Ongoing research in the Pediatric Research Center

Docent Mikael Kuitunen’s study group examines the development of allergic diseases and recovering from them. Can probiotics be used to prevent the incidence of allergies? Do probiotics have an effect on the treatment of allergic diseases?

Allergic and autoimmune diseases have significantly increased over the last decades, and the increase in these diseases has been associated with the decreased microbiota load in early childhood.

Mikael Kuitunen’s research group was established in 1999. The group aims to establish whether a probiotic intervention before, during and immediately after birth reduces the incidence of allergies and whether probiotics accelerate recovery from allergies.

Researchers aim to establish what long-term effect the administration of probiotics will have on the incidence of allergies. In addition, information will be received on whether probiotic interventions are linked to the development of intestinal microbiota and to the onset of allergies and autoimmune diseases.

– Based on the results obtained so far, probiotic interventions reduced the incidence of atopic dermatitis by 25–30% by the age of 2 years. We are looking forward to further studies on microbiota in this research material, Mikael Kuitunen says.

It has been particularly inspiring to collaborate with different research groups and to follow the expansion of allergy research to new areas of pediatrics.

Contact details

Mikael Kuitunen
Helsinki University Hospital Children and Adolescents
mikael.kuitunen(a)hus.fi

Professor Mika Mäkelä’s research group studies pediatric asthma and severe food allergies. The aim is to develop better methods for the diagnostics and treatment of allergic diseases in children.

The new information will also contribute to cooperation between healthcare professionals and families when making treatment decisions.

– The identification and diagnostics of pediatric asthma are still based on relatively vague deductions on symptoms. For this reason, we are also studying the pathophysiology of the disease, the onset of the disorder, in order to be able to choose the best possible treatment plans for different types of asthma, Mika Mäkelä explains.

HUS Skin and Allergy Hospital was the first Nordic centre to launch research into oral immunotherapy to foods in 2005. Researchers have since developed a distinction into mild and severe food allergies and sought new forms of therapy for the patients who are the most difficult to treat.

– The objective is to increase information related to asthma and food allergies to assist professionals in diagnostic decision-making but also in conjunction with the families. The more information we can provide on the treatment and progress of diseases, the better we can create a functional dialogue to support the implementation of therapy and to help children and their families cope, Mäkelä says.

The research group examines factors determining the permanent nature of the disease and its severity in tissues and in respiratory physiology. In terms of food allergies, the focus has so far been to develop diagnostics based on molecular-allergological definitions and sensitisation to food.

Asthma diagnostics in small children

The results of work completed by the group include, for instance, the asthma diagnostics method for small children which has been adopted in Finland.

– We have also shown that in infants and toddlers, the chronic and irreversible asthma-induced changes to the bronchial mucosa have not yet begun. This way it will be possible to consider therapies relatively calmly with the families.

One of the research group’s great achievements is also the development of methods for desensitization to food.

Thanks to desensitization, patients in whom food previously caused a sudden and severe general allergic reaction or anaphylactic shock, are able to enjoy this type of food daily without fearing harmful exposure.

Mäkelä’s research group’s activities were launched in 2000, and it has significantly expanded over the years. It currently includes 10 to 15 people. Most of them are pediatricians and pediatric allergologists. The majority of young researchers preparing their dissertation are planning a career as pediatricians. The group has strong competencies in pediatric allergology and clinical physiology. The group also cooperates with pediatric gastroenterologists and many laboratory fields.

Contact details

Mika Mäkelä
Helsinki University Hospital Inflammation Center, Skin and Allergy Hospital and Helsinki University
mika.makela(a)hus.f

Links to studies:

Component-resolved diagnostics demonstrates that most peanut-allergic individuals could potentially introduce tree nuts to their diet. Clin Exp Allergy. 2018 Jan 29. [Epub ahead of print].

Measurement of tidal breathing flows in infants by using impedance pneumography. Eur Respir J, 2017 Feb 15;49(2).

