury and disease. While most progenitor or stem cells have poor efficacy in this context, muscle progenitor cells, or myoblasts, have encouraging results. Myoblasts enhance arteriogenesis and secrete cytokines or chemokines that recruit monocytes to injury sites. Implanting these adherent cells in a hydrogel construct near natural bypasses in peripheral vasculature increases the size of nearby collateral vessels, pointing to a potentially effective cellular therapy for PAOD. However, many aspects of this novel therapy are yet to be characterized. Given the impact of inflammation and anoikis on transplanted cell survival, one such aspect is the beginning stages of the localized immune response to the implantation of the polymer/cell construct and the impact myoblasts have on this response. This research aims to elucidate the inflammatory response occurring within and locally around poly N-isopropylacrylamide (PNIPAM) polymer constructs post-implantation, focusing on the population and classification of cells within and on the surface of the construct. We hypothesize that the implantation will trigger a local foreign body response (FBR) and recruit multiple immune cell types, primarily macrophage lineage, to the injury site. Cell presence on the construct will be analyzed via confocal microscopy and cell populations within the construct will be typed and quantified via flow cytometry. The goal of this thesis is to characterize the impact of myoblasts in a PNIPAM construct implanted in-vivo in a mouse model on the immune response and use this characterization to help interpret how the construct is modulating the immune response and how we can adjust this response more favorably.

Made available in DSpace on 2016-08-19T18:15:54Z (GMT). No. of bitstreams: 1 Silvia Teresa Evangelista.pdf: 209991 bytes, checksum: 497a2c5c02aa5d734a85bd23ce11c2b1 (MD5) Previous issue date: 2007-09-24 / Airway aspiration of foreign body (FB) is a universal problem and an important cause of morbidity and mortality especially for children and the elderly. FB aspiration was evaluated in 72 children and teenagers varying from 7 months to 15 years of age who underwent rigid bronchoscopy at the CMUH (Children Maternal University Hospital), in São Luís-MA/ Brazil, for FB aspiration in the period from 1995 to 2005. For data collecting, an index card was filled out for each patient. Epi-info and Bio-estata programs were used for processing and statistical analysis. A major prevalence of FB aspiration from 1998 through 2001 was observed. Most patients were from the countryside (55.6%). The predominant age was the firsts three years of life (81.9%). The prevalence was greater among the male sex (63.9%). In 83.3% of the cases the initial diagnosis was FB aspiration. The elapsed time between the aspiration and the bronchoscopy was greater than 72h (52.8 %). The most frequent site was the right lung (38.9 %). The most common types of FB found were of organic nature (83.3 %). The most prevailing radiological finding was hypotransparence (56.9%). Bronchitis was the most frequently reported complication related to FB aspiration (45.9%), and glottis edema was a major complication upon bronchoscopy (47.6%), with no deaths reported in the studied group. It is concluded that bronchoscopy is a safe, highly sensible and efficient procedure for the diagnosis and treatment of FB aspiration, and that a late diagnosis suggests a need for better qualification of the health professionals. / A aspiração de corpo estranho (ACE) para via aérea é um problema universal e uma importante causa de morbidade e mortalidade, especialmente em crianças e idosos. Avaliou-se a aspiração de corpo estranho em 72 crianças na faixa etária de 7 meses a 15 anos submetidas à endoscopia respiratória no Hospital Universitário Materno Infantil (HUMI) por ACE, no período de 1995 a 2005, São Luís - Maranhão. Para cada paciente estudado foi preenchida uma ficha de coleta de dados. Utilizou-se os programas Epi- Info e BioEstata para o processamento e análise estatística. Observou-se uma maior prevalência de ACE nos anos de 1998 a 2001. A maior procedência foi das cidades do interior (55,6%). A idade predominante foi nos três primeiros anos de vida (81,9%). A prevalência foi maior no sexo masculino (63,9%). Em 83,3% dos casos, o diagnóstico inicial foi de ACE. O tempo decorrido entre a aspiração e o exame endoscópico foi maior que 72h (52,8%). A localização mais freqüente foi o pulmão direito (38,9%). O tipo de corpo estranho (CE) mais encontrado foi o orgânico (83,3%). O achado radiológico mais prevalente foi a hipotransparência (56,9%). A complicação mais freqüente relacionada ao CE foi a bronquite (45,9%) A complicação relacionada ao exame endoscópico mais freqüente foi o edema de glote (47,6%), não havendo óbitos. Concluiu-se que a endoscopia respiratória mostrou-se um procedimento seguro, eficaz e de alta sensibilidade no diagnóstico e tratamento do ACE e que a demora no seu diagnóstico sugere a necessidade de melhor qualificação dos profissionais de saúde.

Although medical devices and biomaterial implants are used clinically in a variety of applications, the process of implanting them damages local tissue and initiates a localized non-specific inflammatory response that is detrimental to device performance. Extensive research efforts have focused on developing material surface treatments and systems to deliver anti-inflammatory agents to abrogate such biomaterial-mediated inflammation, yet long-term use of these traditional materials in vivo is limited due to continued inflammation and fibrous encapsulation. This work aims to address these limitations by developing a versatile implant coating with non-fouling properties using a system based on hydrogel microparticles (i.e. microgels). The overall objective of this project was to evaluate host responses to these microgel coatings. Microgel particles were synthesized from poly(N-isopropyl acrylamide) cross-linked with poly(ethylene glycol)-diacrylate and were successfully deposited onto polymeric substrates using a simple and reproducible spin coating technique. We determined that microgel-coated samples adsorbed significantly lower levels of human fibrinogen than controls. Further characterization using an in vitro culture system demonstrated that microgel coatings significantly reduced the adhesion and spreading of murine macrophages and primary human blood-derived monocytes compared to controls. Materials were then evaluated for early cellular responses following implantation in the intraperitoneal cavity of mice to model acute inflammation. Analyses of explanted biomaterials using immunofluorescence staining techniques revealed that microgel-coated samples significantly reduced the density of surface-adherent cells. Additional analysis using flow cytometry revealed that microgel-coated samples exhibited significantly lower levels of pro-inflammatory cytokines in adherent leukocytes compared to controls, indicating that these coatings modulate cellular pro-inflammatory activities. Finally, we implanted samples subcutaneously in rats to determine the efficacy of microgel coatings at longer time points using an established model of chronic inflammation. Explants were processed histologically and stained for various markers. Importantly, staining demonstrated that the microgel coatings significantly reduced fibrous capsule thickness, the capsules appeared less compact and structurally ordered than controls, and also contained significantly fewer cells. Collectively, these results demonstrate that microgel particles can be applied as polymeric coatings to modulate inflammation and achieve more desirable host responses in vivo, with the potential to extend implant lifetime.

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 298-310).