New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Collagen XVII and pathomechanisms of junctional epidermolysis bullosa and gestational pemphigoid

Abstract Transmembrane collagen XVII (BP180) is a structural component of hemidesmosomes that connects the two layers of skin. Collagen XVII is associated with both autoimmune and inherited bullous skin diseases. Mutations in collagen XVII gene cause junctional epidermolysis bullosa, and in the diseases of the pemphigoid group autoantibodies target collagen XVII. In this work, collagen XVII was studied in both junctional epidermolysis bullosa and gestational pemphigoid. Two novel glycine substitution mutations were found in the largest collagenous domain of collagen XVII. Analysis of recombinantly produced mutated proteins showed that these novel mutations and previously described glycine substitution mutations decrease the thermal stability of collagen XVII ectodomain. In addition, these mutations were found to cause intracellular accumulation of the mutated proteins and affect the post-translational modifications of collagen XVII. Meanwhile, an in-frame deletion of nine amino acids had no effect on the thermal stability or secretion of the collagen XVII ectodomain. Gestational pemphigoid autoantigen collagen XVII has been mainly studied in the skin, and its expression and function during pregnancy are so far largely unknown. For the first time, collagen XVII was shown to be expressed by cytotrophoblasts of the first trimester human placenta and by cultured cytotrophoblasts. Transmigration assay of cytotrophoblasts indicated that collagen XVII promotes trophoblast invasion, and may thus have a role in placental formation. In addition, significant amounts of in vivo produced collagen XVII were found in the amniotic fluid throughout pregnancy. Collagen XVII expression was also observed in hemidesmosomes of amniotic membranes and in cells cultured from amniotic fluid. These findings suggest that collagen XVII could have a function, albeit so far unknown, during pregnancy

Reply to:Bridging the gap:commentary on “The high prevalence of skin diseases in adults aged 70 and older"

Abstract This letter comments on the letter by Shreya Sreekantaswamy

Kuinka tunnistaa DRESS, yleisoireinen lääkeainereaktio?

Abstract DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare, severe multiorgan adverse drug reaction. Antiepileptic agents and antibiotics are the most frequently reported causative agents. Compared with other drug reactions, DRESS demonstrates a long latency period thus complicating recognition and diagnosis. DRESS is defined as presence of fever, skin eruption, hematologic abnormalities and systemic involvement, especially liver injury. Withdrawal of the culprit drug, commencement of systemic corticosteroid and supportive care are the mainstay of treatment. The majority of patients recover completely after drug withdrawal and appropriate therapy. Some patients suffer from chronic sequelae or even death.Tiivistelmä DRESS (drug reaction with eosinophilia and systemic symptoms) eli yleisoireinen eosinofiilinen oireyhtymä on harvinainen, vakava lääkkeen laukaisema yliherkkyysreaktio. Tyypillisiä oireita ovat korkea kuume, ihottuma, eosinofilia, imusolmukesuurentumat sekä sisäelinmanifestaatiot. Muihin lääkeainereaktioihin verrattuna DRESS kehittyy hitaasti, ja sen on raportoitu liittyvän vain osaan lääkeaineista. Reaktion nopea tunnistaminen ja aiheuttavan lääkkeen lopettaminen ovat hoidon kulmakiviä. Lieväoireisissa tapauksissa H1-antihistamiini ja paikallisglukokortikoidit voivat olla riittävä hoito. Vaikeissa tapauksissa tarvitaan tehohoitoa. DRESS-reaktion aiheuttama kuolleisuus on noin 10 %

Rakkuloita iholla:mikä on diagnoosi?

