We present a system for data-driven therapy decision support based on techniques from the field of recommender systems. Two methods for therapy recommendation, namely, Collaborative Recommender and Demographic-based Recommender, are proposed. Both algorithms aim to predict the individual response to different therapy options using diverse patient data and recommend the therapy which is assumed to provide the best outcome for a specific patient and time, that is, consultation. The proposed methods are evaluated using a clinical database incorporating patients suffering from the autoimmune skin disease psoriasis. The Collaborative Recommender proves to generate both better outcome predictions and recommendation quality. However, due to sparsity in the data, this approach cannot provide recommendations for the entire database. In contrast, the Demographic-based Recommender performs worse on average but covers more consultations. Consequently, both methods profit from a combination into an overall recommender system.

We present a system for data-driven therapy decision support based on techniques from the field of recommender systems. Two methods for therapy recommendation, namely, Collaborative Recommender and Demographic-based Recommender, are proposed. Both algorithms aim to predict the individual response to different therapy options using diverse patient data and recommend the therapy which is assumed to provide the best outcome for a specific patient and time, that is, consultation. The proposed methods are evaluated using a clinical database incorporating patients suffering from the autoimmune skin disease psoriasis. The Collaborative Recommender proves to generate both better outcome predictions and recommendation quality. However, due to sparsity in the data, this approach cannot provide recommendations for the entire database. In contrast, the Demographic-based Recommender performs worse on average but covers more consultations. Consequently, both methods profit from a combination into an overall recommender system.

Background: Financial constraints challenge evidence of the effectiveness of dermatological inpatient management. Objective: To evaluate the effectiveness of hospitalization in atopic dermatitis and psoriasis regarding initial and sustained benefits. Methods: Prospective study on adults with psoriasis vulgaris (n = 22) and atopic dermatitis (n = 14). At admission, discharge, and 3 months after discharge, validated outcomes of objective and subjective disease severity were assessed by trained investigators. Results: Hospitalization resulted in substantial benefit in quality of life and clinical disease severity. Looking at mean scores, the observed benefit appeared stable until 3-month follow-up. The analysis of individual patient data revealed significant changes in disease severity between discharge and 3-month follow-up with some patients relapsing, others further improving. Reasons for hospitalization and treatment performed were not related to sustained benefit. Conclusions: In psoriasis vulgaris and atopic dermatitis, hospitalization effectively improved quality of life and clinical disease severity. Further research should focus on prognostic factors for sustained improvement. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Abstract Hidradenitis suppurativa (HS) is a chronic inflammatory disease of hair follicles, characterized by subcutaneous inflammatory nodules and abscesses, typically on the axillary, genitofemoral, and perianal skin. Symptoms of HS, such as foul-smelling discharge from the inflamed lesions, pain, and disease location in sensitive areas, markedly diminish patients’ quality of life. Smoking and obesity are associated with HS, which also has several common comorbidities. While there is a growing body of evidence of somatic comorbidities in HS, psychiatric comorbidities have received less attention. Furthermore, literature on comorbidities in young patients with HS is scarce, and