Burden of allergy diets in Finnish day care reduced by change in practices. Allergy. 2016 Oct;71(10):1453-60.

Health care resource utilization and characteristics of patients with eosinophilic asthma in secondary health care in Finland. Eur Clin Respir J. 2018 Apr 15.

Professor Mikael Knip’s PEDIA research group studies type 1 diabetes in children and adolescents and other immune-mediated diseases such as celiac disease and allergies. Why is diabetes so common in Finland? Is it possible to prevent the development of immune-mediated diseases?

The research group is currently particularly interested in the intestinal microbiota, i.e. the importance of intestinal bacteria, viruses and fungi in the development of immune-mediated diseases. According to the group’s hypothesis, the intestinal microbiota has a two-stage effect on the development of type 1 diabetes.

– At first, a weak immune system exposes children to immune-mediated diseases in infancy. At the second stage, the dysbiosis of the intestinal microbiota and the lack of diversity of these bacteria in toddlers lead to the progression of the disease from an asymptomatic initial stage to clinical symptoms and diagnosis, Knip explains.

The other current goal of the research group is to determine the heterogeneity of type 1 diabetes. The group has found out that there are more than just one phenotype or endotype of type 1 diabetes. 

Prevention of immune-mediated diseases

The objective of studying immune-mediated diseases is to find ways of effectively preventing the onset of these diseases.

The long-term objective is to develop safe and effective methods for the prevention of diabetes and to learn about the effects of intestinal microbiota on pediatric health.

Effective prevention of type 1 diabetes would significantly reduce its prevalence in the Finnish pediatric population and thus improve the quality of life for children and their families. The research group also participates in a study aimed at developing a coxsackievirus vaccine that prevents diabetes. In the best-case scenario, such a vaccine could be in common use in approximately 5 years’ time.

The PEDIA research group was created in 2000 after Mikael Knip became Professor of Pediatrics at Helsinki. Before this, Knip closely cooperated with Professor Hans Åkerblom and his research group.

The research group includes approximately 30 members with medical, genetic, epidemiological, immunological and nutritional competencies as well as competencies in nursing science.

The group has collaborated with Professor Ramnik Xavier from Boston and his research group which is active at the Broad Institute. Dr. Xavier is an expert in gastroenterology and molecular biology.

– We successfully combined unique clinical research material (DIABIMMUNE) and cutting-edge methods for studying intestinal microbiota and for analyzing the results by means of bioinformatics, Mikael Knip says.

Contact details:
Mikael Knip
Helsinki University Hospital Children and Adolescents
mikael.knip(a)helsinki.fi

Website
https://www.helsinki.fi/en/researchgroups/pediatric-diabetes-research-group

Professor Taneli Raivio’s research group examines the genetic and hormonal regulation of growth and development. What launches puberty, which factors regulate growth in height and the function of the pituitary gland? Which factors affect the regulation of sexual development?

The research group examines the hereditary causes of growth and development, uses induced pluripotent stem cells to model rare diseases and develops evidence-based treatments for patients with delayed puberty.

The most important research topics include the regulation of sexual development and the hormonal and genetic factors affecting growth. Among other things, the research results will be beneficial to families with rare diseases.

Helping patients as a measure of success

There have been several scientific successes. The research group was the first in the world to differentiate human ‘puberty neurons’ from stem cells, which is one step towards discovering the mechanisms behind puberty.

– I have always been fascinated by the mechanisms regulating growth and development. As researchers, we are excited to know that the results will also be useful to patients and their families in practice. For instance, we have described a new cause for a growth defect, Raivio explains.

Identifying the KCNQ1 gene defect as a cause of failure of the pituitary gland opened up a new field of research on an international level: how do ion channels regulate the growth of children?

The research group has recently completed a national multicentre trial and is now finding out the mechanisms of two rare diseases. Project funding from the Academy of Finland will help to launch another study into the KCNQ1 gene mutation.

