Cutaneous reparative processes, including wound healing, are highly developed procedures in which a chain of actions occurs to reconstitute the function of the wounded tissue. To prevent a delayed or excessive reparative process it is important to understand how this procedure develops and is maintained. One of the major extracellular matrix components of the skin is the glycosaminoglycan hyaluronan (HA). HA contributes to an extracellular environment, which is permissive for cell motility and proliferation, features that may account for HA’s unique properties observed in scarless foetal wound healing. The molecule is found at high concentration whenever proliferation, regeneration and repair of tissue occur. The aims of the present studies were to analyse the distribution of HA and to investigate its possible role in various cutaneous conditions associated with an impaired reparative process like in scar tissue formation in healing wounds, changed skin characteristics in diabetes mellitus and proliferating activity in basal cell carcinomas. Tissue biopsies were obtained from healthy human skin, type-I diabetic skin and various scar tissues. The samples were analysed in the light microscope with a hyaluronan-binding-probe, antibodies for collagen I, III, PCNA and Ki-67. Ultrastructural analyses were performed on the same tissue samples. In normal skin HA was present mainly in the papillary dermis. In epidermis HA was located in between the keratinocytes in the spinous layer. In the different scar tissues the localization of HA varied, with an HA distribution in mature scar type resembling that in normal skin. In keloids the papillary dermis lacked HA, but the thickened epidermis contained more HA than the other scar types. Ultrastructural studies of keloids revealed an altered collagen structure in the dermal layers, with an abundance of thin collagen fibers in the reticular dermis and thicker collagen fibers in the papillary dermis. Furthermore, the keloids displayed epidermal changes, which involved the basement membrane (BM), exhibiting fewer hemidesmosomes, and an altered shape of desmosomes in the entire enlarged spinous layer. These alterations in epidermis are suggested to influence the hydrodynamic and cell regulatory properties of the wounded skin. In diabetic patients, a reduced HA staining in the basement membrane zone was seen. The staining intensity of HA correlated to the physical properties of the skin reflected by their grades of limited joint mobility (LJM). Furthermore, the HA staining correlated with serum concentration of the HbA1c. In basal cell carcinomas (BCC), HA occurred predominantly in the tumour stroma. The distribution was most intense in the highly developed superficial BCC type, and resembled that of the papillary dermis of normal skin. In contrast, in the infiltrative BCC type, the tumour stroma stained weakly in the infiltrative part of the tumour. Moreover, the surrounding dermal layer was deranged and devoid of HA. The findings suggest that the tumour stroma in superficial BCC causes a slow, well-regulated cell growth in which the tumour cells do not substantially disturb the normal skin function. In the infiltrative BCC type, the tumour cells cause a disintegration of the tumour stroma as well as the normal surrounding dermis, which permits further spreading of the tumour. In fact, the behaviour of the infiltrative BCC tumour, growing beyond its boundaries, resembles that of the keloid. The mapping of the distribution of HA could be a useful tool for prognostic information, for evaluating the degree of progress and for deciding the choice of treatment in various diseases of the skin. In skin malignancies such as BCC it can be used to determine the radicality at the surgical excision of the tumour. Keywords: Hyaluronan, scar tissue, diabetes mellitus, basal cell carcinoma, skin, wound healing

Loss of physiological function, uncomfortable symptoms and various disease processes are thought to be directly related to the formation of scar tissue following tissue damage. Between ten and thirty percent of patients requiring spinal surgery suffer from failed back surgery syndrome. The pain and instability resulting from failed back syndrome often requires medical treatment and may even require additional surgeries to alleviate its associated symptoms. Following surgery, scar tissue forms that often becomes adherent to the dura and entangled in the ganglia and nerve fibers of the spinal nerves. This scar tissue is considered to play a major role in the development of failed back syndrome. Following tissue injury, excessive oxidative stress and inflammation are considered to be the primary stimulators behind increased fibroblast proliferation and activation, resulting in abundant extracellular matrix deposition. The excessive laying down of extracellular matrix ultimately leads to abundant scar tissue formation. I hypothesized that reducing oxidative stress and inflammation will mitigate scar tissue formation and produce a better outcome after spinal surgeries. Quercetin is a dietary flavonoid with anti-oxidant and anti-inflammatory properties that has been shown to improve the outcome following injury to the spinal cord and reduce the proliferation of fibroblasts. L-2-Oxothiazolidine-4-carboxylate (OTC) also minimizes inflammation and protects against oxidative stress by promoting the synthesis of the potent antioxidant and anti-inflammatory agent glutathione. OTC reduces airway inflammation in asthma models and is potentially capable of modulating extracellular matrix production. <p>Treatment with these two agents was hypothesized to decrease oxidative stress and inflammation, thereby causing an amelioration of scar tissue formation following spinal surgery and improve the outcome. Morphological changes observed initially indicated that improvements in wound healing were occurring in the experimentally treated tissues. In addition, the scar tissue area and the lateral widths of the peridural scar forming between the muscular tissue areas suggested a reduction in the scar size. Although inflammatory cell numbers increased slightly in the experimental treatment groups, particularly during the initial three day post laminectomy time point, this increase was not statistically significant. <p>While quercetin and OTC did not appear to inhibit the influx of inflammatory cells following laminectomy, they did appear to induce a more beneficial wound healing environment. It is possible that these agents are affecting parameters of wound healing not considered by these studies. For instance the myriad of processes mediated by growth factors and cytokines involved in wound healing process may play a much greater role than the inflammatory cells themselves. In conclusion, reducing oxidative stress and inflammation by these agents to ameliorate scar tissue formation following spinal laminectomy was supported by the observed morphology, but not supported by the quantification of inflammatory cells. Additional studies investigating the efficacy of quercetin and OTC on the wound healing process are needed to further understand the role they play in repair and scar tissue formation.

