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Atopic dermatitis, AD (synonym eczema) is a chronic inflammatory skin disease. It affects between 10 to 20% of children and 1 to 3% of adults worldwide. It is an important cause of morbidity and is estimated to cost £465 million per annum to the UK. AD is part of a family of Th-2 driven diseases and is often the first of these atopic diseases to manifest. The development of AD is often followed by asthma and allergic rhinitis later in life (a phenomenon known as the ‘atopic march’). Up to 50% of moderate to severe AD cases have been associated with genetic mutations affecting the epidermal barrier protein filaggrin. Filaggrin aggregates keratin filaments during terminal keratinocyte differentiation, allowing normal epidermal stratification. The role of filaggrin in maintaining a functional skin barrier is further supported by a clinical study conducted by ourselves. This is the first clinical study on a European cohort (58 participants) which showed that FLG mutations were associated with experimentally demonstrable defects of skin barrier function (increased baseline transepidermal water loss), more so following exposure to a chemical irritant. However, the majority of patients with AD, especially the milder cases, do not have FLG mutations. Some of the wild-type patients in our study were noticed to have accumulation of the large filaggrin proprotein and a lack of filaggrin monomers, indicating defective proteolysis of profilaggrin into the functional monomers. Our study also found disproportionately raised protease inhibitory activities amongst the AD participants. This inappropriately raised protease inhibition may interfere with profilaggrin proteolysis, leading to the development of AD in some wild-type patients. Having demonstrated that deficiency of filaggrin monomers is associated with a defective skin barrier, we focused on the function of filaggrin in the skin and attempted to improve the skin barrier function. In addition to keratin aggregation, filaggrin constitutes the natural moisturizing factors in the epidermis following its natural breakdown into amino acids. We note that filaggrin is disproportionately rich in amino acid histidine, implying that this amino acid may have a particular significance in maintaining a functional epidermal barrier. Using an in-house skin-equivalent model, we have shown that by increasing the histidine content in the cell culture media, we could increase the expression of filaggrin monomers and reduce the penetration of a fluorescent dye into the skin-equivalents. The latter indicates improved barrier function. Finally, we conducted a pilot human study which showed that histidine, when applied to mechanically damaged skin in AD and healthy participants, was associated with a faster recovery of the skin barrier function. These studies suggest that histidine is of therapeutic benefits in AD. A histidine-based treatment may be developed as an alternative to current anti-inflammatory and immunosuppressive agents used to treat AD.

Orientador: Edméa Cássia Baptista / Banca: Vanusa Alves de Sousa / Banca: Leonardo Nepomuceno / Resumo: Este trabalho propõe uma abordagem que utiliza uma associação dos métodos de barreira modificada e da Lagrangiana aumentada para a resolução do problema de fluxo de potência ótimo. Para isso, foi realizado um levantamento bibliográfico que explicitou os métodos de Newton-Lagrangiano, de barreira modificada e da função lagrangiada aumentada. Na abordagem proposta, as restrições canalizadas são desmembradas em duas desigualdades. Estas são transformadas em igualdades a partir do acréscimo de variáveis de folga ou de excesso positivas, as quais são tratadas pela função barreira modificada. As restrições de igualdade originais do problema são tratadas pelo método da função Lagrangiana aumentada e as igualdades restantes através da função Lagrangiana. As condições necessárias de primeira ordem são aplicadas resultando num sistema não linear o qual é resolvido pelo método de Newton. A eficiência do método foi verificada utilizando um exemplo matemático e em problemas de fluxo de potência ótimo / Abstract: This work proposes an approach that uses an association of the modified barrier method and augmented Lagrangian method for the solution of the optimal power flow problem. On this purpose, a bibliographical review was accomplished the methods Newton-Lagrangian, modified barrier and augmented Lagrangian function. In this approach, the bounded constraints are transformed in equalities by additing the non-negative slack variables. Those slack variables are handled by the modified barrier function. The original equality constrains of the problem are handled by the method of augmented Lagrangian function and the remaining equalities are handled by the Lagrangian function. The first order necessary conditions are applied resulting a nonlinear system which is solved by Newton's method. The effectiveness of the proposed approach has been examined by solving a mathematical example and optimal power flow problems / Mestre

