Abstract Neurofibromatosis type 1 syndrome (NF1) is caused by mutations of the NF1 gene. The NF1 protein (neurofibromin) contains a domain which is related to the GTPase-activating protein (GAP) and accelerates the switch of active Ras-GTP to inactive Ras-GDP. The NF1 protein has been referred to as a tumor suppressor, since the cells of malignant schwannomas of NF1 patients may display a loss of heterozygosity of the NF1 gene. Psoriasis is characterized by hyperproliferation of the epidermis and by down-regulated levels of NF1 mRNA and protein. Ca2+ is an universal signal transduction element modulating cell growth and differentiation. Many cell types coordinate their activities by transmitting waves of elevated intracellular calcium levels from cell to cell. The propagation of calcium waves had not been studied previously in human keratinocytes. Thus, the aim of the present study was to find out which pathways may play a role in Ca2+ signaling at different extracellular calcium concentrations in NF1 and and psoriatic keratinocytes versus normal control keratinocytes. The results demonstrated that NF1 and psoriatic keratinocytes have a tendency to form cultures characterized by altered Ca2+-mediated cell signaling compared to normal keratinocytes. Specifically, the main route of calcium-mediated signaling was gap-junctional in normal keratinocytes. In contrast, ATP-mediated calcium signaling predominated and capacitative calcium influx was defective in NF1 and psoriatic keratinocytes. The results of the present study suggest that mutations of the NF1 tumor suppressor gene or lowered levels of NF1 protein/mRNA may eventually lead to altered intercellular communication.

Abstract Neurofibromatosis type 1 (NF1) is a dominantly inherited neurocutaneous disorder caused by mutations in the NF1 gene. Common clinical manifestations associated with NF1 are neurofibromas, café-au-lait macules (CALM), axillary freckling and Lisch nodules of the iris. Other important manifestations are vasculopathy, a variety of osseous lesions, including short stature, scoliosis and pseudoarthrosis, optic gliomas and an increased risk for certain malignancies. The best characterized function of the NF1 gene is to act as a downregulator of Ras proto-oncogene signalling by accelerating the switch of active Ras-GTP into inactive Ras-GDP. The NF1 gene is considered a tumor suppressor since some malignancies may display a loss of heterozygosity or homozygotic inactivation of the gene. The present study investigated the behaviour and function of the NF1 gene during keratinocyte differentiation, wound healing and psoriasis using human epidermis and epidermal keratinocytes as a model. The NF1 protein was shown to associate with the intermediate filament network during keratinocyte differentiation both in vitro and in vivo, and it is thus suggested to play a role in the cytoskeletal re-organization or in the formation of cell adhesions. NF1 gene expression was also studied in psoriasis, in which keratinocytes are hyperproliferative and cell differentiation is altered. NF1 gene expression was downregulated in psoriatic keratinocytes both in vivo and in vitro, suggesting that the NF1 gene might have role in downregulating keratinocyte proliferation. During epidermal wound healing, NF1 gene expression was increased. However, the process of wound healing showed no apparent differences between NF1 patients and controls. Furthermore, an increased number of cells immunoreactive for active Ras-MAPK was demonstrated in vascular tissues of NF1 patients, but not in epidermal keratinocytes or dermal fibroblasts. The finding suggests that the NF1 protein functions as a Ras-GAP in some, but not all tissues.