Biological tissues were studied with synchrotron infrared (IR) microspectroscopy, a technique that allows the spatially resolved determination and mapping of multiple components in situ at high spatial resolution. The first project involved studying brain tissue from TgCRND8 mice, a transgenic model of Alzheimer’s disease (AD). AD is the main cause of dementia in the ageing population, marked by the deposition of plaques composed of the Aβ peptide. Dense-cored and diffuse plaques were IR mapped and the results correlated with histochemistry and immunostaining. Spectral analysis confirmed that congophilic plaque cores were composed of highly aggregated protein in a β-sheet conformation. The amide I maximum of plaque cores was 1623 cm-1; there was no evidence of the high frequency (1680-1690 cm-1) peak seen in in vitro Aβ fibrils and attributed to anti-parallel β-sheet. A significant elevation in phospholipids was found around dense-cored plaques in TgCRND8 mice ranging in age from 5 to 21 months. This was due to an increase in cellular membranes from dystrophic neurites and glial cells around the core, but could also contribute to Aβ aggregation through the interaction of newly secreted Aβ with phospholipids. In contrast, diffuse plaques were not associated with infrared detectable changes in protein secondary structure or relative concentrations of other tissue components. In addition, focally elevated deposits of creatine, a molecule with a crucial role in energy metabolism, were discovered in AD brain tissue with IR microspectroscopy. The creatine deposits may be a previously undiscovered disease marker. A second project was part of a larger Natural Sciences and Engineering Research Council Collaborative Health Research Project (NSERC-CHRP) to test the hypothesis that treatment with anti-oxidants, L-2-oxo-thiazolidine-4-carboxylate (OTC) and quercetin, following spinal surgery may reduce oxidative stress, inflammation, and scarring. The effect of OTC and quercetin on scar tissue formation was evaluated in rats that had undergone laminectomy. Synchrotron IR microspectroscopy data were collected on scar tissue from OTC, quercetin and saline (control) treated animals, sacrificed at 3 and 21 days post-surgery. Spectral differences could be correlated with the stages of wound healing. / May 2007

Loss of physiological function, uncomfortable symptoms and various disease processes are thought to be directly related to the formation of scar tissue following tissue damage. Between ten and thirty percent of patients requiring spinal surgery suffer from failed back surgery syndrome. The pain and instability resulting from failed back syndrome often requires medical treatment and may even require additional surgeries to alleviate its associated symptoms. Following surgery, scar tissue forms that often becomes adherent to the dura and entangled in the ganglia and nerve fibers of the spinal nerves. This scar tissue is considered to play a major role in the development of failed back syndrome. Following tissue injury, excessive oxidative stress and inflammation are considered to be the primary stimulators behind increased fibroblast proliferation and activation, resulting in abundant extracellular matrix deposition. The excessive laying down of extracellular matrix ultimately leads to abundant scar tissue formation. I hypothesized that reducing oxidative stress and inflammation will mitigate scar tissue formation and produce a better outcome after spinal surgeries. Quercetin is a dietary flavonoid with anti-oxidant and anti-inflammatory properties that has been shown to improve the outcome following injury to the spinal cord and reduce the proliferation of fibroblasts. L-2-Oxothiazolidine-4-carboxylate (OTC) also minimizes inflammation and protects against oxidative stress by promoting the synthesis of the potent antioxidant and anti-inflammatory agent glutathione. OTC reduces airway inflammation in asthma models and is potentially capable of modulating extracellular matrix production. <p>Treatment with these two agents was hypothesized to decrease oxidative stress and inflammation, thereby causing an amelioration of scar tissue formation following spinal surgery and improve the outcome. Morphological changes observed initially indicated that improvements in wound healing were occurring in the experimentally treated tissues. In addition, the scar tissue area and the lateral widths of the peridural scar forming between the muscular tissue areas suggested a reduction in the scar size. Although inflammatory cell numbers increased slightly in the experimental treatment groups, particularly during the initial three day post laminectomy time point, this increase was not statistically significant. <p>While quercetin and OTC did not appear to inhibit the influx of inflammatory cells following laminectomy, they did appear to induce a more beneficial wound healing environment. It is possible that these agents are affecting parameters of wound healing not considered by these studies. For instance the myriad of processes mediated by growth factors and cytokines involved in wound healing process may play a much greater role than the inflammatory cells themselves. In conclusion, reducing oxidative stress and inflammation by these agents to ameliorate scar tissue formation following spinal laminectomy was supported by the observed morphology, but not supported by the quantification of inflammatory cells. Additional studies investigating the efficacy of quercetin and OTC on the wound healing process are needed to further understand the role they play in repair and scar tissue formation.