– We will continue our long-span activities in national and international scientific networks for the benefit of our patients. We expect to be able to further improve the diagnostics and treatment of puberty disorders.

Taneli Raivio established the group in 2007 after returning to Finland from a research fellowship in the United States. The group includes 13 people: physicians, doctoral students and postdoctoral researchers. In addition, a few medical students are carrying out their advanced studies.

Contact details

Taneli Raivio
Helsinki University Hospital Children and Adolescentstaneli.raivio(a)hus.fi

Twitter
@RaivioTaneli

Website

https://www.helsinki.fi/en/researchgroups/genetics-and-disease-modeling-with-human-pluripotent-stem-cells

Links to studies and surveys

Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis. Nature Communications, 2017 Nov 3;8(1):1289. doi:10.1038/s41467-017-01429-z.

Development of Gonadotropin-Releasing Hormone-Secreting Neurons from Human Pluripotent Stem Cells. Stem Cell Reports, 2016 Aug 9;7(2):149-57. doi: 10.1016/j.stemcr.2016.06.007

Expert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism–pathogenesis, diagnosis and treatment. Nature Reviews Endocrinology, 2015 Sep;11(9):547-64. doi: 10.1038/nrendo.2015.112

Docent Päivi Miettinen, MD, studies children’s growth and the regulation of puberty development with Professor Taneli Raivio, and pediatric monogenic diabetes with Docent Tiinamaija Tuomi and Professor Timo Otonkoski.

Miettinen was actively involved in basic research until the 2010s. Since then, her focus has shifted more to clinical research. Miettinen’s translational research combines clinical research and basic research (methods of cellular and molecular biology as well as transgenic and knockout animal models in developmental biology).

In her studies, she attempts to find out how the function of beta cells is regulated and how disorders related to it are reflected in clinical diabetes.

– I’m interested in diabetes and growth defects and disorders in the development of puberty. They often originate in problems during fetal development which may only be solved by more precise knowledge of their minute details, Pediatric Endocrinologist Päivi Miettinen says.

MODY gene identified

Monogenic diabetes (MODY) is caused by a defect in genes involved in the function of beta cells. The aim is to map out the prevalence of these genes in Finland. At the same time, the researchers will study in vitro which medication would provide the best treatment for each MODY patient group.

– Once we are familiar with the cause of the disease on a functional level, we may test which treatment is best for the patient. We will also be able to provide the patients and their families with a more accurate prognosis and also better diagnose the disease in the patients’ relatives.

Diabetes studies have already shown that the Rfx6 gene defect can cause a mild beta cell malfunction and raise blood sugar levels. Thus, it may be classified as the new MODY gene.

– We also established that if the patient suffers from HNF1B-MODY, he/she may also have bile-duct development disorders which must be carefully monitored in adulthood.

The other important observation is that if the patients have cysts in their kidneys as well as diabetes, or HNF1B diabetes, their bile ducts must be carefully examined.

The aim of pediatric growth studies is to examine the prevalence of the congenital failure of the pituitary gland as well as new genes regulating the development of the pituitary gland in the Finnish population. The study, which is still at an early stage, uses both patient record systems and medical registers.

Contact details

Päivi Miettinen
Helsinki University Hospital Children and Adolescents
paivi.miettinen(a)hus.fi

Professor Timo Otonkoski’s research group studies the mechanisms of pluripotency and the biology of pancreatic beta cells. The objective is to develop new treatment methods for the insulin deficiency which lies in the background of diabetes.

– We are searching for answers to questions such as how the gene defects in pancreatic beta cells lead to the development of diabetes or congenital hyperinsulinism, where the pancreas secretes too much insulin. We want to find out whether a stem-cell-based beta cell model can be used to discover new remedies for these diseases, Timo Otonkoski says.

Among other things, the research group studies whether human cells can be reprogrammed to early stem cell stages by modifying the operation of genes found in the cells themselves so that the stem cells produced are ‘healthier’ than the cells produced by means of older methods.

