Takrolimuusivoide atooppisen ihottuman hoidossa : pitkäaikaishoidon vaikutukset ihoon ja hengitystieoireisiin

Objective: Patients with atopic dermatitis often have a poor long-term response to conventional topical or systemic treatments. Staphylococcal superinfections, skin atrophy due to corticosteroid use, and asthma and allergic rhinitis are common. Only a few, usually short-term, studies have addressed the effects of different treatments on these problems. Tacrolimus ointment is the first topical compound suitable for long-term treatment. The aim of this thesis was to evaluate the effects of long-term topical tacrolimus treatment on cutaneous staphylococcal colonization, collagen synthesis, and symptoms and signs of asthma and allergic rhinitis. Methods: Patients with moderate-to-severe atopic dermatitis were treated with intermittent 0.1% tacrolimus ointment in prospective, open studies lasting for 6 to 48 months. In Study I, cutaneous staphylococcal colonization was followed for 6 to 12 months. In Study II, skin thickness and collagen synthesis were followed by skin ultrasound and procollagen I and III propeptide concentrations of suction blister fluid samples for 12 to 24 months and compared with a group of corticosteroid-treated atopic dermatitis patients and with a group of healthy subjects. Study III was a cross-sectional study of the occurrence of respiratory symptoms, bronchial hyper-responsiveness, and sputum eosinophilia in atopic dermatitis patients and healthy controls. In Study V, the same parameters as in Study III were assessed in atopic dermatitis patients before and after 12 to 48 months of topical tacrolimus treatment. Study IV was a retrospective follow-up of the effect of tacrolimus 0.03% ointment on severe atopic blepharoconjunctivitis and conjunctival cytology. Results: The clinical response to topical tacrolimus was very good in all studies (p≤0.008). Staphylococcal colonization decreased significantly, and the effect was sustained throughout the study (p=0.01). Skin thickness (p<0.001) and markers of collagen synthesis (p<0.001) increased in the tacrolimus-treated patients significantly, whereas they decreased or remained unchanged in the corticosteroid-treated controls. Symptoms of asthma and allergic rhinitis (p<0.0001), bronchial hyper-responsiveness (p<0.0001), and sputum eosinophilia (p<0.0001) were significantly more common in patients with atopic dermatitis than in healthy controls, especially in subjects with positive skin prick tests or elevated serum immunoglobulin E. During topical tacrolimus treatment the asthma and rhinitis (p=0.005 and p=0.002) symptoms and bronchial hyper-responsiveness (p=0.02) decreased significantly, and serum immunoglobulin E and sputum eosinophils showed a decreasing trend in patients with the best treatment response. Treatment of atopic blepharoconjunctivitis resulted in a marked clinical response and a significant decrease in eosinophils, lymphocytes, and neutrophils in the conjunctival cytology samples. No significant adverse effects or increase in skin infections occurred in any study. Conclusions: The studies included in this thesis, except the study showing an increase in skin collagen synthesis in tacrolimus-treated patients, were uncontrolled, warranting certain reservations. The results suggest, however, that tacrolimus ointment has several beneficial effects in the long-term intermittent treatment of atopic dermatitis. Tacrolimus ointment efficiently suppresses the T cell-induced inflammation of atopic dermatitis. It has a normalizing effect on the function of the skin measured by the decrease in staphylococcal colonization. It does not cause skin atrophy as do corticosteroids but restores the skin collagen synthesis in patients who have used corticosteroids. Tacrolimus ointment has no marked systemic effect, as the absorption of the drug is minimal and decreases along with skin improvement. The effects on the airway: decrease in bronchial hyper-responsiveness and respiratory symptoms, can be speculated to be caused by the decrease in T cell trafficking from the skin to the respiratory tissues as the skin inflammation resolves, as well as inhibition of epicutaneous invasion of various antigens causing systemic sensitization when the skin barrier is disrupted as in atopic dermatitis. Patients with moderate-to-severe atopic dermatitis seem to benefit from efficient long-term treatment with topical tacrolimus.Taustaa: Atooppinen ihottuma on yleinen, pitkäaikainen ihosairaus, joka alkaa usein varhaislapsuudessa ja voi jatkua läpi aikuisiän. Sen hoito on perustunut 