Bakgrund: Psoriasis är en kronisk och smärtsam folksjukdom som kan leda till lidande för den drabbade. Uppskattningsvis 2 % -10 % lever med hudsjukdomen i världen. Individuellt anpassad behandling och omvårdnad kan ge förutsättningar till en god livskvalitet och självkänsla. Syfte: Syftet med denna litteraturöversikt var att belysa psoriasis påverkan på livskvaliteten samt de drabbade personernas hantering av sjukdomen. Metod: En litteraturöversikt användes där kvantitativa och kvalitativa studier redovisades. Resultat: Resultatet visade att psoriasis både påverkade den psykiska, sociala samt den fysiska hälsan. För att hantera sjukdomen visade det sig vara viktigt med tillräcklig kunskap samt att utveckla individuella hanteringsstrategier. Diskussion: Många individer med psoriasis uppfattade sig som märkta av sjukdomen vilket påverkade livet i stor utsträckning. Reflektion över utseende och andras åsikter kan leda till en psykisk belastning samt känsla av stigmatisering. Detta kan ses som en förklaring till att depression förekommer hos en stor del av personer med psoriasis. Slutsats: För att sjuksköterskan ska kunna ge en god omvårdnad samt utbilda och stödja personer med psoriasis behövs en djupare kunskap om hur det individuella stödet kring den psykiska, sociala och fysiska hälsan ska utformas. / <p>Godkännande datum: 2016-11-01</p>

Psoriasis is a chronic skin condition that can impair physical, psychological and social functioning. A sub-population of people living with psoriasis believe that psychological stress exacerbates their physical symptoms. Stress may exacerbate psoriasis via a psychoneuroimmunological pathway. The cortisol awakening response can be used to indicate whether this pathway is functional or dysfunctional. People with psoriasis have an elevated risk of emotional distress (anxiety and depression) and an impaired quality of life. Mindfulness based cognitive therapy has been effective in reducing stress, emotional distress, quality of life impairment as well as improving physical health. The aim of this thesis is to examine the efficacy and acceptability of mindfulness-based intervention for people living with psoriasis and whether the cortisol awakening response mediates the relationship between perceived stress and physical severity of psoriasis. This thesis adopted a mixed-methods design. A pilot, randomised control trial examined the effects of mindfulness based cognitive therapy upon the physical severity, perceived stress, emotional distress, quality of life and cortisol awakening response of people living with psoriasis. These variables were entered into a correlation analysis to examine whether the cortisol awakening response was associated with any of the reported study outcomes (physical severity, perceived stress, emotional distress and quality of life). Completers of the mindfulness intervention were invited to a semi-structured interview to explore the characteristics of the participants who adhered to the intervention and their experiences of participating. The mindfulness intervention significantly improved physical (z=1.96, p=0.05) and quality of life (z=2.30, p=0.02) measurements without changing perceived stress (z=0.07, p=0.94), emotional distress (z=1.60, p=0.12) or cortisol awakening responses (z=-0.33, p=0.74). The overall cortisol awakening response was not associated with physical severity (r=-0.30, p=0.07) or perceived stress (r=-0.20, p=0.25) but was significantly correlated with emotional distress (r=-0.35, p=0.04). The intervention was perceived as an acceptable adjunct treatment option. Participants reported some process barriers that inhibited their learning of mindfulness skills. A profile emerged that described a sub-population of people with psoriasis. This sub-population may be more likely to accept and adhere to mindfulness based cognitive therapy.This thesis provides preliminary support to the concept that increasing mindfulness skill can reduce the physical severity and quality of life impairment in people with psoriasis. It recommends that a fully powered trial be conducted to examine the effectiveness of mindfulness in improving physical and overall functioning for people with psoriasis. This thesis suggests clinicians screen their patients and offer a psychological intervention best suited to their needs and characteristics.

