Pre- ja postnataalne kasv lastel 1. tüüpi diabeedi riski kandvate HLA genotüüpidega

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Üle kogu maailma tõuseb insuliinisõltuva ehk 1.tüüpi diabeedi (T1D) esinemissagedus keskmiselt 3-4% aastas. Tegemist on autoimmuunhaigusega, kus organismi enda immuunsüsteem hakkab hävitama kõhunäärmes asuvaid insuliini tootvaid β-rakke. Kuigi tegemist on geneetilise eelsoodumusega haigusega, kus pärilikku riski määravad eeskätt HLA geenid, haigestub vaid ca 5% geneetilise eelsoodumusega inimestest. Seetõttu arvatakse, et T1D haigestumuse tõusu põhjuseks on eeskätt muutuv elukeskkond. Suurem sünnikaal ja kiirem lapseea kasv suurendavad riski haigestuda T1D. Aktseleratsiooni hüpoteesi kohaselt tänapäeva Lääne ühiskonnas, kus esineb pidev toidu üleküllus ja sellest tingitud rasvumine, on insuliini vajadus tõusnud juba varasest lapsepõlvest alates. Ülekoormatud β-rakud võivad aga muutuda immuunsüsteemile sihtmärgiks, põhjustades nii nende rakkude autoimmuunse kahjustuse. T1D eelsoodumust põhjustavate geenide roll kiirenenud pre- ja postnataalses (ehk sünnieelses ja -järgses) kasvus ei ole selge. Samuti pole täpselt teada ka lapseea kasvu reguleeriva väga olulise faktori, insuliini sarnase kasvufaktori I (IGF-I) ja seda veres kandva valgu IGFBP-3, roll haiguse kujunemises. Varasemad uuringud on näidanud, et mõlemad võivad olla olulised T1D väljakujunemises. Rahvusvahelise projekti DIABIMMUNE raames määrati T1D geneetiline risk kolmes riigis (Eestis, Soomes ja Karjalas Venemaal) ca 9000 vastsündinul. Uurisime, kas laste sünnikaal ja sünnijärgne kasv sõltuvad HLA geeni tüüpidest. Lisaks uurisime geneetilise eelsoodumusega lastel (ca 500 last) veel seda, kas IGF-I või IGFBP-3 võiksid mõjutada laste kasvu või β-rakkude vastase autoimmuunsuse tekkimist. Leidsime, et T1D riski kandvad HLA geenid üldiselt ei mõjuta sünnikaalu. Samas kasvavad lapsed kõrge geneetilise riskiga kahel esimesel eluaastal aeglasemalt ja nende IGF-I ja IGFBP-3 tase veres on oluliselt madalam võrreldes lastega, kel suurenenud geneetiline risk haigestuda T1D puudub. Juba käimasoleva autoimmuunse protsessiga lastel on IGF-I sisaldus veres madalam võrreldes teiste lastega. Samuti esines neil lastel oluliselt suurem IGFBP-3 taseme tõus vahetult enne autoimmuunsuse teket. Kokkuvõttes leidsime, et T1D riski kandvad HLA geenid ei mõjuta sünnikaalu, küll aga varajast lapseea kasvu, kus olulist rolli võivad mängida ka IGF-I ja IGFBP-3. Viimastel võib olla oma osa β-rakkude vastase autoimmuunsuse väljakujunemises.The incidence of type 1 diabetes (T1D) is increasing by 3-4% annually all over the world. T1D is an autoimmune disease where immune system destroys the insulin-producing β-cells in pancreas. T1D has a genetic susceptibility conferred by specific HLA genes. However, only ca 5% of people with genetic susceptibility develops T1D. Therefore it has been suggested that the reasons for the increasing incidence of T1D are related to the changes in living environment. An increased birth weight and early childhood growth have been found to be risk factors for T1D. According to acceleration hypothesis, in modern Western society the food overload and consecutive obesity increase the insulin demand already from early childhood. The over activity of β-cells leads to their targeting by immune system and facilitates the onset of autoimmunity. The role of genetic factors conferring susceptibility to T1D in pre- and postnatal (i.e. before and after birth) growth is unclear. Also, the role of one of the most important growth factors in childhood – insulin-like growth factor I (IGF-I) and its binding protein (IGFBP-3), is not clear. Previous studies have shown that both can play role in the development of T1D. As a part of large international study DIABIMMUNE, genetic risk by HLA genes was determined in ~9000 newborns born in three countries - Estonia, Finland and Russian Karelia. We investigated whether those genes affect the birth weight and postnatal growth. In ~500 children with increased genetic susceptibility to T1D we also studied whether IGF-I and IGFBP-3 influence childhood growth or are associated with β-cells autoimmunity. We have found that generally there was no significant association between the HLA genes and birth weight. However, children with highest genetic risk for T1D grew slower during the first 24 months and they had lower plasma IGF-I and IGFBP-3 levels compared with others. The children with signs of autoimmunity had lower IGF-I and their IGFBP-3 showed a faster increment just before the emerge of autoimmunity compared to children without signs of autoimmunity. We conclude that HLA genes associated with T1D risk influence early childhood growth, but not birth weight. IGF-I and IGFBP-3 may have both role in early growth as well as in the development of T1D autoimmunity