1950-luvulta alkaen kortisonivoiteisiin. Kortisonivoiteet on tarkoitettu kuitenkin kuuriluontoiseen, lyhytaikaiseen käyttöön, koska ne vähentävät ihon kollageenimuodostusta ja siten ohentavat ihoa, ja niiden teho vähenee pitkäaikaiskäytössä. Etenkin vaikeaa-keskivaikeaa ihottumaa sairastavat potilaat joutuvat kuitenkin käyttämään niitä paljon ja ovat alttiita sivuvaikutuksille. He jäävät usein alihoidetuiksi. Atooppinen iho on lähes aina kolonisoitunut stafylokokkibakteereilla, jotka tulehduttavat herkästi ihon. Ihoatoopikot kärsivät usein muista atooppisista sairauksista kuten astmasta ja allergisesta nuhasta. Tämän arvellaan johtuvan siitä, että allerginen herkistyminen tapahtuu alun perin ihottumaisen ihon kautta, jonka suojamekanismi on heikentynyt. Pitkäaikaistutkimuksia atooppisen ihottuman hoidosta on vähän. Takrolimuusivoide on ensimmäinen paikallishoitolääke, joka sopii atooppisen ihottuman pitkäaikaishoitoon. Väitöskirjatyössä selvitettiin pitkäaikaisen takrolimuusivoidehoidon vaikutusta atooppista ihottumaa sairastavien potilaiden ihon stafylokokkikolonisaatioon, kollageenisynteesiin, ohuiden ihoalueiden, kuten silmäluomien, hoitoon, sekä astman ja allergisen nuhan oireisiin ja löydöksiin. Menetelmät: Keskivaikeaa-vaikeaa atooppista ihottumaa sairastavia potilaita hoidettiin 6-48 kk ajan jaksottaisesti tarpeen mukaan takrolimuusivoiteella yksittäishoitona. Ihon stafylokokkikolonisaatiota seurattiin bakteeriviljelyin 6 -12 kk ajan hoidon alusta. Ihon kollageenisynteesiä seurattiin ihon imurakkulanesteen kollageeniesiasteiden pitoisuuksista 12-24 kk ajan hoidon alusta ja sitä verrattiin kortisonivoiteilla hoidettuihin potilaisiin ja terveisiin verrokkeihin. Takrolimuusihoidon tehoa ja vaikutusta silmän sidekalvon tulehdussolujen määriin selvitettiin vaikeaa atooppista silmäluomi-ihottumaa sairastavilla potilailla. Astman ja allergisen nuhan oireita, keuhkoputkien supistumisherkkyyttä ja yskösten eosinofiilisten tulehdussolujen määrää verrattiin atooppista ihottumaa sairastavilla potilailla ja terveillä verrokeilla. Näitä tutkittiin atoopikoilla myös 12-48 kk kestäneen takrolimuusivoidehoidon jälkeen. Tulokset: Takrolimuusivoide oli erittäin tehokas ihottuman hoito kaikissa tutkimuksissa. Merkittäviä tai vaikeita sivuvaikutuksia ei esiintynyt voiteelle tyypillistä alkuvaiheen kuumotusvaikutusta lukuunottamatta. Ihon stafylokokkibakteerien määrä väheni selvästi ja pysyvästi hoidon aikana. Ihon kollageenisynteesi oli atoopikoilla ennen hoitoa matalammalla tasolla kuin terveillä. Takrolimuusivoiteella hoidetuilla potilailla se lisääntyi selvästi ja väheni hieman kortisonivoiteella hoidetuilla potilailla 12 kk aikana. Kun takrolimuusihoitoa jatkettiin 24 kk:een asti, kollageenisynteesi palautui terveiden verrokkien tasolle. Takrolimuusivoiteella oli hyvä vaste myös silmäluomi-ihottuman hoidossa ja se vähensi sidekalvon tulehdussolujen määriä merkittävästi. Astmaa ja allergista nuhaa ja niiden oireita, keuhkoputkien supistumisherkkyyttä ja yskösten eosinofiilisiä tulehdussoluja esiintyi merkittävästi enemmän atooppista ihottumaa sairastavilla potilailla kuin terveillä. Myös ihottumapotilailla, joilla ei ollut astmadiagnoosia, näitä oli enemmän kuin terveillä. Pitkäaikaisen takrolimuusivoidehoidon aikana astman ja allergisen nuhan oireet ja keuhkoputkien supistumisherkkyys vähentyi selvästi. Yskösten eosinofiiliset tulehdussolut vähenivät vain parhaimman pitkäaikaisen ihottuman hoitovasteen saavuttaneilla potilailla. Johtopäätökset: Takrolimuusivoiteella näyttää olevan useita suotuisia vaikutuksia atooppisen ihottuman pitkäaikaishoidossa, vaikka osa tuloksista oli saatu tutkimuksista, joissa ei ollut vertailuryhmää. Takrolimuusivoide vähentää tehokkaasti atooppiseen ihottumaan liittyvää tulehdusta. Ihon stafylokokkikolonisaation väheneminen tukee käsitystä että se normalisoi ihon toimintaa ja suojamekanismeja. Se ei ohenna ihoa vaan palauttaa ihon kollageenisynteesin normaaliksi potilailla, joilla se on alentunut aiemman kortisonihoidon takia, ja sopii myös ohuille ihoalueille. Takrolimuusi ei käytännössä imeydy iholta verenkiertoon, joten vaikutusten katsotaan tulevan ihon kautta. Hengitysteiden atooppisten ilmentymien lieveneminen hoidon aikana johtuu todennäköisesti siitä, että tervehtyneeltä iholta ei enää kulkeudu tulehdussoluja imusolmukkeiden kautta hengitysteihin ja toisaalta siitä, että allergeenit eivät enää pääse aiheuttamaan allergista herkistymistä ihon kautta. Hoidosta hyötyvät erityisesti keskivaikeaa-vaikeaa ihottumaa sairastavat potilaat, joilla hyvän pitkäaikaishoitovasteen saavuttaminen kortisonivoiteilla on ollut vaikeaa