no systematic evaluation of mortality in HS has yet been undertaken. This study aimed to clarify the associations between HS and mental disorders, to explore both somatic and psychiatric comorbidities of HS in children and adolescents, and to determine the life expectancy and cause-specific risks of death in patients with HS. The study population comprised over 4300 cases with HS diagnosed in Finnish hospitals between 1987 and 2014. Age- and sex-matched patients with psoriasis and melanocytic nevi served as controls. Patient data were obtained from the statutory Finnish Care Register for Health Care. Information on dates and causes of death of the cases and controls were acquired from Statistics Finland. This study showed a heavy psychiatric disease burden in patients with HS. The prevalence rates and risks of all studied psychiatric comorbidities were higher in the HS than in the control groups. This was also evident in children and adolescents with HS, not only in adults. Furthermore, younger patients also had elevated risks for many somatic disorders including inflammatory bowel and joint diseases. Remarkably, the mean age at death in the HS group was only 60.5 years. The most common causes for death in the order of likelihood were: cardiovascular diseases, neoplasms, ‘accidents, suicides or violence’ and alcohol-related diseases. Suicide risk was elevated in women with HS. HS patients should be cautiously monitored for possible somatic and psychiatric comorbidities. It is clear that these patients require effective, comprehensive and multidisciplinary care to improve their quality of life and prevent premature death. / Tiivistelmä Hidradenitis suppurativa (HS) on krooninen tulehduksellinen karvatuppien sairaus, joka heikentää elämänlaatua merkittävästi. Kivuliaat kyhmyt ja paiseet sekä vuotavat käytävät, jotka sijaitsevat useimmiten kainaloissa, nivusissa, genitaalialueella ja pakaravaossa, ovat sen tyypillisimpiä ilmenemismuotoja. HS-potilailla on moninaisia terveysongelmia, joita ovat mm. tupakointi, lihavuus ja suurentunut riski useisiin somaattisiin sairauksiin. Tutkimustieto HS-potilaiden psykiatrisista sairauksista on kuitenkin vähäistä eikä liitännäissairauksista lapsilla ole juuri lainkaan tietoa. Tämän lisäksi HS-potilaiden kuolemansyitä tai eliniänodotetta ei ole perusteellisesti selvitetty. Tällä tutkimuksella haluttiin määrittää psykiatristen sairauksien riski HS-potilailla ja selvittää sekä somaattisten että psykiatristen liitännäissairauksien todennäköisyyttä lapsuudessa ja nuoruudessa. Tarkoituksena oli myös tutkia, mihin sairauksiin HS-potilailla on suurentunut riski kuolla ja minkä ikäisinä he menehtyvät. Terveyden ja hyvinvoinnin laitoksen hoitoilmoitusjärjestelmästä etsittiin tiedot kaikista Suomen sairaaloissa vuosina 1987–2014 diagnosoiduista HS-tapauksisista (N=4381). Liitännäissairauksien tutkimista varten verrokeiksi valittiin psoriaasi- tai luomidiagnoosin saaneet henkilöt, jotka kaltaistettiin iän ja sukupuolen mukaan. Kuolintiedot menehtyneistä tutkimuspotilaista saatiin Tilastokeskukselta. HS-potilailla havaittiin selkeästi suurentunut psykiatristen sairauksien riski niin aikuisena kuin myös jo alle 18 vuoden iässä. Lisäksi monien somaattisten sairauksien, esim. tulehduksellisten suoli- ja nivelsairauksien, riski oli suurentunut lapsuudessa. HS-potilaiden todettiin menehtyvän huomattavan nuorella iällä, sillä heidän keskimääräinen elinikänsä oli vain 60,5 vuotta. Yleisimmät kuolinsyyt olivat sydän- ja verisuonitaudit, kasvaimet, ’onnettomuudet, itsemurhat ja väkivalta’ sekä alkoholiin liittyvät kuolemat. Itsemurhariski havaittiin suurentuneeksi naisilla. Tämän tutkimuksen perusteella HS-potilailla on runsaasti psykiatrisia liitännäissairauksia. Sekä somaattisten että psykiatristen sairauksien riski onkin pidettävä mielessä aina HS-potilaita hoidettaessa. Tehokas, kokonaisvaltainen ja moniammatillinen hoito on tärkeää potilaiden elämänlaadun parantamiseksi ja ennenaikaisen kuoleman ehkäisemiseksi.