Kasvuhormoonravi saanud laste kliiniline kirjeldus ja ravi efektiivsus – Tartu Ülikooli Kliinikumi lastekliiniku viimase 12 aasta kogemus

Taust. Kasvuhormoonravi sagedaimad näidustused lastel on kasvuhormooni puudulikkus (KHP), Turneri sündroom (TS) ja Praderi-Willi sündroom (PWS). Ravi põhieesmärk on suurendada lõplikku kehapikkust. Eesmärk. Töö sihiks oli kirjeldada 2002.–2013. aasta TÜ Kliinikumi lastekliinikus kasvuhormoonravi saanud patsiente ning uurida ravi efektiivsust. Metoodika. Analüüsiti nimetatud ajaperioodil ravi saanud laste haiguslugusid. Kehapikkuste võrdlemiseks teisendati need standarditud skoorideks (SDS). Ravi efektiivsust hinnati kui kehapikkuse SDSi juurdekasvu ravi jooksul. Tulemused. Ravi sai 65 patsienti. Näidustuseks olid KHP (n = 37, neist 27 poissi), TS (n = 18), PWS (n = 7, kõik tüdrukud), üsasisene kasvupeetus (1 tüdruk), krooniline neerupuudulikkus (1 poiss) ja idiopaatiline lühike kasv (1 tüdruk). Mediaanvanus ravi alustamisel oli KHP-rühmas 9,3 (2,4–15,3) a, TSi-rühmas 10,5 (7,0–14,7) a ja PWSi-rühmas 8,1 (1,5–11,2). Ravi lõpetanud laste (n = 32) kehapikkuse SDSi mediaanjuurdekasv oli KHP-rühmas +2,1 (1,0–3,5), TSi-rühmas +1,6 (0,4–2,0) ning PWSi-rühmas +1,3 (0,2–2,1). Järeldused. Poisse oli KHP-rühmas ligi kolm korda rohkem ning see viitab KHP aladiagnoosimisele tüdrukutel, poiste puudumine PWSi-rühmas aga selle aladiagnoosimisele poistel. Nii KHP, TSi kui ka PWSi puhul oli vanus ravi alustamisel ja ravi efektiivsus sarnane kirjanduses tooduga. Õigeaegse diagnoosi ja ravi alustamise eelduseks on, et laste kasvu jälgitakse kasvugraafiku alusel regulaarselt ning veelgi järjekindlamalt.Eesti Arst 2015; 94(1):12–1