Researchers are also interested in the operation of the genes which are the first to be activated when a human embryo develops. In addition, the objective is to examine the regulation of the development of the metabolism of pancreatic beta cells, where cells begin to secrete insulin based on the glucose level.

Putting stem cell technology to good use

Otonkoski says that the most recent potential of stem cell technology and genome modification is being used. These methods can be used to produce so-called iPS cells in laboratory conditions.

– We have shown that regulating the manifestation of genes by means of CRISPR activators is an efficient way to control the reprogramming and differentiation of cells. For the first time in the world, we have used this method to produce iPS stem cells by exclusively activating the genes found in the cells themselves, Otonkoski explains.

From stem cells to beta cells

Next, an attempt is made to optimise the method in order to be able to reprogram stem cells directly for instance into nerve cells, heart cells or beta cells.

The research group has developed an efficient method to differentiate the iPS cells into pancreatic beta-like cells. It has been possible to use it in combination with mutation correction for examining the mechanisms of neonatal diabetes, a rare type of diabetes diagnosed at under six months of age. iPS stem cells produced from the patient’s skin cells have been used to examine the mechanisms of several new genes causing neonatal diabetes.

The research group includes approximately 20 people, most of whom are biologists. The group includes two docents, five postdoc students, five PhD students, several undergraduate students and four technicians. The same group is also in charge of the operation of the stem cell Core Facility of the Medical Faculty.

The research group began to form when Otonkoski returned from his own postdoc period in the United States in 1994. The group initially operated at the Haartman Institute transplantation laboratory. Since 2001, it has been part of the Biomedicum research programmes. Starting in 2019, the group will belong to the new STEMM research programme involving several researchers from the Children’s Hospital.

Contact details

Timo Otonkoski
Children’s Hospital, University of Helsinki
timo.otonkoski(a)helsinki.fi

Website

https://www.helsinki.fi/en/researchgroups/pluripotency-and-disease-modeling

Associate Professor Marita Lipsanen-Nyman’s group studies a rare disease occurring in Finland, the Mulibrey nanism (MUL). Clinical and translational research in conjunction with Professor Hannu Jalanko examines the manifestation of the growth disorder and its course by studying the functional, metabolic and histopathological changes in MUL patients.

The central goal of the research group is to examine the mechanisms of the TRIM37 disease gene on a cellular level. The physiological role of the TRIM37 protein in the human body is as yet unknown. The disease gene was discovered in 2000 at the Folkhälsan Research Center as a collaborative project between Professor Anna-Elina Lehesjoki and HUS Children’s Hospital. Lehesjoki’s group has also produced knockout MUL model on mice.

– Our clinical research has indicated that the Mulibrey nanism is a growth and developmental disorder occurring at the fetal stage but also a disease affecting multiple organs and causing multiple problems. In addition to a permanent growth defect, the clinical picture also strongly involves heart disease, fatty liver and insulin resistance as well as a risk of developing tumors and reduced fertility, Marita Lipsanen-Nyman says.

The group is examining how the disordered function of a single gene, TRIM37, can affect the onset of so many phenomena.

Currently, features such as the onset mechanism of liver disease and metabolic risk factors, infertility as well as the pathology of bones and adrenaline glands are being studied. Thus, we will also come to understand the onset of general disease conditions, such as growth defects, the metabolic syndrome, the risk of developing tumours, or reduced fertility.

Most comprehensive research material and clinical experience found at the New Children’s Hospital

– As a result of our research, HUS Children’s Hospital and now the New Children’s Hospital have been the national and international center for clinical expertise on this extremely rare disease for the last few decades. We are being contacted from around the world for diagnostics and treatment procedures, Marita Lipsanen-Nyman explains. She continues:

– We also have the world’s most comprehensive material on this disease. The research is based on forty years of monitoring patients, which has been necessary in order for the researchers to gradually discover the course and the various features of the disease.