Tiivistelmä Ihon rakkulaisia muutoksia ovat pienet rakkulat eli vesikkelit, kookkaat bullat ja sameaa eritettä sisältävät pustelit. Rakkuloita voivat aiheuttaa useat tekijät ihon mekaanisesta hankautumisesta harvinaisiin perinnöllisiin ­ihosairauksiin. Diagnoosin jäljille johtavat yleensä potilaan ikä, rakkuloiden ulkonäkö ja sijainti sekä mahdolliset muut ­iholöydökset. Autoimmuunirakkulatautien diagnoosi varmistetaan ihokoepalan immunofluoresenssitutkimuksella ja ­spesifisillä vasta-ainetutkimuksilla. Muissa rakkulataudeissa diagnoosi perustuu pääosin esitietoihin ja ­kliiniseen tutkimukseen

Risk of non-cutaneous cancers in individuals with basal cell carcinoma:a population-based cohort study

Abstract Evidence of the association between a personal history of basal cell carcinoma and the risk of non-cutaneous malignancies is conflicting. The aim of this study was to retrospectively clarify the risk of non-cutaneous cancers in individuals with basal cell carcinoma using nationwide Finnish registry data for 96,304 patients and 394,503 randomly selected population controls. In this study, individuals with basal cell carcinoma have an increased risk of other cancers (odds ratio (OR) 1.38; 95% confidence interval (95% CI) 1.36–1.40). The risk was most prominent for lip cancer (OR 5.29; 95% CI 4.50–6.21), mycosis fungoides (OR 3.13; 95% CI 2.31–4.23) and soft tissue cancers (OR 2.77; 95% CI 2.43–3.16). In age-adjusted model, men had higher risk of cancers overall compared with women (p< 0.05). In conclusion, the study found increased overall cancer risk among patients with basal cell carcinoma compared with randomly selected population controls

Ihopsoriaasia sairastavien potilaiden biologinen lääkehoito Oulun yliopistollisen sairaalan ihotautiklinikassa:potilaiden kliininen kuva ja aiemmat hoidot

Tiivistelmä Johdanto: Psoriaasi on krooninen tulehduksellinen ihotauti, johon liittyy myös liitännäissairastavuutta. Osa potilaista tarvitsee vaikeisiin tautimuotoihinsa biologisia lääkehoitoja. Biologisilla lääkkeillä hoidettavien ihopsoriaasipotilaiden rekisteri ei ole vielä laajassa käytössä Suomessa, joten kokonaiskuva tästä vaativasta potilasryhmästä on jäänyt vajaaksi. Menetelmät: Tutkimusaineiston muodostivat 95 potilasta, joille on Oulun yliopistollisessa sairaalassa aloitettu ihopsoriaasin hoitoon biologinen lääke. Sairauskertomusmerkinnöistä kerättiin tietoja potilaiden kliinisestä tilanteesta, liitännäissairauksista sekä aikaisemmin käytetyistä hoidoista. Tulokset ja päätelmät: Potilaista 86 % oli käyttänyt tavanomaisia systeemisiä psoriaasilääkkeitä. Neljäsosalla potilaista oli ollut käytössä kaksi biologista lääkettä. Potilaista 80 %:lla oli vähintään yksi ja yli puolella vähintään kaksi liitännäissairautta, minkä vuoksi potilasryhmä hyötyisi erityisen paljon kokonaisvaltaisesta terveydentilan tarkastelusta.Abstract Patients receiving biologic therapy for psoriasis in Oulu University Hospital : clinical picture and prior treatments Background: Some European countries collect data in national registers of patients receiving expensive biologic therapy for psoriasis vulgaris. In Finland, a similar register is not yet in active use and the overall picture of this group of patients is therefore lacking. Patients and methods: Our research material consisted of patients who had received biologic therapy for psoriasis vulgaris in Oulu University Hospital (n = 95). Results and conclusions: Ustekinumab was the most common biologic agent when only the most recently started agents were considered. One fourth of the patients had tried two different biological agents. It is of note that 80% of the patients had at least one comorbid disease associated with psoriasis. When treating patients with psoriasis, the increased risk for comorbidities should also be taken care of along with the skin disease