Integral Quadratic Constraints with Infinite-Dimensional Channels

Modern control theory provides us with a spectrum of methods for studying the interconnection of dynamic systems using input-output properties of the interconnected subsystems. Perhaps the most advanced framework for such input-output analysis is the use of Integral Quadratic Constraints (IQCs), which considers the interconnection of a nominal linear system with an unmodelled nonlinear or uncertain subsystem with known input-output properties. Although these methods are widely used for Ordinary Differential Equations (ODEs), there have been fewer attempts to extend IQCs to infinite-dimensional systems. In this paper, we present an IQC-based framework for Partial Differential Equations (PDEs) and Delay Differential Equations (DDEs). First, we introduce infinite-dimensional signal spaces, operators, and feedback interconnections. Next, in the main result, we propose a formulation of hard IQC-based input-output stability conditions, allowing for infinite-dimensional multipliers. We then show how to test hard IQC conditions with infinite-dimensional multipliers on a nominal linear PDE or DDE system via the Partial Integral Equation (PIE) state-space representation using a sufficient version of the Kalman-Yakubovich-Popov lemma (KYP). The results are then illustrated using four example problems with uncertainty and nonlinearity

Employing Feature Selection Algorithms to Determine the Immune State of a Mouse Model of Rheumatoid Arthritis

The immune response is a dynamic process by which the body determines whether an antigen is self or nonself. The state of this dynamic process is defined by the relative balance and population of inflammatory and regulatory actors which comprise this decision making process. The goal of immunotherapy as applied to, e.g. Rheumatoid Arthritis (RA), then, is to bias the immune state in favor of the regulatory actors - thereby shutting down autoimmune pathways in the response. While there are several known approaches to immunotherapy, the effectiveness of the therapy will depend on how this intervention alters the evolution of this state. Unfortunately, this process is determined not only by the dynamics of the process, but the state of the system at the time of intervention - a state which is difficult if not impossible to determine prior to application of the therapy. To identify such states we consider a mouse model of RA (Collagen-Induced Arthritis (CIA)) immunotherapy; collect high dimensional data on T cell markers and populations of mice after treatment with a recently developed immunotherapy for CIA; and use feature selection algorithms in order to select a lower dimensional subset of this data which can be used to predict both the full set of T cell markers and populations, along with the efficacy of immunotherapy treatment

Coeliac disease and HLA-conferred susceptibility to autoimmunity are associated with IgE sensitization in young children.

Non peer reviewe

Maternal breast milk microbiota and immune markers in relation to subsequent development of celiac disease in offspring

The potential impact of the composition of maternal breast milk is poorly known in children who develop celiac disease (CD). The aim of our study was to compare the microbiota composition and the concentrations of immune markers in breast milk from mothers whose offspring carried the genetic predisposition to CD, and whether they did or did not develop CD during follow-up for the first 3 years of life. Maternal breast milk samples [CD children (n = 6) and healthy children (n = 18)] were collected 3 months after delivery. Enzyme-linked immunosorbent assays were used to measure TGF-beta 1, TGF-beta 2, sIgA, MFG-E8 and sCD14. For microbiota analysis, next generation (Illumina) sequencing, real-time PCR and denaturing gradient gel electrophoresis were used. Phylotype abundance and the Shannon 'H' diversity index were significantly higher in breast milk samples in the CD group. There was higher prevalence of the phyla Bacteroidetes and Fusobacteria, the classes Clostridia and Fusobacteriia, and the genera Leptotrichia, Anaerococcus, Sphingomonas, Actynomyces and Akkermansia in the CD group. The immunological markers were differently associated with some Gram-negative bacterial genera and species (Chryseobacterium, Sphingobium) as well as Gram-positive species (Lactobacillusreuteri, Bifidobacteriumanimalis). In conclusion, the microbiota in breast milk from mothers of genetically predisposed offspring who presented CD showed a higher bacterial phylotype abundance and diversity, as well as a different bacterial composition, as compared with the mothers of unaffected offspring. These immune markers showed some associations with bacterial composition and may influence the risk for development of CD beyond early childhood.Peer reviewe

Early childhood infections and the use of antibiotics and antipyretic-analgesics in Finland, Estonia and Russian Karelia.