Mulibrey nanism is still little known, particularly outside of Finland. Thus, research carried out at the Children’s Hospital will play a central role when developing new forms of treatment or when drafting new monitoring instructions.

– A cure is not yet known, but it is important to identify patients who can still be helped in many ways. The trust of patients and their families as well as a positive attitude towards research have been an absolute requirement and the icing on the cake of this project, Lipsanen-Nyman says.

Professor Outi Mäkitie acts as the accountable leader of the Mulibrey project, continuing extensive research into the disease with Associate Professor Marita Lipsanen-Nyman’s research group. The group includes postdoc and dissertation researchers, and it cooperates with clinicians and researchers from various fields for subprojects.

The research was launched as early as the 1970s when Professor Jaakko Perheentupa described a new disease, the Mulibrey nanism, at the Helsinki Children’s Hospital. Professor Perheentupa was in charge of the Mulibrey research until the 1990s.

Links to studies

Premature Ovarian Insufficiency and Early Depletion of the Ovarian Reserve in the monogenic Mulibrey nanism disorder. Hum Reprod 2018;33:1254-1261.

High frequency of tumours in Mulibrey nanism. J Pathol 2009a;218:163-171.

Insulin resistance syndrome in subjects with mutated RING finger protein TRIM37. Diabetes 2005;54:3577-3581. 

Mulibrey nanism: clinical features and diagnostic criteria. Med Genet 2004a;41:92–98.

Mulibrey heart disease: clinical manifestations, long-term course, and results of pericardiectomy in a series of 49 patients born before 1985. Circulation 2003;107:2810-2815.

Silver-Russell syndrome providing insight into the causes of short stature

Since the 1990s, Marita Lipsanen-Nyman has studied the epigenetics and genetics of the rare Silver-Russell syndrome (SRS) and other types of short stature originating in the fetal period, in conjunction with the research group of Professor Juha Kere and Associate Professor Katariina Hannula-Jouppi.

The research is a collaborative project between the HUS Children and Adolescents, the University of Helsinki, and the Karolinska Institutet at Stockholm.

Genes regulating growth had already been identified in the 1990s for rare syndromes related to short stature, but the causes of SRS remained unclear. A new discipline, epigenetics, was used to study SRS. In some of the patients, the maternal uniparental disomy for chromosome 7 (matUPD7) was detected, or the hypomethylation of imprinting control region in chromosome 11p15. In uniparental disomy (UPD), both chromosomes of the chromosome pair are only inherited from one of the parents. As for gene imprinting, it results in a gene being active only when inherited from the mother or the father, not from both. Imprinting occurs through DNA methylation during the development of the fetus.

– By studying SRS, we want to generally increase the understanding of the regulation of human growth. Our findings will also help specify and facilitate the diagnostics of SRS, Lipsanen-Nyman explains.

At HUS Children and Adolescents, the research group has collected an internationally unique patient cohort which includes 450 children who were of short stature at birth for an unknown reason. Fifty-five of the patients have SRS. By using molecular genetic methods, it has also been possible to identify new genes regulating growth and epigenetic changes in this cohort.

Now, researchers are examining the causes of short stature in genome-wide studies where SRS is used as a model.

The research group received the international Endocrine Society award for the best clinical report 2009, dealing with the differences between the manifestations of the molecular genetic subgroups of the SRS syndrome.

After Marita Lipsanen-Nyman, Professor Outi Mäkitie will act as the accountable leader for clinical research in the cooperation project at Children and Adolescents.

Contact information

marita.lipsanen-nyman(a)helsinki.fi
outi.makitie(a)helsinki.fi

Links to studies

Hypomethylation of HOXA4 promoter is common in Silver-Russell syndrome and growth restriction and associates with stature in healthy children. Sci Rep 2017; 7(1):115693

Differentially methylated regions in maternal and paternal uniparental disomy for chromosome 7. Epigenetics. 2014;9:351-65.