Biological tissues were studied with synchrotron infrared (IR) microspectroscopy, a technique that allows the spatially resolved determination and mapping of multiple components in situ at high spatial resolution. The first project involved studying brain tissue from TgCRND8 mice, a transgenic model of Alzheimer’s disease (AD). AD is the main cause of dementia in the ageing population, marked by the deposition of plaques composed of the Aβ peptide. Dense-cored and diffuse plaques were IR mapped and the results correlated with histochemistry and immunostaining. Spectral analysis confirmed that congophilic plaque cores were composed of highly aggregated protein in a β-sheet conformation. The amide I maximum of plaque cores was 1623 cm-1; there was no evidence of the high frequency (1680-1690 cm-1) peak seen in in vitro Aβ fibrils and attributed to anti-parallel β-sheet. A significant elevation in phospholipids was found around dense-cored plaques in TgCRND8 mice ranging in age from 5 to 21 months. This was due to an increase in cellular membranes from dystrophic neurites and glial cells around the core, but could also contribute to Aβ aggregation through the interaction of newly secreted Aβ with phospholipids. In contrast, diffuse plaques were not associated with infrared detectable changes in protein secondary structure or relative concentrations of other tissue components. In addition, focally elevated deposits of creatine, a molecule with a crucial role in energy metabolism, were discovered in AD brain tissue with IR microspectroscopy. The creatine deposits may be a previously undiscovered disease marker. A second project was part of a larger Natural Sciences and Engineering Research Council Collaborative Health Research Project (NSERC-CHRP) to test the hypothesis that treatment with anti-oxidants, L-2-oxo-thiazolidine-4-carboxylate (OTC) and quercetin, following spinal surgery may reduce oxidative stress, inflammation, and scarring. The effect of OTC and quercetin on scar tissue formation was evaluated in rats that had undergone laminectomy. Synchrotron IR microspectroscopy data were collected on scar tissue from OTC, quercetin and saline (control) treated animals, sacrificed at 3 and 21 days post-surgery. Spectral differences could be correlated with the stages of wound healing.

Biological tissues were studied with synchrotron infrared (IR) microspectroscopy, a technique that allows the spatially resolved determination and mapping of multiple components in situ at high spatial resolution. The first project involved studying brain tissue from TgCRND8 mice, a transgenic model of Alzheimer’s disease (AD). AD is the main cause of dementia in the ageing population, marked by the deposition of plaques composed of the Aβ peptide. Dense-cored and diffuse plaques were IR mapped and the results correlated with histochemistry and immunostaining. Spectral analysis confirmed that congophilic plaque cores were composed of highly aggregated protein in a β-sheet conformation. The amide I maximum of plaque cores was 1623 cm-1; there was no evidence of the high frequency (1680-1690 cm-1) peak seen in in vitro Aβ fibrils and attributed to anti-parallel β-sheet. A significant elevation in phospholipids was found around dense-cored plaques in TgCRND8 mice ranging in age from 5 to 21 months. This was due to an increase in cellular membranes from dystrophic neurites and glial cells around the core, but could also contribute to Aβ aggregation through the interaction of newly secreted Aβ with phospholipids. In contrast, diffuse plaques were not associated with infrared detectable changes in protein secondary structure or relative concentrations of other tissue components. In addition, focally elevated deposits of creatine, a molecule with a crucial role in energy metabolism, were discovered in AD brain tissue with IR microspectroscopy. The creatine deposits may be a previously undiscovered disease marker. A second project was part of a larger Natural Sciences and Engineering Research Council Collaborative Health Research Project (NSERC-CHRP) to test the hypothesis that treatment with anti-oxidants, L-2-oxo-thiazolidine-4-carboxylate (OTC) and quercetin, following spinal surgery may reduce oxidative stress, inflammation, and scarring. The effect of OTC and quercetin on scar tissue formation was evaluated in rats that had undergone laminectomy. Synchrotron IR microspectroscopy data were collected on scar tissue from OTC, quercetin and saline (control) treated animals, sacrificed at 3 and 21 days post-surgery. Spectral differences could be correlated with the stages of wound healing.

