Diabeettisten komplikaatioiden uusien fenotyyppiprofiilien etsintä, sekä ryhmien välisten geneettisten komponenttien tunnistus koneoppimismenetelmiä hyödyntäen

Patients with Type 1 diabetes (T1D) may develop a wide variety of additional slowly progressing complications, which have been shown to be partly heritable and to correlate with each other. However, the genetic and biological mechanisms behind them are still mostly unknown. The goal of this work was to use machine learning and data mining approaches that could capture the progressive nature of multiple complications simultaneously, and create novel phenotype classes that could help to solve the pathogenesis and genetics of diabetic complications. To achieve this, a dual-layer self-organizing map (SOM) was trained using clinical and environmental patient data from the FinnDiane study, and the trained SOM node prototypes were clustered to classes using agglomerative hierarchical clustering. The genetic differences between the created classes were evaluated using heritability estimates, and the genetic markers associated with the class assignments showing significant heritability were analysed in genome-wide association study (GWAS). The created class assignments were biologically plausible, and were estimated to be up to 42% genetically determined. The GWAS analyses detected a genetic marker (rs202095311, located in the last intron of the gene NRIP1) genome-wide significantly (p<5×10^-8) associated with one of the created class assignments. In addition, GWAS detected multiple other genetic regions with suggestive p-values that contained mostly genes and processes previously linked to diabetic complications or their risk factors. Overall, the new approach to study the genetics of complex diseases was found to perform well in case of T1D and its complications, and could be used to study also other complex traits and diseases.Tyypin 1 diabetikoille saattaa kehittyä useita hitaasti eteneviä lisäsairauksia, jotka ovat osittain perinnöllisiä sekä keskenään korreloivia. Sekä geneettiset että biologiset mekanismit näiden taustalla ovat kuitenkin pääasiassa vielä tuntemattomia. Tämän työn tarkoituksena oli hyödyntää koneoppimis- ja tiedonlouhintamenetelmiä, joiden avulla pystyttäisiin vangitsemaan samanaikaisesti useiden diabeettisten komplikaatioden etenevä luonne, sekä muodostamaan uusia fenotyyppiluokkia diabeettisten komplikaatioiden ja niiden genetiikan tutkimuksen avuksi. Työssä opetettiin monitasoinen itseorganisoituva kartta (SOM) käyttäen FinnDiane tutimuksessa kliinisistä muuttujista sekä ympäristötekijöistä kerättyä potilasdataa. Uusien fenotyyppiluokkien luomiseksi opetetun kartan prototyyppialkiot klusteroitiin kokoavalla hierarkkisella klusteroinnilla. Luokkien välisiä geneettisiä eroja vertailtiin heritabiliteettiestimaateilla. Lisäksi luokkajakoon assosioituvien geneettisten markkereiden vaikutusta tutkittiin perimänlaajuisessa assosiaatiotutkimuksessa (GWAS) niiden luokkien välillä, jotka saavuttivat merkitseviä estimaatteja heritabiliteeteille. Muodostetut potilasluokat olivat biologisesti mielekkäitä ja muodostetun luokkajaon estimoitiin olevan jopa 42% geneettisesti määräytyvä. Perimänlaajuisissa assosiaatiotutkimuksissa geneettinen variantti (rs202095311 NRIP1 geenin viimeisessä intronissa) assosioitui yhteen muodostetuista luokkajaoista genominlaajuisella merkitsevyystasolla (p<5×10^-8). Lisäksi analyyseissa havaittiin viitteellisillä p-arvoilla useita muita geneettisiä alueita, joilla sijaitsee aiemmin diabeettisiin komplikaatioihin tai niiden riskitekijöihin yhdistettyjä geenejä ja prosesseja. Yleisesti, uusi lähestymistapa kompleksisten sairauksien genetiikan tutkimukseen suoriutui sille asetetuista haasteista tyypin 1 diabeteksen ja sen komplikaatioiden tutkimuksessa ja vastaava lähestymistapa voisi olla hyödynnettävissä myös muiden kompleksisten sairauksien tutkimuksessa

Distribution of lipid nanocapsules in different cochlear cell populations after round window membrane permeation

Hearing loss is a major public health problem, and its treatment with traditional therapy strategies is often unsuccessful due to limited drug access deep in the temporal bone. Multifunctional nanoparticles that are targeted to specified cell populations, biodegradable, traceable in vivo, and equipped with controlled drug/gene release may resolve this problem. We developed lipid core nanocapsules (LNCs) with sizes below 50 nm. The aim of the present study is to evaluate the ability of the LNCs to pass through the round window membrane and reach inner ear targets. FITC was incorporated as a tag for the LNCs and Nile Red was encapsulated inside the oily core to assess the integrity of the LNCs. The capability of LNCs to pass through the round window membrane and the distribution of the LNCs inside the inner ear were evaluated in rats via confocal microscopy in combination with image analysis using ImageJ. After round window membrane administration, LNCs reached the spiral ganglion cells, nerve fibers, and spiral ligament fibrocytes within 30 min. The paracellular pathway was the main approach for LNC penetration of the round window membrane. LNCs can also reach the vestibule, middle ear mucosa, and the adjacent artery. Nuclear localization was detected in the spiral ganglion, though infrequently. These results suggest that LNCs are potential vectors for drug delivery into the spiral ganglion cells, nerve fibers, hair cells, and spiral ligament