Psoriasis is a chronic, clinically heterogeneous, skin condition that affects approximately 2% of the general population. In 1985, Henseler and Christophers, classified psoriasis into early onset (EOP; age at onset ≤40 years-y) and late onset disease (LOP; age at onset >40 y). Previous research suggests that there are genetic and immunological differences between EOP and LOP. In particular, the major genetic determinant for psoriasis, the human leukocyte antigen (HLA)-Cw6 allele, occurs more frequently in EOP (55-80%) compared to LOP (15-20%) patients. Epidermal Langerhans’ cells (LC) migration is also different in these 2 subtypes of psoriasis. The primary aim of this thesis was to further explore the clinical, histological and immunohistochemical (IHC) differences between EOP and LOP. We compared clinical characteristics in a total of 497 subjects, including 340 psoriasis patients (108 recruited prospectively; 76 EOP and 32 LOP, mean age of onset 20.3±9.9 and 55.6±7y respectively, and 232 retrospectively; 202 EOP and 30 LOP, mean age of onset 20.7±9.9 and 55.2±7.2y respectively) and 157 controls (mean age 66±11.2y). Information on demographics, family history of psoriasis, clinical features, treatment and co-morbidities were recorded. Patients were also assessed for health-related quality of life and psychological distress. A total of 31 psoriasis patients, ≥ 50y of age, participated in the histological and IHC evaluation; 17 EOP and 14 LOP, mean age of onset 21.1±8.5 and 55.4±7.7y respectively. Skin biopsies were taken from involved (PP) and uninvolved (PN) skin and stained with haematoxylin and eosin (H&E) and IHC antibodies against various T-cell (CD3, CD4, and CD8) and LC (CD1α) markers. The H&E parameters (morphological and inflammatory) were graded with the use of a study specific histological score, whilst IHC positive epidermal cells were counted per microscopic field at 200X magnification. The dermal IHC infiltrate was assessed with a semi-quantitative (0-3) scale. Gender, body mass index, disease duration and severity, diagnosed hypertension and dyslipidemia were treated as covariates. The clinical data showed that LOP patients had a lower likelihood of having a positive family history of psoriasis (62% of EOP versus 35.6% of LOP patients; chi square-x2, P=0.001). In addition, patients with EOP parent(s) were 91% less likely to develop LOP than EOP (odds ratio-OR=0.093, P=0.025, 95% confidence interval-CI 0.012-0.74). Moreover, compared to LOP, EOP patients had a more severe disease (x2, P=0.021), usually requiring 3rd line treatments (x2; P=0.010). They also experienced frequent flares, following upper respiratory tract infections (x2, P=0.049). When data were segregated by age (≥50years) and after accounting for covariates, we observed that, compared to the non-psoriasis population, LOP patients were approximately 3 times more likely to develop type 2 Diabetes Mellitus (OR=2.56, P=0.05, 95% CI 1.01-6.54), whilst, EOP subjects were 98% less likely to develop autoimmune thyroiditis (OR=0.025, P=0.02, 95% CI 0.001-0.55). Psychologically, LOP patients were found to be a clinically more anxious group compared to EOP (t-test, P=0.006). Microscopically, the results from the H&E study showed an increased total inflammatory infiltrate in LOP, PP sections compared to EOP, PP ones (t-test, P=0.028). With IHC stains, we observed that in the epidermis of LOP PP, there was a significantly higher count of CD4+ cells; mean CD4+ in LOP of 15.1 ± 6.2 versus 6.7±4.6 in EOP (Analysis of variance-ANOVA, P<0.001). This subsequently led to a higher epidermal CD4+/CD8+ ratio of 1.3 in the LOP versus 0.5 for the EOP sections (ANOVA, P=0.002). In the PP dermis, CD4+ were also more abundant in the LOP tissue (x2, P=0.049). To assess whether these CD4+ cells were either T-lymphocytes or LC, we examined for differences in the CD3+ and CD1α+ cells. The mean epidermal CD3+ tended to be higher in LOP PP sections; mean epidermal CD3+ in the LOP 42.8 ± 13.3 versus 31.7 ± 17.5 in the EOP group (ANOVA, P= 0.061), while the dermal infiltrate showed a similar pattern (x2,P=0.067). Finally, there was no difference in epidermal and dermal CD1α+ and CD8+ cells in PP between EOP and LOP sections. These data indicate differences in clinical phenotype, heritability, comorbidities and immunopathomechanism between EOP and LOP. Taken together they provide further evidence that EOP and LOP may be different diseases.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22000号 / 医博第4514号 / 新制||医||1038(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 竹内 理, 教授 杉田 昌彦 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(生命科学) / 甲第23335号 / 生博第453号 / 新制||生||60(附属図書館) / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 野田 岳志, 教授 杉田 昌彦, 教授 千坂 修 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

The aim of this diploma thesis is to study and design experimental improvement of the convolutional neural network for disease detection. Another goal is to extend the classifier with a new type of detection. he new type of detection is damage fingerprint by pressure. The experimentally improved convolutional network is implemented by PyTorch. The network detects which part of the fingerprint is damaged and draws this part into the fingerprint. Synthetic fingerprints are used when training the net. Real fingerprints are added to the synthetic fingerprints.