Submicroscopic genomic alterations in Silver-Russell syndrome and Silver-Russell like patients. Journal of Medical Genetics 2010;47:816-22.

Clinically distinct epigenetic subgroups in Silver-Russel syndrome; the degree of H19 hypomethylation associates with SRS phenotype severity and genital and skeletal anomalies. J Clin Endocrinol Metab 2009; 94(2):579-587.

Genetic screening for maternal uniparental disomy of chromosome 7 in pre- and postnatal growth retardation of unknown etiology. Pediatrics 2002;109:441-448.

Do patients with uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype? J Med Genet 2001; 38: 273-278.

Resident in pediatrics, Juha Grönholm MD, PhD, studies primary immunodeficiencies. The study utilizes exome and genome sequencing to identify gene mutations causing new immunodeficiency syndromes in material collected on Finnish patients.

These diseases are rare, but their number is exceptionally high in Finland. In his study, Grönholm focuses on the congenital defects related to the acquired immunity. The studies will also provide new information on the function of the human immune system.

In 2016, Grönholm returned to Finland after a three-year postdoc period at the National Institutes of Health in the United States. There, in collaboration with British and American researchers, he discovered the primary immunodeficiency syndrome caused by BACH2 gene mutations.

Grönholm is currently involved in Docent Mikko Seppänen’s projects at the University of Helsinki. The research is in its early stages, but there are already several potential disease gene candidates for further studies. This will lead to the discovery of novel primary immunodeficiency syndromes and potentially even entirely new genes affecting the human defence system.

The study requires competencies in both immunology and cellular and molecular biology. During his postdoc years, Grönholm has obtained particular experience in flow cytometry and functional assays with T and B lymphocytes.

– With Mikko Seppänen’s group and, among others, with the laboratories of Professor Juha Kere and Docent Markku Varjosalo, we will examine what types of changes the discovered gene mutations will cause in the function of the proteins coded by the respective genes. Results from the in vitro experiments will then indicate whether the mutation causes the changes detected in patients on a cellular level and their symptoms, Juha Grönholm explains.

Currently, most of the studied patients are adults, but in the future, the aim is to concentrate more on pediatric patients.

Although it is not yet possible to correct congenital genetic mutations, discovering the cause of the disease is important to patients.

– When we are familiar with the exact molecular mechanism of the disease, we are able to develop targeted therapies. Knowledge of the inheritance of the disease is also useful to families planning to have children. The information allows for the early screening of the disease-causing gene variant and in children, and for instance, the early-onset of the intravenous immunoglobulin therapy or other potential treatment for affected individuals, Juha Grönholm says.

The objective is to increase the number of researchers within his personal research group and to transform it into an independent research group in the future.

Contact details

Juha Grönholm
Helsinki University Hospital Children and Adolescents
juha.gronholm(a)hus.fi

Link to the study

https://www.nature.com/articles/ni.3753

Docent Mikko Seppänen’s clinical immunology research group studies rare and congenital immune disorders which are either new or have accumulated in Finland. They are usually caused by a single mutation in the genome. The development of targeted treatment would significantly change the patients’ well-being.

Mikko Seppänen’s research group, which has been active for six years, includes experts in the genetics of primary immunodeficiency and clinical treatment. The group cooperates closely with research groups in rheumatology, hematology, gastroenterology and dermatology and with university hospitals, European research groups, cellular biologists, researchers in translational medicine and laboratory immunologists.

– We study immunodeficiency, autoinflammation and autoimmune diseases. There is a lot to study, since according to estimates, there are still thousands of new immunodeficiency genes and their phenotypes which have not been described. It has been found that Finland has the second-highest prevalence of primary immunodeficiencies in the world, but little research has been made in the field, Mikko Seppänen states.

The research patients in Seppänen’s group have been previously examined by means such as clinical exome sequencing, but these studies did not discover mutations explaining well-known immunodeficiency genes. The group continues to analyse the results or perform a genome sequencing procedure, which will lead to the discovery of the candidate gene.