Vascular endothelial cells (VECs) maintain vascular integrity by regulating the passage of solutes, macromolecules, and cells between the vascular and perivascular space and are critical in a wide number of physiological processes, such as the delivery of nutrients and oxygen to surrounding tissues, leukocyte trafficking, angiogenesis, and tissue repair. VEC permeability is regulated, at least in part, by VE-cadherin-based adherens junctions that coordinate inter-VEC contacts and communicate the strength of these interactions to the cell via the actin cytoskeleton. Although the ubiquitous second messenger, cyclic adenosine 3'€™, 5'€™-monophosphate (cAMP), has been shown to reduce VEC permeability, the molecular basis of this effect is currently unclear. Herein, we report that cAMP and its two effectors, cAMP-dependent protein kinase A-II (PKA-II) and exchange protein activated by cAMP-1 (EPAC1), improve barrier function and differentially coordinate this effect through both VE-cadherin and actin cytoskeletal structures. We have also identified cyclic nucleotide phosphodiesterase (PDE) 4 as the major PDE regulating VEC barrier function. Through the use of cAMP-elevating agents and RNAi-mediated knockdown of PKA-Cα, EPAC1 and PDE4D, we have identified a dominant role for EPAC1 in VEC permeability as well as recognized PDE4D as a potential adaptor protein VE-cadherin-based complexes. Our results are consistent with previous reports of a role for both PKA and EPAC1 in controlling VE-cadherin mediated barrier function and additionally provide novel insight into the differential roles that PKA, EPAC1 and PDE4D play in stabilizing VEC barrier function. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2009-09-18 16:09:59.12

Inflammatory bowel disease (IBD), characterised by chronic intestinal inflammation, is hypothesised to arise from the interplay between susceptibility genes, the immune system, environmental factors, and gut microbiota. Akkermansia muciniphila is a symbiotic bacterium that accounts for 1-5% of the human fecal microbiota. This microbe has been hailed as a next-generation probiotic, principally with regards to its plethora of beneficial host interactions, including the ability to influence mucin secretion and strengthen the intestinal barrier. Though a clear-cut role and mechanism by which A. muciniphila influences inflammatory conditions is unknown, evidence indicates this microbe is depleted in IBD, suggesting it may have protective effects that are lost in these conditions. Here, we investigate the role and mechanism of A. muciniphila in intestinal inflammation and its influence on intestinal barrier function by utilizing barrier-disrupting models of colitis, including dextran sulphate sodium (DSS) and Trichuris muris. Though only minor benefits were derived from this microbe in germ-free mice, in specific pathogen-free (SPF) mice, administration of pasteurized A. muciniphila in a DSS recovery model ameliorated inflammation severity and promoted recovery compared to controls. When gavaged prior to DSS administration, both live and pasteurized A. muciniphila failed to diminish inflammatory markers indicating minimal preventative effects. T. muris-infected SPF mice treated with live A. muciniphila showed increased levels of Th2 and anti-inflammatory cytokines, decreased worm burden, and enhanced levels of the mucin, Muc5ac, compared with those receiving control broth or pasteurized bacteria. Further, both live and pasteurized A. muciniphila ameliorated the severity of inflammation in mucin 2 deficient (Muc2-/-) mouse model of spontaneous colitis, indicating that these protective effects are Muc2-independent. These observations provide us not only with an enhanced understanding of the role A. muciniphila plays in the pathogenesis of intestinal inflammatory conditions but also may fuel novel avenues of treatment for those with IBD. / Thesis / Master of Science (MSc) / Akkermansia muciniphila is a bacterium that accounts for 1-5% of the human fecal microbiota and has been shown to stimulate intestinal mucus production and strengthen the gut barrier. Though several studies have linked inflammatory bowel disease (IBD) with decreased levels of A. muciniphila, the precise role of this microbe in gut inflammation is unknown. In this research, we investigate the role of A. muciniphila in gut barrier function and inflammation. Across several experimental models, we find that supplementation with live, and in some cases, pasteurized A. muciniphila, can help curb established inflammation and promote a more anti-inflammatory gut environment. We also identify that these changes are independent of this bacteria’s ability to influence mucin 2, the main building block of intestinal mucus. This study has the potential to both enhance our understanding of microbial influence in intestinal inflammation and may also lead to the development of future treatments for IBD.

Aims and objectives: The research aims and objectives of this study were: Firstly to determine the positive effects and possible disadvantages of three types of barrier creams on skin barrier function by determining skin barrier function by measuring stratum corneum hydration transepidermal water loss (TEWL) and skin surface pH. Secondly to compare different racial skin types (African skin to Caucasian skin) by determining the effects of barrier cream on skin barrier function. Finally to compare the effect of the three different barrier creams on four different anatomical areas. Methods: Thirty eight non-smoking male test subjects took part in this study where three different types of barrier creams were tested on their arms and hands in a controlled laboratory environment. The thirty eight test subjects consisted of nineteen African and nineteen Caucasian test subjects. Three parameters were measured namely TEWL, stratum corneum hydration and pH condition of the skin. TEWL was measured using a Vapometer (Delfin Technology Ltd. Finland). The Multi probe Adapter system (MPA) (Courage and Khazaka, Germany) was used with a temperature and humidity sensor and with the following probes all from Courage and Khazaka, Germany: a Corneometer measuring skin hydration and a pH-Meter measuring skin surface pH. The measurements were repeated on each of the four sampling areas (forearm, wrist, back of hand and palm) with a reasonable time interval between each measurement. After the baseline measurement the barrier cream was applied by the researcher on the test subjects’ dominant arm. The long term effects were determined after the baseline measurement in intervals of 2 hours. Directly after each measurement the barrier cream was reapplied. Results: Gloves In A Bottle™ increased stratum corneum hydration, had no effect on TEWL and increased skin surface pH, whereas Reinol™ increased stratum corneum hydration and decreased TEWL and had no effect on pH values. Travabon™ decreased stratum corneum hydration and TEWL and had no effect on skin surface pH. The results indicated that there were significant differences between Caucasian and African test subjects with the use of barrier creams, because of the baseline differences and the reaction to barrier creams showed different results. There were also statistically significant differences in the four different anatomical areas where the barrier creams were applied. Conclusion: Barrier creams are beneficial in the workplace, although it should be taken into consideration that different ethnicities react differently to barrier creams under different workplace situations and therefore this should be taken into account when selecting a barrier cream. / Thesis (MSc (Occupational Hygiene))--North-West University, Potchefstroom Campus, 2013

Aims and objectives: The research aims and objectives of this study were: Firstly to determine the positive effects and possible disadvantages of three types of barrier creams on skin barrier function by determining skin barrier function by measuring stratum corneum hydration transepidermal water loss (TEWL) and skin surface pH. Secondly to compare different racial skin types (African skin to Caucasian skin) by determining the effects of barrier cream on skin barrier function. Finally to compare the effect of the three different barrier creams on four different anatomical areas. Methods: Thirty eight non-smoking male test subjects took part in this study where three different types of barrier creams were tested on their arms and hands in a controlled laboratory environment. The thirty eight test subjects consisted of nineteen African and nineteen Caucasian test subjects. Three parameters were measured namely TEWL, stratum corneum hydration and pH condition of the skin. TEWL was measured using a Vapometer (Delfin Technology Ltd. Finland). The Multi probe Adapter system (MPA) (Courage and Khazaka, Germany) was used with a temperature and humidity sensor and with the following probes all from Courage and Khazaka, Germany: a Corneometer measuring skin hydration and a pH-Meter measuring skin surface pH. The measurements were repeated on each of the four sampling areas (forearm, wrist, back of hand and palm) with a reasonable time interval between each measurement. After the baseline measurement the barrier cream was applied by the researcher on the test subjects’ dominant arm. The long term effects were determined after the baseline measurement in intervals of 2 hours. Directly after each measurement the barrier cream was reapplied. Results: Gloves In A Bottle™ increased stratum corneum hydration, had no effect on TEWL and increased skin surface pH, whereas Reinol™ increased stratum corneum hydration and decreased TEWL and had no effect on pH values. Travabon™ decreased stratum corneum hydration and TEWL and had no effect on skin surface pH. The results indicated that there were significant differences between Caucasian and African test subjects with the use of barrier creams, because of the baseline differences and the reaction to barrier creams showed different results. There were also statistically significant differences in the four different anatomical areas where the barrier creams were applied. Conclusion: Barrier creams are beneficial in the workplace, although it should be taken into consideration that different ethnicities react differently to barrier creams under different workplace situations and therefore this should be taken into account when selecting a barrier cream. / Thesis (MSc (Occupational Hygiene))--North-West University, Potchefstroom Campus, 2013

Abstract In Oulu University Hospital Haematological Ward during the years 1990–1991, a manual blood culture system was able to detect bloodstream infection (BSI) in 23% of febrile episodes of patients with acute myeloid leukaemia (AML), whereas during the years 1992–1993 an automated continuous-monitoring blood culture system (CMBCS) BacT/Alert® detected BSI in 40% of febrile episodes (p = 0.043). During the years 1997–2003, regimens containing high-dose cytarabine predisposed patients to laboratory-confirmed BSI (LCBI) with an odds ratio (OR) of 2.3 (with 95% confidence interval (CI) from 1.2 to 4.2). The LCBI risk was lowest after thioguanine-containing regimens (OR 0.26, 95% CI; 0.12–0.58). In the register data (years 1992–2006) from the prospective multi-centre AML -92 trial, when compared to cycle I, the OR for LCBI was significantly higher (from 4.8 to 5.8) in subsequent cycles (p < 0.001). In all, 67% of mortality due to BSI occurred in patients with active leukaemia. An inoculum of microorganisms to produce 10 colony-forming units (cfu)/ml of 10 gram-positive coccal strains, 10 gram-negative bacillar strains and 8 Candida yeast strains was cultured in BacT/Alert® blood culture bottles in the presence of several chemotherapeutic drugs. Of the chemotherapeutic drugs tested, the anthracyclines exhibited inhibitory effects on the growth of microorganisms in concentrations corresponding to the therapeutic levels. In the standard bottles, doxorubicin increased the incubation time of gram-positive cocci and idarubicin increased the incubation time of Candida glabrata. However, no increase in the incubation time of any microbes was detected in the antimicrobial-neutralizing FAN bottles. In conclusion, the use of CMBCSs has resulted in an increased LCBI rate in neutropenic AML patients. In general, chemotherapeutic agents have no significant inhibitory effects on the growth of common microbial pathogens in blood culture. The detection of some difficult-to-culture microbial strains – C. glabrata for example – in blood cultures may be impaired by the presence of chemotherapeutics in blood. The chemotherapeutics may also affect the LCBI rate in other ways. As a predictor of adverse outcome of infection, the presence of active leukaemia is more important than the type of chemotherapy being administered.

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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A deficiÃncia de vitamina A (DVA) à considerada um importante problema de saÃde pÃblica em todo o mundo e o papel da DVA na integridade epitelial intestinal ainda nÃo està bem compreendido. O objetivo do trabalho foi investigar a associaÃÃo do retinol (vitamina A) e carotenÃides com a barreira funcional intestinal em crianÃas de uma comunidade urbana em Fortaleza, no Nordeste do Brasil. Participaram do estudo 102 crianÃas de 2 meses a 9 anos de idade. O estado nutricional das crianÃas foi avaliado atravÃs do escore âzâ de peso por altura (WHZ), mostrando que 19,6% (20/102) das crianÃas apresentaram desnutriÃÃo leve (âzâ escore de -1 a -2). Todas as crianÃas tiveram as concentraÃÃes de retinol determinadas e nenhuma estava severamente deficiente (< 0,35 ÂM); 2,9% (3/102) das crianÃas apresentaram nÃveis moderados de deficiÃncia de vitamina A (0,36 - 0,70 ÂM); 20,6% (21/102) apresentaram leve deficiÃncia (0,71 - 1,05 ÂM) e 76,5% (78/102) apresentaram concentraÃÃes suficientes de retinol no sangue (> 1,05 ÂM). A razÃo de lactulose/manitol (L/M) estava anormal em 49% (47/97) das crianÃas quando comparadas com crianÃas saudÃveis de uma mesma regiÃo geogrÃfica. Os carotenÃides, luteÃna, &#946;-criptoxantina e beta-caroteno no soro das crianÃas do Parque UniversitÃrio, apresentaram correlaÃÃes inversas significativas com a razÃo de L/M. As proteÃnas de fase aguda (proteÃna C reativa, CRP e glicoproteÃna &#945;1-Ãcida, AGP) apresentaram correlaÃÃes inversas com retinol. O retinol correlacionou-se significativamente com a proteÃna ligadora de retinol (RBP) e com a transtiretina (TTR). Esses dados sugerem que a alteraÃÃo na barreira funcional intestinal provavelmente ocorreu atravÃs do caminho paracelular com baixas concentraÃÃes de carotenÃides no soro. Os carotenÃides, precursores do retinol, poderiam assim promover um melhor marcador para a barreira funcional intestinal alterada do que as medidas de RBP ou retinol. As concentraÃÃes sanguÃneas de retinol correlacionaram-se com a RBP e TTR e correlacionaram-se inversamente com a AGP e com a CPR / Vitamin A deficiency (VAD) is considered an important public health problem worldwide and the role of VAD on intestinal epithelial integrity is not well understood. To investigate the association of retinol (vitamin A) and carotenoids with the intestinal barrier function from children in an urban community in Fortaleza, Northeastern Brazil, one hundred and two children from 2 months to 9 years old participated in the study. The nutritional status of these children, measured by weight for height z-score (WHZ), showed that 19.6% (20/102) of them had mild malnutrition (-1 to â2 z-score). All children had their serum retinol concentration measured and none were severely deficient (<= 0.35 ÂM), 2.9% (3/102) were moderately (0.36 â 0.70 ÂM), 20.6% (21/102) were mildly (0.71 â 1.05 ÂM) deficiencies; 76.5% (78/102) were vitamin A sufficient (> 1.05 ÂM). The lactulose:mannitol (L/M) ratio was abnormal in 49% (47/97) of children when compared to healthy children in the same geographic area. Serum carotenoids, lutein, beta-cryptoxanthin and beta-carotene showed significant inverse correlation with the L/M ratio. Acute phase proteins (C-reactive protein; CRP; and &#945;-acid glycoprotein; AGP) were significantly inversely correlated with retinol. Retinol was significantly correlated with retinol-binding protein (RBP), and with transthyretin (TTR). These data suggest a disruption of intestinal barrier function due to paracellular pathway with low serum concentrations of carotenoids. The retinol precursors, carotenoids, may provide a better marker for disrupted intestinal barrier function than measurements of RBP or retinol. Serum retinol concentrations correlate with RBP and TTR and inversely correlate with AGP and CRP