Submitted by SBI Biblioteca Digital (sbi.bibliotecadigital@puc-campinas.edu.br) on 2017-04-12T13:26:24Z No. of bitstreams: 1 ALEXANDRA APARECIDA DOS REIS.pdf: 2254046 bytes, checksum: bf0291b84101fecae5af414bf1032ff7 (MD5) / Made available in DSpace on 2017-04-12T13:26:24Z (GMT). No. of bitstreams: 1 ALEXANDRA APARECIDA DOS REIS.pdf: 2254046 bytes, checksum: bf0291b84101fecae5af414bf1032ff7 (MD5) Previous issue date: 2017-02-21 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / INTRODUCTION: Psoriasis, chronic inflammatory skin disease, Characterized by pink or reddish lesions, covered by whitish and dry scales,Its plaque format is the most common type.In all forms of psoriasis, nail involvement may be present in about 50% of cases.Individuals with psoriasis have nail deformities and a tendency to develop psoriatic arthritis.Psoriatic arthritis inflammatory disease of the joints in a divergent way involves the spine and peripheral joints, can affect up to 30% of people with psoriasis between 5 to 12 years after their development as dactylitis, enthesitis and peripheral joints.This complicates the diagnosis because the involvement of the skin can affect before the joint involvement. There is an immunological development in the pathogenesis of this disease immunized by Th1 and Th17 cells.Recently there is evidence that plays a crucial role in the pathology of psoriatic arthritis.The prevalence of 06% to 42% of patients with psoriasis develop a joint disease. Some studies have been analyzing these items in detail, thus giving rise to methods for measuring quality of life, since to obtain a quality life it is necessary to evaluate the individual as a whole in psychological, social and physical aspects. The questionnaires are instruments, in which they collect information and characterize a composite research technique, in the objective form of questions presented in writing in the research, in application of the knowledge of the researcher.PASE-P: developed as a screening tool for PAs more effectively in individuals with Ps and validated by Husni, et al.2007. Its sensitivity is 76% and specificity is 82%. NAPSI instrument that evaluates each nail by dividing them into four quadrants, to be evaluated for the presence of any alteration coming from both the nail matrix and nail bed. PASI: An instrument developed in 1978 to quantify the severity of Ps in order to evaluate the body surface and was segmented into 04 regions of the head, trunk, lower limbs and upper limbs evaluated on a scale of 0 to 72.DLQI: Questionnaire aiming to obtain detailed data on the quality of life of patients with psoriasis.And it consists of 10 questions about symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment. CASPAR: Investigates the presence of joint manifestations, dermatological diseases or family history, typical nail changes, the existence of joint swelling and radiological changes. OBJECTIVES: To evaluate the presence of arthritis in male and female patients with Ps, aged between 18 and 80 years using a specific questionnaire to evaluate the severity of psoriasis, using PASE-P, NAPSI, PASI, DLQI AND CASPAR. And determine by means of laboratory variables the PCR and FR. OBJECTIVE: To compare and correlate the severity parameters of psoriasis PASE-P, NAPSI, PASI, DLQI and CASPAR in a screening with patients from the dermatology outpatient clinic to identify psoriatic arthritis, seeking correlations with literature content.METHOD: The study used a cross-sectional, longitudinal and prospective study, approved by the Research Ethics Committee (CEP) of the Celso Pierro Hospital and Maternity Hospital (HMCP) in Campinas-SP. RESULTS: During the study, 63 patients did not present withdrawal, 57.1% were men and 42.9% were women. We obtained a statistically significant correlation between PASE-B, which depicts the functionality and the CRP that characterizes the inflammatory activity.Patients with a PASE-P score greater than 44, defined as suspected APs, 15.9% of arthritis. Correlations for PASE-P greater than 44 obtained the following statistically significant correlations PASE-B with PASI r = 0.736, p = 0.037, DLQI with PCR r = 0.900, p = 0.037, PASE-B with PCR; R = 0.360, p-0.021, PASI with NAPSI ML, r = 0.353. There was a statistically significant correlation between PASE-B which depicts functionality and the CRP that characterizes inflammatory activity. DISCUSSION: The choice of PASE-P, NAPSI, DLQI, PASI and CASPAR instruments in psoriasis was to evaluate their applicability in clinical practice. PASE-P has proved to be relevant, since it is a simple and quick and practical resource, and so far there are few studies with the publication in the Portuguese language version. The questionnaire PASS a recent tool to evaluate psoriatic arthritis, developed by Husni, et al, 2007. CONCLUSION: PASE-P as a specific instrument has been shown to be effective in the detection of some PA patients in a group of patients with psoriasis, as seen in the literature. Each case should be individualized and treated according to the association of disease severity parameters. It can be emphasized, therefore, that the association of PASE, CASPAR, NAPSI and DLQI can be of great assistance in clinical practice for both evolutionary follow-up and therapeutic decision-making. Taking into account that according to what was shown in this study the