Introduktion: Psoriasis är en kronisk inflammatorisk systemsjukdom som drabbar främst hud och leder.  På grund av mycket snabbt tillväxt av hudceller ger psoriasis utslag på huden.  En av de vanligaste typerna av psoriasis är plack-psoriasis som kännetecknas av större än 0,5 cm i diameter runda fjällande hudutslag som kliar. Mekanismen som ligger bakom plack-psoriasis medieras med hjälp av T-celler och dendritiska celler som är en viktig del av immunsystemet. Stimulering av dessa immunceller leder till frisättning av följande proinflammatoriska cytokiner såsom IL-17, IFN-γ, TNF samt IL-22. Dessa cytokiner utövar sin effekt på keratinocyter genom att öka psoriatisk inflammation. Flera biologiska läkemedel utvecklas nu för behandling av plack-psoriasis. I detta arbete har fokus lagts på två av dem, sekukinumab som är en IL-17A hämmare och ustekinumab, som är en IL-12 och IL-23 hämmare. Syfte: Syftet med arbetet är att undersöka effektivitet av sekukinumab vid behandling av plack-psoriasis. Vidare undersöks även hur behandling av plack-psoriasis med sekukinumab skiljer sig från behandling med ustekinumab gällande minskning av plack-psoriasis. Metod: Detta arbete är en litteraturstudie som inkluderar fem vetenskapliga artiklar som baserades på randomiserade kontrollerade studier som sponsrades av läkemedelsföretag.  Resultat: Resultatet av de fem studier visar att behandling med hjälp av sekukinumab 300 mg och 150 mg var mer effektiv än behandling med ustekinumab 45/90 mg, enligt PASI 75, PASI 90 och PASI 100. Diskussion: Alla fem studierna var dubbel-blinda randomiserade kontrollerade studier vilket leder till säkra och tillförlitliga resultat. Däremot var samtliga studier sponsrade av läkemedelsföretag vilket kan leda till att positiv effekt beskrivs i större utsträckning för att kunna sälja sin produkt.  Slutsats: Sekukinumab 300 mg och 150 mg är signifikant mer effektiv än placebo och signifikant mer effektiv än ustekinumab 45/90 mg vid behandling av medelsvår och svår plack-psoriasis. / Introduction: Psoriasis is a chronic inflammatory systemic disease that mainly affects the skin and joints. Due to the very rapid growth of skin cells, psoriasis causes rashes on the skin. One of the most common types of psoriasis is plaque psoriasis which is characterized by larger than 0.5 cm in diameter round scaly skin rash that itches. The mechanism behind plaque psoriasis is mediated by T cells and dendritic cells, which are an important part of the immune system. Stimulation of these immune cells leads to the release of the following proinflammatory cytokines such as IL-17, IFN-γ, TNF and IL-22. These cytokines exert their effect on keratinocytes by increasing psoriatic inflammation.  Several biological drugs are now being developed for the treatment of plaque psoriasis. In this study, the focus has been on two of them, secukinumab which is an IL-17A inhibitor and ustekinumab, which is an IL-12 and IL-23 inhibitor. Purpose: The purpose of this study is to investigate the efficacy of secukinumab in the treatment of plaque psoriasis. Furthermore, it is also investigated if the treatment of plaque psoriasis with secukinumab differs from treatment with ustekinumab regarding reduction of plaque psoriasis. Method: This work is a literature study that includes five scientific articles based on randomized controlled trials sponsored by pharmaceutical companies.  Results: The results of the five studies show that treatment with secukinumab 300 mg and 150 mg was more effective than treatment with ustekinumab 45/90 mg, according to PASI 75, PASI 90 and PASI 100. Discussion: All five studies were double-blind randomized controlled trials leading to safe and reliable results. On the other hand, all studies were sponsored by pharmaceutical companies, which may lead to a positive effect being described to a greater extent in order to be able to sell their product. Conclusion: Secukinumab 300 mg and 150 mg are significantly more effective than placebo and significantly more effective than ustekinumab 45/90 mg in the treatment of moderate to severe plaque psoriasis.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12957号 / 論医博第2099号 / 新制||医||1011(附属図書館) / 32356 / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 岩井 一宏, 教授 椛島 健治 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM