<p>Hereditary ichthyosis is a collective name for many dry and scaly skin disorders ranging in frequency from common to very rare. The main groups are autosomal recessive lamellar ichthyosis, autosomal dominant epidermolytic hyperkeratosis and ichthyosis vulgaris, and x-linked recessive ichthyosis. Anhidrosis, ectropion and keratodermia are common symptoms, especially in lamellar ichthyosis, which is often caused by mutations in the transglutaminase 1 (TGM1) gene. The aim of this work was to study patients with different types of ichthyosis regarding (i) the patho-aetiology (TGM1 and electron microscopy [EM] analysis), (ii) skin signs and symptoms (clinical score and subjective measure of disease activity), (iii) quality of life (questionnaires DLQI, SF-36 and NHP and face-to-face interviews) and (iv) a search for new ways of topical treatment. Patients from Sweden and Estonia with autosomal recessive congenital ichthyosis (n=83) had a broader clinical spectrum than anticipated, but a majority carried TGM1 mutations. Based on DNA analysis and clinical examinations the patients were classified into three groups, which could be further subdivided after EM analysis. Our studies indicate that patients with ichthyosis have reduced quality of life as reflected by DLQI and by some domains of SF-36, by NHP and the interviews. All the interviewees reported that their skin disease had affected them negatively to varying degrees during their entire lives and that the most problematic period was childhood. All patients with ichthyosis use topical therapy. In a double-blind study creams containing either 5% urea or 20% propylene glycol were found inferior to a cream formulation containing lactic acid 5% and propylene glycol 20% both regarding clinical improvement and thinning of the skin barrier. Improved topical therapy may reduce the need of more toxic, oral drugs. Future studies should elucidate whether this increases the quality of life of ichthyosis patients, especially if combined with more detailed information about the aetiology and inheritance of the diseases.</p>

Hereditary ichthyosis is a collective name for many dry and scaly skin disorders ranging in frequency from common to very rare. The main groups are autosomal recessive lamellar ichthyosis, autosomal dominant epidermolytic hyperkeratosis and ichthyosis vulgaris, and x-linked recessive ichthyosis. Anhidrosis, ectropion and keratodermia are common symptoms, especially in lamellar ichthyosis, which is often caused by mutations in the transglutaminase 1 (TGM1) gene. The aim of this work was to study patients with different types of ichthyosis regarding (i) the patho-aetiology (TGM1 and electron microscopy [EM] analysis), (ii) skin signs and symptoms (clinical score and subjective measure of disease activity), (iii) quality of life (questionnaires DLQI, SF-36 and NHP and face-to-face interviews) and (iv) a search for new ways of topical treatment. Patients from Sweden and Estonia with autosomal recessive congenital ichthyosis (n=83) had a broader clinical spectrum than anticipated, but a majority carried TGM1 mutations. Based on DNA analysis and clinical examinations the patients were classified into three groups, which could be further subdivided after EM analysis. Our studies indicate that patients with ichthyosis have reduced quality of life as reflected by DLQI and by some domains of SF-36, by NHP and the interviews. All the interviewees reported that their skin disease had affected them negatively to varying degrees during their entire lives and that the most problematic period was childhood. All patients with ichthyosis use topical therapy. In a double-blind study creams containing either 5% urea or 20% propylene glycol were found inferior to a cream formulation containing lactic acid 5% and propylene glycol 20% both regarding clinical improvement and thinning of the skin barrier. Improved topical therapy may reduce the need of more toxic, oral drugs. Future studies should elucidate whether this increases the quality of life of ichthyosis patients, especially if combined with more detailed information about the aetiology and inheritance of the diseases.