PASE-P is a specific instrument and that in a dynamic and effective way when detecting PAs in patients. / INTRODU??O: Psor?ase doen?a inflamat?ria cr?nica da pele, caracterizada por les?es r?seas ou avermelhadas, recobertas por escamas esbranqui?adas e secas, seu formato em placas ? o tipo mais comum. Em todas as formas de psor?ase o envolvimento ungueal pode estar presente em cerca de 50% dos casos. Os indiv?duos com psor?ase apresentam deformidades nas unhas e tend?ncia a desenvolver artrite psori?sica. A artrite psori?sica doen?a inflamat?ria das articula??es de maneira divergente envolve a coluna vertebral e articula??es perif?ricas, pode afetar at? 30% das pessoas portadoras da psor?ase entre 5 a 12 anos ap?s seu desenvolvimento como dactilite,entesite e articula??es perif?ricas. O que dificulta o diagn?stico pois os envolvimento cut?neo pode acometer antes do comprometimento articular. Existem um desenvolvimento imunol?gico na patog?nese desta doen?a imunodiada por c?lulas Th1 e Th17. Recentemente h? evidencias que desempenham um papel crucial na patologia da artrite psori?sica. A preval?ncia de 06% a 42% dos pacientes com psor?ase desenvolvem uma doen?a articular. Alguns estudos vem analisando minuciosamente estes itens, surgindo assim m?todos para mensurar a qualidade de vida, pois para obter uma vida com qualidade ? necess?rio avaliar o indiv?duo como um todo em aspectos psicol?gicos, social e f?sico. Os question?rios s?o instrumentos, nos quais coletam informa??es e caracterizam uma t?cnica de investiga??o composta, na forma objetiva de quest?es apresentadas por escrito na pesquisa, em aplica??o do conhecimento do pesquisador. PASE-P: desenvolvidos como uma ferramenta de triagem para APs de forma mais eficaz em indiv?duos com Ps e validados por Husni, et al.2007.Sua sensibilidade e de 76% e especificidade de 82%. NAPSI instrumento que avalia cada unha dividindo as em quatro quadrantes, para ser avaliada quanto a presen?a de qualquer altera??o provenientes tanto da matriz da unha quanto leito ungueal. PASI: Instrumento desenvolvido em 1978, para quantificar a gravidade da Ps, com o objetivo de avaliar a superf?cie corporal e para isto foi segmentado em 04 regi?es cabe?a, tronco, membros inferiores e membros superiores, avaliado em uma escala de 0 a 72.DLQI: Question?rio com intuito em obter dados de forma detalhada sobre a qualidade de vida dos portadores da psor?ase. E composto por 10 quest?es sobre sintomas e sentimentos, atividades di?rias, lazer, trabalho e escola, rela??es pessoais e tratamento. CASPAR: Investiga a presen?a de manifesta??es articulares, doen?as dermatol?gicas ou hist?rico familiar, mudan?as ungueais de forma t?pica, exist?ncia de incha?o articular e altera??es radiol?gicas. OBJETIVOS: Avaliar a presen?a da artrite em pacientes do g?nero masculino e feminino com Ps, com idade entre 18 a 80 anos atrav?s de question?rio espec?fico para avalia??o da gravidade da psor?ase, atrav?s de instrumentos de avalia??o e classifica??o PASE-P, NAPSI, PASI, DLQI E CASPAR. E determinar por meio de vari?veis laboratoriais o PCR e FR. OBJETIVO ESPECIFICO: Comparar e correlacionar os par?metros de gravidade da psor?ase PASE-P, NAPSI, PASI, DLQI E CASPAR em uma triagem com pacientes do ambulat?rio de dermatologia afim de identificar a artrite psori?sica, buscando correla??es com conte?do da literatura. M?TODO: A pesquisa utilizou um estudo transversal, longitudinal e prospectivo, aprovado pelo Comit? de ?tica em Pesquisa (CEP) do Hospital e Maternidade Celso Pierro (HMCP) em Campinas-SP. RESULTADOS: Durante a pesquisa fizeram parte da popula??o 63 pacientes n?o havendo desist?ncia, sendo 57,1% eram homens e 42,9% eram mulheres. Obtivemos correla??o estatisticamente significativa entre o PASE-B, que retrata a funcionalidade e o PCR que caracteriza a atividade inflamat?ria. Pacientes com escore de PASE-P maior que 44, definiram se como suspeita de APs, 15,9% de artrite. Correla??es para o PASE-P maior que 44 obtivemos as seguintes correla??es estatisticamente significativas PASE-B com PASI r= 0,736, p=0,037, DLQI com PCR r=0,900, p=0,037, PASE-B com PCR; r=0,360, p- 0,021, PASI com NAPSI ML, r=0, 353.Houve correla??o estatisticamente significativa entre PASE-B que retrata funcionalidade e o PCR que caracteriza atividade inflamat?ria. DISCUSSAO: A escolha dos instrumentos PASE-P, NAPSI, DLQI, PASI E CASPAR, na psor?ase foram para avaliar suas aplicabilidades na pratica cl?nica. O PASE-P mostrou se relevante, pois e um recurso simples r?pido e pr?tico, e at? o momento h? poucos estudos com a publica??o na vers?o da l?ngua portuguesa. O question?rio PASE uma ferramenta recente em avaliar a artrite psori?sica, desenvolvido por Husni, et al,2007. CONCLUS?O: O PASE-P como instrumento especifico se mostrou eficaz na detec??o de alguns pacientes com APs em um grupo de pacientes com psor?ase, como visto na literatura. Cada caso deve ser individualizado e tratado de acordo com a associa??o dos par?metros de gravidade da doen?a. Pode-se ressaltar, portanto, que a associa??o do PASE, CASPAR, NAPSI e DLQI pode servir de grande aux?lio na pr?tica cl?nica tanto para o acompanhamento evolutivo, quanto para a tomada de decis?es terap?uticas. Levando em considera??o que de acordo com o que foi mostrado neste estudo o PASE-P ? um instrumento espec?fico e que de forma din?mica e eficaz ao detectar a APs em pacientes.