Aim Infections in early childhood are common reasons to seek medical attention. This study compares the prevalence of infections, and the use of antibiotics and antipyretic-analgesics, in children from Finland, Estonia and Russian Karelia. Methods Children with a genetically increased risk for type 1 diabetes (N = 797) were observed from birth up to 3 years of age. Illnesses and medications were reported by parents continuously. All reported infections, antibiotics and antipyretic-analgesics were compared between Finland and Estonia, and to a lesser extent with Russian Karelia, due to poor study compliance. Results Compared with Estonians, Finns reported more infections during the first and second years of life. During the follow-up, Finnish children had 10 infections while Estonians only had 8 (p <0.001). Finns also used more antibiotics and antipyretic-analgesics in each year during the follow-up. Russian Karelians reported the lowest frequency of infections and the most infrequent use of antibiotics and antipyretic-analgesics in the first two years of life. Conclusion Infections and the use of antibiotics and antipyretic-analgesics in early childhood were most frequent in Finland, where socio-economic conditions are the most developed and microbial encounters are sparse. This may reflect on the hygiene hypothesis, a less effective immune system that allows normally harmless microbes to attack and cause clinical infections.Peer reviewe

Exploring the risk factors for differences in the cumulative incidence of coeliac disease in two neighboring countries : the prospective DIABIMMUNE study

Background: During the last several decades the prevalence of coeliac disease (CD) has increased worldwide. Aim: To compare the cumulative incidence of CD between Estonian and Finnish children and to identify the risk factors. Materials and methods: Children were recruited as part of the DIABIMMUNE Study. In the birth cohort (BC) 258 children from Estonia and 305 from Finland, and in the young children's cohort (YCC) 1363 and 1384 children were followed up, respectively. The diagnosis of CD was made in accordance with the ESPGHAN guidelines-the presence of IgA-tTG antibodies and small bowel villous atrophy. Results: During the study period 29 children developed CD. The cumulative incidence of CD was significantly higher in Finland (0.77% vs 0.27%; P = 0.01). No difference was seen between the children with CD and the controls in the duration of breastfeeding or the age at cereal introduction. The BC children with CD had had significantly more episodes of infections with fever by the age of 12 months compared to the controls (3.4 vs 1.4; P = 0.04). Conclusion: The 5-year cumulative incidence of childhood CD is significantly higher in Finland than in Estonia. Sequential infections early in life may increase the risk for developing CD. (C) 2016 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.Peer reviewe

Contrasting microbiotas between Finnish and Estonian infants : exposure to Acinetobacter may contribute to the allergy gap

Background Allergic diseases are more common in Finland than in Estonia, which-according to the biodiversity hypothesis-could relate to differences in early microbial exposures. Methods We aimed at defining possible microbial perturbations preceding early atopic sensitization. Stool, nasal and skin samples of 6-month-old DIABIMMUNE study participants with HLA susceptibility to type 1 diabetes were collected. We compared microbiotas of sensitized (determined by specific IgE results at 18 months of age) and unsensitized Estonian and Finnish children. Results Sensitization was differentially targeted between populations, as egg-specific and birch pollen-specific IgE was more common in Finland. Microbial diversity and community composition also differed; the genusAcinetobacterwas more abundant in Estonian skin and nasal samples. Particularly, the strain-level profile ofAcinetobacter lwoffiiwas more diverse in Estonian samples. Early microbiota was not generally associated with later sensitization. Microbial composition tended to differ between children with or without IgE-related sensitization, but only in Finland. While land-use pattern (ie green areas vs. urban landscapes around the children's homes) was not associated with microbiota as a whole, it associated with the composition of the genusAcinetobacter. Breastfeeding affected gut microbial composition and seemed to protect from sensitization. Conclusions In accordance with the biodiversity hypothesis, our results support disparate early exposure to environmental microbes between Finnish and Estonian children and suggest a significant role of the genusAcinetobacterin the allergy gap between the two populations. The significance of the observed differences for later allergic sensitization remains open.Peer reviewe