Myringotomy plays an important role in otological therapy. The procedure requires an efficient anesthesia, which can be obtained without general anesthesia. However, the use of local anesthetics on the tympanic membrane (TM) has been abandoned in many places, as general anesthesia has been readily available. In the present study the effects of some commonly used topical anesthetics on the TM structure and inner ear were tested in an animal model (rat and guinea pig).Four different anesthetic compounds—Xylocaine®, Bonain's liquid, phenol and Emla®—were applied to the TMs of the animals, which were sacrificed 10 minutes to 5 months after application. Morphological effects regarding time after treatment and number of applications were elucidated. At sacrifice the tissue was fixed and the TMs analysed by light microscopy (LM) and transmission electron microscopy (TEM). In nine animals phenol, Xylocaine® Spray or Emla® was applied to the round window niche and ABR recordings were made at 24 h to 6 months after exposure. After the final ABR evaluation the animals were sacrificed and the cochleae prepared for LM and scanning electron microscopy (SEM).On the TM phenol and Bonain's liquid caused instant destruction of the keratinizing stratified squamous epithelium followed by long-lasting hyperplasia of this epithelium and the underlying connective tissue. A pronounced hyperplasia of these two layers was also noted for the Xylocaine® Spray group, but without immediate destruction of the keratinizing epithelium. The extent of structural changes differed in relation to the extent of spreading of the agent. Emla® showed little, if any, sign of epithelial reaction and had no effect on the connective tissue. Regarding the inner ear Emla®, Xylocaine® Spray and phenol induced significantly impaired ABR thresholds mainly affecting the higher frequencies. However, the impaired ABR thresholds were reversible and at the end of the experiment there was no significant impairment compared to the control data. All agents, except Xylocaine®, damaged the hair cells in the basal part of the cochlea as shown by cytocochleogram and SEM analysis.Instant destruction of the epidermis seems to be necessary for an instant anesthetic effect. All agents caused profound connective tissue reactions. The manner of application, depending on the physical properties of the agent, determined the extent of the structural changes. The changes of the connective tissue were concentrated to the submucosal layer, which seems to be the area for reconstruction of the damaged TM. All agents caused functional inner ear changes. With the exception of Xylocaine® they also caused morphological alterations of the cochlea. The functional changes were partly reversible. Topical anesthetics applied to the TM should be used with caution and when used in an appropriate manner they can be considered safe, especially in an inflamed middle ear, with a thickened round window membrane, which should prevent the agents from reaching the inner ear structures. / digitalisering@umu

Gene transfer represents an important advance in the treatment of both genetic and acquired diseases. Topical gene therapy involves administration of the genetic material onto the surface of skin and mucosal membranes. Cationic gemini surfactants (m-s-m, where m represents the carbon atoms in the alkyl tail and s represents the carbon atoms in the spacer) are a novel category of delivery agents with especially high potential for polynucleotides. This is due to their structural versatility, ability to bind and condense DNA, and relatively low toxicity. <p>The objectives were to design, construct and characterize a cationic, non-viral gemini surfactant-based delivery system for an IFN-ã coding plasmid suitable for cutaneous gene therapy and to evaluate this novel therapeutic approach in a Tsk (tight-skin scleroderma) mouse model to determine its clinical feasibility. <p>The delivery systems were characterized by microscopy, dynamic light scattering (DLS), circular dichroism (CD) and small angle X-ray scattering (SAXS). <i>In vitro</i> gene expression was evaluated in PAM 212 keratinocyte culture. The extent of topical delivery of the plasmid using nanoparticle and nanoemulsion formulations was evaluated by measuring IFN-ã levels in CD1, IFN-ã-deficient and Tsk mice. The effect of transgene expression on collagen synthesis was evaluated in Tsk animals by real-time PCR.<p>The <i>in vitro</i> plasmidgeminilipid (PGL) system showed heterogeneous particle size (100-200 nm small particles and 300-600 nm aggregates). Electrostatic interactions between the DNA and PGL systems shifted the negative æ-potential of the DNA (-47 mV) to positive values (30-50 mV). At the same time, condensation of the DNA, and formation of Ø DNA was indicated by the increase of the overall negative signal in the CD spectra, due to the flattening of the 290 nm peak and shift of the 260 nm peak into the negative region in a structure-dependent manner. Lipid organization of the DNADOPE system, in the absence of gemini surfactants, shows hexagonal structure, while addition of gemini surfactant at +/- charge ratio of 10 caused lamellar phase organization. For short spacers (n=3-6), additional Pn3m cubic phase also appear to be present. <p><i> In vitro</i> transfection efficiency in the 12-n-12 series was found to be dependent on the length of the spacer between the two positively charged head groups, with the n=3 spacer showing the highest activity. The PGL systems with 12-3-12 and 12-4-12 led to significantly higher transgene expression compared to the other surfactants of the series. The transfection efficiency significantly correlated with the surface area occupied by one molecule (a). The effect of the tail length influenced the transfection efficiency, with longer tails being associated with higher protein expression. The highest <i>in vitro</i> transfection efficiency was recorded with the 18:1-3-18:1 surfactant (1.4±0.3 ng/5x10E4 cells). <p><i>In vivo</i>, high levels of IFN-ã expression were detected in the skin of animals treated with both nanoparticle (359±239 pg/cm2) and nanoemulsion (607±411 pg/cm2) formulations compared to topical naked DNA (136±125 pg/cm2). IFN-ã levels in the skin of animals injected with 5 ìg DNA were 256±130 pg/cm2. IFN-ã levels in the lymph nodes were higher for the nanoparticle formulation (433±456 pg/animal) compared to nanoemulsion (131±136 pg/animal) suggesting different delivery pathway of the two formulations.<p>IFN-ã expression was at high levels in the skin of Tsk mice after 4-day and 20-day treatments (472±171 and 345±276 pg/cm2). Both 4-day and 20-day treatments reduced the procollagen type I á1 mRNA levels for the topical treatment (64 and 70% reduction) and intradermal injection (58 and 72% reduction). Intercellular adhesion molecule-1 (ICAM-1) was upregulated by 50% in both topically treated and injected animals after 20-day treatment. <p>Here, it has been demonstrated that cationic gemini surfactant-based delivery systems are able to transfect epidermal cells <i>in vivo</i>, and the transgene IFN-ã expression is sufficient to cause significant reduction of collagen in an animal model of scleroderma. It has been shown for the first time that topical gene therapy is a feasible approach for the modulation of excessive collagen synthesis in scleroderma-affected skin.