A psoríase é uma doença inflamatória crônica com uma elevada incidência, que afeta a pele. A patogênese da psoríase caracteriza-se pela participação de inúmeras células, incluindo os queratinócitos que são as principais células efetoras da citocina IL-17, críticas para a doença, que produzidas pelas células T. Evidências crescentes sugerem o importante papel da piruvato quinase M2 (PKM2) na regulação da resposta inflamatória, mas o mecanismo subjacente permanece obscuro. Nesse sentido, no presente estudo investigamos o papel da PKM2 no desenvolvimento da psoríase. Observamos o aumento de PKM2 em biópsia humana, em modelo de psoríase induzida por imiquimode e em modelos espontâneos K14-IL-17Aind e DC-IL-17Aind. Em adição, esse aumento observado na enzima foi predominante nos queratinócitos e isso foi associado a marcadores de ativação de queratinócitos. Utilizando o inibidor de PKM2, Shikonin (SKN), como abordagem farmacológica, observamos que o tratamento com esse composto foi capaz de reverter a psoríase experimental e a reduzir marcadores associados a doença como: K17, LCN2, TNF-?, KC, S100A8, S100A9, IL-6 e IL-17A. Associado a isso, observamos a redução na frequência de células T (?? e ??) produtoras de IL-17 e do número de neutrófilos na pele em modelo de imiquimode após inibição da PKM2. O SKN, também, reduziu o número de neutrófilos no modelo DC-IL-17Aind. Em nosso próximo passo, observamos que queratinócitos HACAT estimulados com IL-17A apresentou um aumento da expressão de PKM2 e que a sua inibição foi associada a redução da ativação de queratinócitos e de mediadores inflamatórios como a IL-8. Além disso, a deleção da PKM2, utilizando a tecnologia CRISPR/Cas9, reduziu a expressão do receptor de IL-17. Por fim, o desenvolvimento da psoríase por imiquimode foi atenuada em animais deficientes para PKM2 em queratinócitos (K14-PKM2fl/+), no qual foi observado a redução de neutrófilos na pele e, além disso, evidenciamos a redução da expressão de IL-17A nesses animais. O conjunto de resultados apresentados nesse trabalho demonstram que a PKM2 apresenta um papel crítico no desenvolvimento da psoríase e que a ativação do receptor de IL-17 promove um aumento da PKM2 em queratinócitos e esta contribui para ativação de mediadores que é responsável diretamente para o desenvolvimento da psoríase. Esses resultados, ainda, sugerem a PKM2 como um biomarcador para diagnóstico da psoríase e consequentemente, um potencial alvo terapêutico para tratamento dessa doença e outras doenças inflamatórias. / Psoriasis is a chronic inflammatory skin disease with high incidence in the global population. The pathogenesis of psoriasis is characterized by involvement of many cells, including keratinocytes that are targets for IL-17-producing T cells. Evidences suggests a critical role of pyruvate kinase M2 (PKM2) in inflammatory response, but the underlying mechanism remains unclear. In this context, here we investigated the role of PKM2 in the development of psoriasis. We observed overexpression of PKM2 in psoriatic human skin, imiquimod-induced psoriasis and spontaneous K14-IL-17Aind and DC-IL-17Aind models. In addition, the overexpression of this enzyme was observed in keratinocytes associated with keratinocytes activation markers. Using the PKM2 inhibitor, Shikonin (SKN), as a pharmacological approach, we observed that the treatment with this compound was able to reduce experimental psoriasis and disease-associated markers such as K17, LCN2, TNF-?, KC, S100A8, S100A9, IL-6 and IL-17A. Moreover, we observed reduction of frequency of IL-17-producing T cells (?? and ??) and the number of neutrophils in the skin after imiquimod application plus inhibition of PKM2. SKN, also, reduced the number of neutrophils in the DC-IL-17Aind model. In our next step, we observed overexpression of PKM2 in human keratinocytes HACAT stimulated with IL-17A and that its inhibition was associated with less keratinocytes activation and inflammatory mediators such as IL-8. In addition, deletion of PKM2, using CRISPR/Cas9 technology, reduced IL-17 receptor expression. Finally, the development of imiquimod-induced psoriasis was attenuated in