Self-regulation in higher education: Students’ motivational, regulational and learning strategies, and their relationships to study success

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Active Learning and Self-Regulation Enhance Student Teachers’ Professional Competences

The study identifies the relationships between active learning, student teachers’ self-regulated learning and professional competences. Further, the aim is to investigate how active learning promotes professional competences of student teachers with different self-regulation profiles. Responses from 422 student teachers to an electronic survey were analysed using statistical methods. It was found that the use of active learning methods, such as goal-oriented and intentional learning as well as autonomous and responsible group work, are strongly and positively related to the achievement of professional competences. To develop the best competences, student teachers need high learning motivation and excellent self-regulation strategies. The mean scores in professional competences of highly motivated student teachers with excellent self-regulated learning were significantly higher when their experiences of active learning increased. Moreover, student teachers with high motivation and moderate self-regulation also benefited significantly from the use of active learning methods.Peer reviewe

Active Learning and Self-Regulation Enhance Student Teachers’ Professional Competences

The study identifies the relationships between active learning, student teachers’ self-regulated learning and professional competences. Further, the aim is to investigate how active learning promotes professional competences of student teachers with different self-regulation profiles. Responses from 422 student teachers to an electronic survey were analysed using statistical methods. It was found that the use of active learning methods, such as goal-oriented and intentional learning as well as autonomous and responsible group work, are strongly and positively related to the achievement of professional competences. To develop the best competences, student teachers need high learning motivation and excellent self-regulation strategies. The mean scores in professional competences of highly motivated student teachers with excellent self-regulated learning were significantly higher when their experiences of active learning increased. Moreover, student teachers with high motivation and moderate self-regulation also benefited significantly from the use of active learning methods

Direct evidence that maltose transport activity Is affected by the lipid composition of brewer’s yeast