Gene transfer represents an important advance in the treatment of both genetic and acquired diseases. Topical gene therapy involves administration of the genetic material onto the surface of skin and mucosal membranes. Cationic gemini surfactants (m-s-m, where m represents the carbon atoms in the alkyl tail and s represents the carbon atoms in the spacer) are a novel category of delivery agents with especially high potential for polynucleotides. This is due to their structural versatility, ability to bind and condense DNA, and relatively low toxicity. <p>The objectives were to design, construct and characterize a cationic, non-viral gemini surfactant-based delivery system for an IFN-ã coding plasmid suitable for cutaneous gene therapy and to evaluate this novel therapeutic approach in a Tsk (tight-skin scleroderma) mouse model to determine its clinical feasibility. <p>The delivery systems were characterized by microscopy, dynamic light scattering (DLS), circular dichroism (CD) and small angle X-ray scattering (SAXS). <i>In vitro</i> gene expression was evaluated in PAM 212 keratinocyte culture. The extent of topical delivery of the plasmid using nanoparticle and nanoemulsion formulations was evaluated by measuring IFN-ã levels in CD1, IFN-ã-deficient and Tsk mice. The effect of transgene expression on collagen synthesis was evaluated in Tsk animals by real-time PCR.<p>The <i>in vitro</i> plasmidgeminilipid (PGL) system showed heterogeneous particle size (100-200 nm small particles and 300-600 nm aggregates). Electrostatic interactions between the DNA and PGL systems shifted the negative æ-potential of the DNA (-47 mV) to positive values (30-50 mV). At the same time, condensation of the DNA, and formation of Ø DNA was indicated by the increase of the overall negative signal in the CD spectra, due to the flattening of the 290 nm peak and shift of the 260 nm peak into the negative region in a structure-dependent manner. Lipid organization of the DNADOPE system, in the absence of gemini surfactants, shows hexagonal structure, while addition of gemini surfactant at +/- charge ratio of 10 caused lamellar phase organization. For short spacers (n=3-6), additional Pn3m cubic phase also appear to be present. <p><i> In vitro</i> transfection efficiency in the 12-n-12 series was found to be dependent on the length of the spacer between the two positively charged head groups, with the n=3 spacer showing the highest activity. The PGL systems with 12-3-12 and 12-4-12 led to significantly higher transgene expression compared to the other surfactants of the series. The transfection efficiency significantly correlated with the surface area occupied by one molecule (a). The effect of the tail length influenced the transfection efficiency, with longer tails being associated with higher protein expression. The highest <i>in vitro</i> transfection efficiency was recorded with the 18:1-3-18:1 surfactant (1.4±0.3 ng/5x10E4 cells). <p><i>In vivo</i>, high levels of IFN-ã expression were detected in the skin of animals treated with both nanoparticle (359±239 pg/cm2) and nanoemulsion (607±411 pg/cm2) formulations compared to topical naked DNA (136±125 pg/cm2). IFN-ã levels in the skin of animals injected with 5 ìg DNA were 256±130 pg/cm2. IFN-ã levels in the lymph nodes were higher for the nanoparticle formulation (433±456 pg/animal) compared to nanoemulsion (131±136 pg/animal) suggesting different delivery pathway of the two formulations.<p>IFN-ã expression was at high levels in the skin of Tsk mice after 4-day and 20-day treatments (472±171 and 345±276 pg/cm2). Both 4-day and 20-day treatments reduced the procollagen type I á1 mRNA levels for the topical treatment (64 and 70% reduction) and intradermal injection (58 and 72% reduction). Intercellular adhesion molecule-1 (ICAM-1) was upregulated by 50% in both topically treated and injected animals after 20-day treatment. <p>Here, it has been demonstrated that cationic gemini surfactant-based delivery systems are able to transfect epidermal cells <i>in vivo</i>, and the transgene IFN-ã expression is sufficient to cause significant reduction of collagen in an animal model of scleroderma. It has been shown for the first time that topical gene therapy is a feasible approach for the modulation of excessive collagen synthesis in scleroderma-affected skin.