Expression of Toll-like receptors in nasal epithelium in allergic rhinitis

Toll-like receptors (TLRs) are important in barrier homeostasis, but their role in airborne allergies is not fully understood. The aim was to evaluate baseline and allergen-induced expression of TLR proteins in nasal epithelium during allergic rhinitis. Nineteen otherwise healthy non-smoking volunteers both allergic to birch pollen and non-allergic controls were enrolled. We took nasal biopsies before and after off-seasonal intranasal birch pollen or diluent challenge. The expression of epithelial TLR1-7, TLR9-10, and MyD88 proteins was immunohistochemically evaluated from the nasal biopsies. The TLR1-3 and TLR5-10 mRNAs were observed by RNA-microarray. Baseline epithelial expression of TLR proteins was wide and identical in controls and atopics. After off-seasonal intranasal birch pollen challenge, a negative change in the expression score of TLR1 and TLR6 proteins was detected in the atopic group. TLR mRNA expression was not affected by birch pollen challenge. Nasal epithelium seems to express all known TLRs. The mechanisms by which TLR1, and TLR6 proteins could affect pollen allergen transport need further studies.Peer reviewe

High relative density of lymphatic vessels predicts poor survival in tongue squamous cell carcinoma

Tongue cancer has a poor prognosis due to its early metastasis via lymphatic vessels. The present study aimed at evaluating lymphatic vessel density, relative density of lymphatic vessel, and diameter of lymphatic vessels and its predictive role in tongue cancer. Paraffin-embedded tongue and lymph node specimens (n = 113) were stained immunohistochemically with a polyclonal antibody von Willebrand factor, recognizing blood and lymphatic endothelium and with a monoclonal antibody podoplanin, recognizing lymphatic endothelium. The relative density of lymphatic vessels was counted by dividing the mean number of lymphatic vessels per microscopic field (podoplanin) by the mean number of all vessels (vWf) per microscopic field. The high relative density of lymphatic vessels (aeyen80 %) was associated with poor prognosis in tongue cancer. The relative density of lymphatic vessels predicted poor prognosis in the group of primary tumor size T1-T2 and in the group of non-metastatic cancer. The lymphatic vessel density and diameter of lymphatic vessels were not associated with tongue cancer survival. The relative density of lymphatic vessels might have clinically relevant prognostic impact. Further studies with increased number of patients are needed.Peer reviewe

Trends in Promotion and Advertising Techniques of Household Electrical Appliances by the Electric Utility Industry

The purpose of the study was to trace the development of national co-operative appliance advertising and promotional activities of the electric utility industry from 1882 to 1963. The principle source of information was the electrical trade magazines. The advertising program of the electric utility industry has changed from emphasis on direct selling to coordination of national co-operative appliance campaigns. Advertising co-operation between retailers, manufacturers and the electric utility industry has been in existence since 1933. The Live Better Electrically campaign is the most recent and successful of any co-operative promotional and advertising program. The Edison Electric Institute, representing the electric utility industry, assumed leadership of this campaign in 1959. The purpose of the Live Better Electrically campaign has been to add utility company support to the efforts of manufacturers and retailers to increase appliance sales. The campaigns have been geared to the mass consumer market in order to create an image of electric living comparable to the national campaigns by the gas industry. The media mix employed by the electric utility industry has been altered over time to include radio and television along with the newspapers, magazines and direct mail

Molecular Mechanisms of Nasal Epithelium in Rhinitis and Rhinosinusitis

Peer reviewe

Factors Affecting Revision Rate of Chronic Rhinosinusitis

Peer reviewe

Rhinology future debates, an EUFOREA report

The first Rhinology Future Debates was held in Brussels in December 2016, organized by EUFOREA (European Forum for Research and Education in Allergy and Airways diseases). The purpose of these debates is to bring novel developments in the field of Rhinology to the attention of the medical, paramedical and patient community, in a highly credible and balanced context. For the first time in Rhinology, a peer to peer scientific exchange with key experts in the field of rhinology and key medical colleagues from leading industries let to a brainstorming and discussion event on a number of hot issues in Rhinology. Novel developments are presented by key experts from industry and/or key thought leaders in Rhinology, and then followed by a lively debate on the potential positioning of new developments in care pathways, the strengths and weaknesses of the novel development(s), and comparisons with existing and/or competing products, devices, and/or molecules. As all debates are recorded and distributed on-line with limited editing (www.rhinology-future.com), EUFOREA aims at maximizing the education of the target groups on novel developments, allowing a critical appraisal of the future and a more rapid implementation of promising novel tools, techniques and/or molecules in clinical practise in Europe. The next Rhinology Future debate will be held in Brussels in December 2017