PKM2-deficient mice in keratinocytes (K14-PKM2f/+), with reduction in the number of neutrophils in the skin. In addition, we evidenced the reduction of IL-17A expression these animals. Taken together, these results demonstrate that PKM2 plays a critical role in the development of psoriasis and that IL-17 receptor activation promotes an increase of PKM2 in keratinocytes and this contributes to the release of mediators that is directly responsible for development of psoriasis. These results, suggest PKM2 as a biomarker for the diagnosis of psoriasis and consequently a potential therapeutic target for the treatment of this disease and other inflammatory diseases.

<p>Mast cell (MC) accumulation around tumours is an old observation gaining new relevance due to the multifaceted nature of MCs and their many roles in immunity, beyond allergy. Knowledge about tumour specific recruitment of, and interactions with, MCs is needed to unravel the function of their presence.</p><p>This study investigates the participation of mast cells in the tumourigenesis of Hodgkin lymphoma (HL), a tumour with many inflammatory features. We report that MC recruitment into HL lymphomatous tissue is possibly due to the production of CCL5/RANTES by malignant Hodgkin and Reed-Sternberg (HRS) cells. In addition, increased levels of IL-9, a cytokine implicated in mast cell heterogeneity and as an autocrine growth factor for HRS cells, were found in HL patient sera and correlate with negative prognostic factors. The ubiquitous expression of CD30 by HRS cells has been implicated in HL tumour development. In HL tissue MCs were found to be the predominant CD30 ligand (CD30L) expressing cells, and through CD30L/CD30 engagement they induced a proliferative response in HRS cells. This interaction proved to be bi-directional as it induced a degranulation-independent <i>de novo</i> synthesis of a specific set of chemokines in MCs, including IL-8. This novel trigger of MC activation is suggested to be of importance also in atopic dermatitis (AD) and psoriasis since increased numbers of CD30L and IL-8 positive MCs were detected along with increased expression of CD30.</p><p>Data presented in this study supports a specific recruitment of MCs into HL tumours and co-operative interactions between HRS cells and MCs. Our identification of reversed signalling via CD30L as a novel MC trigger provides a mechanism behind leukocyte infiltration and chronic development in diseases associated with CD30 and MCs, such as HL, AD and psoriasis.</p>

<p>The human cytochrome P450 (CYP) family of monooxygenases is important for metabolism of drugs and endogenous compounds, e.g., vitamin A and D, cholesterol, steroids, fatty acids, and eicosanoids. This thesis describes the tissue distribution, catalytic properties, and possible function of CYP4F8 and CYP4F12. To this respect, methods for immunohistological analysis, and real-time PCR for analysis of their transcripts, were developed.</p><p>CYP4F8 was originally cloned from human seminal vesicles and proposed to catalyze 19-hydroxylation of prostaglandin H₂(PGH₂). This notion could now be supported, as cyclooxygenase-2, CYP4F8, and microsomal prostaglandin E synthase-1 were found to be co-localized in the epithelial linings of seminal vesicles. The three enzymes were also co-localized in the suprabasal layers of epidermis, suggesting a similar function of CYP4F8 in skin. Real-time PCR showed that CYP4F8 mRNA was more than 10-fold increased in psoriatic lesions compared to non-lesional skin. CYP4F8 immunoreactivity was also found in kidney cortex, transitional epithelium, corneal epithelium, and retina. Although transcripts of all three enzymes were detectable in retina, no co-localization was found. Pro inflammatory stimuli were found to increase CYP4F8 mRNA expression in cultured epidermal and corneal keratinocytes. In these tissues CYP4F8 might oxidize fatty acids or other eicosanoids than PGH₂.</p><p>CYP4F12 was originally cloned from the liver and small intestine, and found to oxidize arachidonic acid and two anti-histamines. Immunohistological studies showed that CYP4F12 immunoreactivity was present mainly in the gastrointestinal tract, e.g., stomach, ilium, and colon, but also in placenta. Although CYP4F8 and CYP4F12 have catalytic properties in common, there are important differences. CYP4F12 does not oxidize PGH₂, certain eicosanoids, and fatty acids. The prominent expression in the gut suggests that CYP4F12 might be involved in oxidation of drugs.</p>