The disciplines of informatics and information visualization have developed in response to societal needs to find new insight in complex datasets and have been enabled by technological advancements. Joint application of these fields can demonstrate themes and connections that are otherwise not apparent. Methodological approaches, such as direct network analysis, can be applied to policy documents to determine if action or policy recommendations match the goals or objectives stated in the within the same documents. Informatics and information visualization can also be used to analyze changes of themes found within the documents over time. This paper seeks to leverage informatics and information visualization methodologies as a novel approach to policy analysis. In particular, directed network and time burst techniques are used to analyze water management policy documents for the State of Texas. The congruency between the stated goals or objectives and recommendations sections is evaluated at a topical level within each planning document and possible changes in important water policy concepts over time are highlighted by comparing among multiple planning documents. Although there limitations to the process at the time of publication due to the newness of the software utilized, this paper demonstrates that the products still lead to unique and insightful conclusions. / text

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

On appelle suite récurrente stochastique (SRS) dirigée par une suite de matrices aléatoires une suite de variables aléatoires telles que le terme de rang n+1 est obtenu en multipliant celui de rang n par la enième matrice. Cette thèse porte sur le comportement asymptotique de telles suites. Dans la première partie, les matrices sont inversibles et on donne un critère de séparation des exposants de Lyapunov quand la suite de matrices suit une mesure de Gibbs sur un sous-shift de type fini. Dans la seconde partie, les produits se font au sens max-plus. On montre que le comportement des SRS au premier ordre est essentiellement déterminé par celui de certains blocs diagonaux et que la propriété de perte de mémoire, qui assure la stabilité des SRS, est générique. Si une suite de matrices (ou d'applications topicales) aléatoires est i.i.d. et a la propriété de perte de mémoire, alors les SRS qu'elle dirige vérifient des théorèmes limites. Ce résultat est obtenu par la méthode du trou spectral.

Pigmentation disorders occur in multiple conditions (Hakozaki et al., 2006:105). Although many modalities of treatments are available, none are completely satisfactory (Briganti et al., 2003:101). Two cytokines normally present in the skin, transforming growth factor–beta1 (TGF–81) and tumour necrosis factor–alpha (TNF–9), have been shown to inhibit melanin synthesis (Martinez–Esparza, 2001:972). The stratum corneum has been commonly accepted as the main barrier to percutaneous absorption. Many techniques have been applied to overcome this barrier properties and to enhance penetration with varying success (Pellet et al., 1997:92). The objective of this study was to investigate the topical delivery of the above mentioned peptide drugs with aid of the Pheroid drug delivery system. Pheroid technology is a delivery system that promotes the absorption and increases the efficacy of dermatological, biological and oral medicines in various pharmacological groups (Grobler et al., 2008:4). Pheroid entraps drugs with high efficiency and delivers them with remarkable speed to target sites (Grobler, 2004:4). In order to avoid degradation of these peptides, bestatin hydrochloride (an aminopeptidase inhibitor), was used (Lkhagvaa et al., 2008:386). Topical drug delivery was achieved by means of vertical Franz cell diffusion studies performed over a 6 and 12 h period. ELISA (enzyme linked immunosorbent assay) detection was used to detect cytokine concentrations. Entrapped cytokine solutions were monitored by confocal laser scanning microscopy (CLSM). Upon removal of donor and receptor compartments, skin discs were subjected to tape stripping in order to establish the amount of active present within the stratum corneum and epidermis as well as the remaining dermis (Pellet et al., 1997:92). When comparing the two studies with each other, it is evident that the diffused concentration values obtained with PBS (phosphate buffer solution, pH 7.4) was lower than that obtained with the Pheroid drug delivery system. Both cytokine concentrations were successfully delivered topically as a minimum of concentrations for both actives were detected. This positive result was confirmed as well by the amount of active detected in stratum corneum–epidermis and epidermis–dermis solutions. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