Sarcoidosis is a disease characterized as noncaseation granulomas. Granulomas are clusters of cells that form a discrete nodule. This research was important because Black American women develop saroidosis at a higher rate than any other race. The purpose of this phenomenological qualitative study was to examine the impact of sarcoidosis in the lives of Black American women diagnosed with the disease and to consider how occupational experiences may have contributed to participants' development of sarcoidosis. Research states that domestic work such as cleaning, when performed on a daily basis or as an occupation, can contribute to adverse health effects. The framework of this study utilized the transtheoretical model of behavior change while the overall research questions centered on the effects of sarcoidosis on the quality of life of Black American women. This qualitative research included interviews with thirteen Black American women diagnosed and living with sarcoidosis at various stages. Data were collected using the software tool HyperRESEARCH. Both purposive sampling and snowball sampling technique was used for this research. Data were gathered using a general profile of the lived experiences of women with sarcoidosis. The findings revealed that the common lived experience that has potentially put Black American women at risk for developing sarcoidosis is bleach. My recommendations for further research would be to expand the locations of participants to across the United States. The implications for positive social change may result from broader knowledge of the disease through education, even for those who are not at risk for developing it. Chronic sarcoidosis can be fatal if untreated.

No description available.

No / Following traumatic injury, skin has the capacity to repair itself through a complex cascade of biochemical change. The dermis, which contains a load-bearing collagenous network structure, is remodelled over a long period of time, affecting its mechanical behaviour. This study examines the nanomechanical and viscoelastic properties of the upper dermis from human skin that includes both healthy intact and scarred tissue. Extensive nanoindentation analysis shows that the dermal scar tissue exhibits stiffer behaviour than the healthy intact skin. The scar skin also shows weaker viscoelastic creep and capability to dissipate energy at physiologically relevant frequencies than the adjacent intact skin. These results are discussed in conjunction with a visual change in the orientation of collagenous fibrils in the scarred dermis compared with normal dermis, as shown by atomic force microscopy imaging.

The cancers of the skin, melanoma and the keratinocyte cancers, basal cell andsquamous cell carcinomas (BCC and SCC), are among the most common cancersin white populations. While ultraviolet radiation (UVR) is their principal cause,links with non-UVR-related factors have also been noted. Ultimately, theinteraction of these elements results in malignancy however, understanding oftheir specific contributions remains incomplete. This thesis reports findings fromsix studies aiming to investigate gaps in current knowledge of the role of UVR andnon-UVR-related risk factors on skin cancer. The papers are groupedaccording to the aspects of skin cancer epidemiology and aetiology they address. The first two papers address the descriptive epidemiology of melanoma inEngland, a country with low ambient solar UVR. They arise from ecologicalstudies using national melanoma registration data and document rising trends inmelanoma incidence by anatomic site (Paper 1), and by region of residence andsocio-economic deprivation (Paper 2). Their findings were consistent with thesuggestion that increases in recreational UVR exposure are driving rises inmelanoma rates. These results emphasise both the need to closely monitor UVRexposure and melanoma trends and the importance of public health campaigns. The second group of three papers considers the assessment of associations ofnutritional factors with keratinocyte cancer. Two studies use data from aprospective cohort to evaluate the relationship between dietary intake (Paper 3)and blood concentrations (Paper 4) of omega-3 and omega-6 polyunsaturatedfatty acids (PUFA) in relation to BCC and SCC risk. Associations with both PUFAtypes were observed. In addition, Paper 5, a three-way correlational assessment,demonstrated that questionnaire and blood circulating levels of omega-3 PUFAwere highly correlated with measures of skin bioavailability. Collectively, thesestudies give evidence for associations of these nutrients with skin cancer and forthe utility of both intake and biomarker measures for assessing the relationships. The final paper explores the relationship between a widely cited non-UVR riskfactor, namely scars and cancers of the skin. It reports a systematic review of allpublished observational studies quantifying this association. While innumerablecase reports were found, quantitative analyses were rare. The review identifieda major gap in the literature where knowledge of scar malignancies is notevidence-based, but rather founded mainly on cumulative anecdotal reporting. Taken together, this body of published work highlights the largely unrecognisedcomplexity of the aetiology of cancers of the skin. Future research must bebroad in scope in order to advance understanding of the interaction betweenUVR and other risk factors and to provide a base for health messages aimed atreducing the burden of these malignancies.