Mast cell (MC) accumulation around tumours is an old observation gaining new relevance due to the multifaceted nature of MCs and their many roles in immunity, beyond allergy. Knowledge about tumour specific recruitment of, and interactions with, MCs is needed to unravel the function of their presence. This study investigates the participation of mast cells in the tumourigenesis of Hodgkin lymphoma (HL), a tumour with many inflammatory features. We report that MC recruitment into HL lymphomatous tissue is possibly due to the production of CCL5/RANTES by malignant Hodgkin and Reed-Sternberg (HRS) cells. In addition, increased levels of IL-9, a cytokine implicated in mast cell heterogeneity and as an autocrine growth factor for HRS cells, were found in HL patient sera and correlate with negative prognostic factors. The ubiquitous expression of CD30 by HRS cells has been implicated in HL tumour development. In HL tissue MCs were found to be the predominant CD30 ligand (CD30L) expressing cells, and through CD30L/CD30 engagement they induced a proliferative response in HRS cells. This interaction proved to be bi-directional as it induced a degranulation-independent de novo synthesis of a specific set of chemokines in MCs, including IL-8. This novel trigger of MC activation is suggested to be of importance also in atopic dermatitis (AD) and psoriasis since increased numbers of CD30L and IL-8 positive MCs were detected along with increased expression of CD30. Data presented in this study supports a specific recruitment of MCs into HL tumours and co-operative interactions between HRS cells and MCs. Our identification of reversed signalling via CD30L as a novel MC trigger provides a mechanism behind leukocyte infiltration and chronic development in diseases associated with CD30 and MCs, such as HL, AD and psoriasis.

The human cytochrome P450 (CYP) family of monooxygenases is important for metabolism of drugs and endogenous compounds, e.g., vitamin A and D, cholesterol, steroids, fatty acids, and eicosanoids. This thesis describes the tissue distribution, catalytic properties, and possible function of CYP4F8 and CYP4F12. To this respect, methods for immunohistological analysis, and real-time PCR for analysis of their transcripts, were developed. CYP4F8 was originally cloned from human seminal vesicles and proposed to catalyze 19-hydroxylation of prostaglandin H2 (PGH2). This notion could now be supported, as cyclooxygenase-2, CYP4F8, and microsomal prostaglandin E synthase-1 were found to be co-localized in the epithelial linings of seminal vesicles. The three enzymes were also co-localized in the suprabasal layers of epidermis, suggesting a similar function of CYP4F8 in skin. Real-time PCR showed that CYP4F8 mRNA was more than 10-fold increased in psoriatic lesions compared to non-lesional skin. CYP4F8 immunoreactivity was also found in kidney cortex, transitional epithelium, corneal epithelium, and retina. Although transcripts of all three enzymes were detectable in retina, no co-localization was found. Pro inflammatory stimuli were found to increase CYP4F8 mRNA expression in cultured epidermal and corneal keratinocytes. In these tissues CYP4F8 might oxidize fatty acids or other eicosanoids than PGH2. CYP4F12 was originally cloned from the liver and small intestine, and found to oxidize arachidonic acid and two anti-histamines. Immunohistological studies showed that CYP4F12 immunoreactivity was present mainly in the gastrointestinal tract, e.g., stomach, ilium, and colon, but also in placenta. Although CYP4F8 and CYP4F12 have catalytic properties in common, there are important differences. CYP4F12 does not oxidize PGH2, certain eicosanoids, and fatty acids. The prominent expression in the gut suggests that CYP4F12 might be involved in oxidation of drugs.