I Sverige beräknas 130 000 människor leva med en medelsvår till svår demenssjukdom. Demens är en övergripande diagnos för en samling sjukdomar där kognitiva nedsättningar är utmärkande och kommunikativa förmågor påverkade. I tidigare studier har det undersökts hur personer med demens kommunicerar med en samtalspartner utan demens, men hur personer med demens kommunicerar med varandra är fortfarande relativt outforskat. Syftet med föreliggande studie var att undersöka och beskriva hur personer med en demensdiagnos samtalar med varandra och hur de hanterar samtalsämnen och ämnesbyten. Studien genomfördes på en daglig verksamhet för personer med demensdiagnos, där totalt tre samtal spelades in. Ett av samtalen, omfattande 40 minuter, valdes ut för transkription och analyserades enligt samtalsanalytiska principer (CA). I det utvalda samtalet valdes sekvenser ut. Sekvenserna exemplifierade olika typer av ämnesbyten. För en utökad bild av samtalets ämnesflöde gjordes även en topikal analys, där samtalet delades in i totalt 14 olika episoder. I samtalet deltog sex personer med demensdiagnos samt föreliggande studies två författare. Exempel på ämnesbyten som påträffades i det analyserade samtalet var koherenta ämnesbyten i form av preannonseringar, koherent återinförande av ämne och ämnesglidningar. Icke-koherenta ämnesbyten förekom i samtalet i form av icke-koherent återinförande av ett ämne. Samtalet innehöll också exempel på digressioner och inskott. För en utomstående betraktare föreföll det ibland som om deltagarna saknade gemensam grund för samtalet, vilket till synes inte uppmärksammades av samtalsdeltagarna. En slutsats som dras utifrån detta är att för deltagarna är samtalsaktiviteten viktigare än själva innehållet i samtalet. I det aktuella samtalet återkom ofta samma historia och samtalsämne flera gånger. De olika samtalsämnena som uppstod under samtalet hade oftast ett övergripande tema som handlade om hur det var förr i tiden, när deltagarna var unga eller barn. / In Sweden, approximately 130 000 persons suffer from moderate to severe dementia. Dementia is a collective diagnosis for a collection of diseases in which cognitive impairments are distinctive, and communicative abilities are affected. Earlier studies have investigated how people with dementia communicate with an interlocutor without dementia. How people suffering from dementia communicate with each other is still relatively unexplored. The purpose of the present study is to investigate and describe how people suffering from dementia interact with each other, and how they handle topics and topic shifts. The present study was conducted on a day center for people with dementia diagnoses, where a total of three conversations were recorded. One of the conversations, comprising 40 minutes, was transcribed according to conversation analytic principles. From the selected conversation, sequences showing different types of topic changes were selected and exemplified. For an expanded view of the conversation’s topical flow, a topical analysis was made, where the conversation was divided into a total of 14 different episodes. The conversation involved six people with dementia and the two authors of the present study. Examples of topic shifts found in the analyzed conversation were coherent topic shifts in the form of pre-acts, coherent renewal of topic and topic shading. Non-coherent topic shifts occurred in the conversation in the form of non-coherent renewal of a topic. The conversation also contained examples of digressions and inserts. To the outside observer, it seemed at times as if the participants had no common ground for the conversation, which was not noticed by the participants of the conversation. One conclusion drawn from this is that for the participants, the activity is more important than the actual content of the conversation. In the current conversation, the participants returned to the same story and the same topic several times. The different topics occurring during the conversation usually had an overall theme which was what it was like in the old days, when the participants were young or children.