A brewer’s yeast strain was grown with maltose as sole carbon source under strictly anaerobic conditions with and without ergosterol and /or unsaturated fatty acid (Tween 80) supplements. Under all these conditions the MALx1 genes for maltose transporters were strongly expressed during growth. The fatty acid unsaturation indices of growing and stationary phase yeast were increased from about 20% to 56–69% by supplementation with Tween 80. Ergosterol contents were increased up to at least 4- fold by supplementation with ergosterol and Tween 80. Maltose transport activity measured at 20°C was not increased by supplementation with Tween 80 alone, but was increased 2-fold and 3-fold, respectively, in growing and stationary phase yeast by supplementation with ergosterol together with Tween 80. The stimulation of maltose transport by ergosterol was greater when the transport was measured at temperatures (10°C and 0°C) lower than 20°C. The results show that proper function of maltose transporters requires adequate amounts of ergosterol in the yeast. This effect may partly explain the low maltose (and maltotriose) uptake rates both in the second half of brewery fermentations, when the sterol content of yeast has fallen, and when fresh wort is pitched with sterol-deficient cropped yeast.Finnish brewing and malting industry (PBL) ; Leonardo da Vinci programme ; Fundação para a Ciência e a Tecnologia (FCT

One-year Treatment with 0.1% Tacrolimus Ointment versus a Corticosteroid Regimen in Adults with Moderate to Severe Atopic Dermatitis: A Randomized, Double-blind, Comparative Trial

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Kansallisen huumausaineiden seurantakeskuksen huumevuosiraportti EMCDDA:lle (European Monitoring Centre for Drugs and Drug Addiction

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The contribution of filaggrin null mutations to predicting atopic dermatitis (AD) treatment response is not clear, nor have such mutations been studied in the Finnish population. This study tested the association of the 4 most prevalent European FLG null mutations, the 2 Finnish enriched FLG null mutations, the FLG 12-repeat allele, and 50 additional epidermal barrier gene variants, with risk of AD, disease severity, clinical features, risk of other atopic diseases, age of onset, and treatment response in 501 patients with AD and 1710 controls. AD, early-onset AD, palmar hyperlinearity, and asthma showed significant associations with the combined FLG null genotype. Disease severity and treatment response were independent of patient FLG status. Carrier frequencies of R501X, 2282del4, and S3247X were notably lower in Finns compared with reported frequencies in other populations. This data confirms FLG mutations as risk factors for AD in Finns, but also, questions their feasibility as biomarkers in predicting treatment response.The contribution of filaggrin null mutations to predicting atopic dermatitis (AD) treatment response is not clear, nor have such mutations been studied in the Finnish population. This study tested the association of the 4 most prevalent European FLG null mutations, the 2 Finnish enriched FLG null mutations, the FLG 12-repeat allele, and 50 additional epidermal barrier gene variants, with risk of AD, disease severity, clinical features, risk of other atopic diseases, age of onset, and treatment response in 501 patients with AD and 1,710 controls. AD, early-onset AD, palmar hyperlinearity, and asthma showed significant associations with the combined FLG null genotype. Disease severity and treatment response were independent of patient FLG status. Carrier frequencies of R501X, 2282del4, and S3247X were notably lower in Finns compared with reported frequencies in other populations. This data confirms FLG mutations as risk factors for AD in Finns, but also questions their feasibility as biomarkers in predicting treatment response.Peer reviewe

Finnish Centre of Excellence in Physics, Chemistry, Biology and Meteorology of Atmospheric Composition and Climate Change : summary and outlook

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The Center of Excellence in Atmospheric Science (2002–2019) — from molecular and biological processes to the global climate

The study of atmospheric processes related to climate requires a multidisciplinary approach, encompassing physics, chemistry, meteorology, forest science, and environmental science. The Academy of Finland Centre of Excellence in atmospheric sciences (CoE ATM) responded to that need for 18 years and produced extensive research and eloquent results, which are summarized in this review. The work in the CoE ATM enhanced our understanding in biogeochemical cycles, ecosystem processes, dynamics of aerosols, ions and neutral clusters in the lower atmosphere, and cloud formation and their interactions and feedbacks. The CoE ATM combined continuous and comprehensive long-term in-situ observations in various environments, ecosystems and platforms, ground- and satellitebased remote sensing, targeted laboratory and field experiments, and advanced multi-scale modeling. This has enabled improved conceptual understanding and quantifications across relevant spatial and temporal scales. Overall, the CoE ATM served as a platform for the multidisciplinary research community to explore the interactions between the biosphere and atmosphere under a common and adaptive framework