Studying the malfunction in the gene affecting immunity will help understand the human defence mechanism and its malfunctions in terms of more common diseases as well. For most diseases, it will also be possible to detect a change in the inflammation response.

New hope for the treatment of rare diseases

Seppänen’s group has been involved in the description of new diseases, phenotypes and the diseases in the Finnish disease heritage. New monogenic immunity disorders include TOM1 and STAT3 mutation, HYOU1 deficiency, the new phenotypes include CEBPE, NFKB1 and ADA2 mutations, SLFNL1 mutation and SLFN11, SLFN12 and SLFN13 copy-number variations. The new diseases in the Finnish disease heritage include AICDA founder mutation.

The group will continue to intensively study new hereditary immunodeficiencies. The researchers have discovered that the world’s most common serious immunodeficiency, chronic venous insufficiency (CVI), is more than twice as prevalent in Finns than in the rest of the world’s population.

– We are working intensively to establish the cause of this disease. In addition, our short-term objective is to publish information on two other immunodeficiencies. We will also describe in more detail the diseases caused by NFKB1, TMEM173 and TNFAIP3 mutations. We will naturally continue to study several new candidate genes in conjunction with the other groups.

Each new monogenic disease which results in more effective targeted treatment of patients brings great satisfaction to the research group.

Contact details

Mikko Seppänen
Helsinki University Hospital, Rare Diseases Center
mikko.seppanen(a)hus.fi

The project of Santtu Heinonen, MD, studies pediatric respiratory infections. The group examines why RSV causes difficult infections in small babies in particular. In addition, the aim is to identify potential targets for developing medicinal products and vaccines.

RSV or the respiratory syncytial virus causes difficult respiratory infections in small babies and often requires inpatient care. Vaccines or medication for the infection do not yet exist. In developing countries, RSV causes significant mortality.

Santtu Heinonen explains that the purpose of this study is to acquire new information on the immunological mechanisms of the disease and on the factors increasing its severity, in order to be able to develop more effective medicinal products and vaccines for the treatment of RSV in the future.

The study began with a pilot stage that tested if the research methods were suitable. To date, over 50 babies who have had RSV have been recruited in the study. In addition, healthy babies who are coming in for elective procedures have been recruited in the control group. Winter 2020–2021 was atypical as the RSV epidemic did not occur due to the restrictions related to the COVID-19 pandemic. However, the study continued during winter 2021–2022 when the RSV epidemic was exceptionally intense.

After an examination of the immunological mechanisms at the acute stage, the researchers will monitor the children involved in the study and their subsequent respiratory morbidity. The children will be invited to a control visit at the age of four to six years.

– We are very pleased that the parents of small children have been so positive about the study and actively involved in it although their own child cannot expect direct benefits from the study. The parents consider it important that the involvement of their child in the study may help other children in the future.

Pediatric excellence

Santtu Heinonen launched his study in 2017 by means of Pediatric Academic track funding and he was granted funding as a clinical researcher by the Academy of Finland for 2019–2023 to continue the study. Heinonen is a pediatrician at HUS Helsinki University Hospital. He completed his dissertation on pediatric influenza and then worked as a postdoc researcher at the Nationwide Children’s Hospital, Columbus, Ohio. There, he focused on the immunological mechanisms of RSV infections.

This study uses the new single cell RNAseq methods which can examine the expression of genes on the level of single cells. Individual samples can be used to simultaneously analyse thousands of cells and to acquire an extremely accurate view of the function of the body’s defence cells during infections.

The research group has extensive competencies in pediatric infectious diseases, clinical microbiology, and immunology. The study is carried out in conjunction with Eliisa Kekäläinen’s laboratory (University of Helsinki, Translational Immunology Research Program).

As the project expands and the collection of material progresses, the aim is to engage a research nurse and recruit a dissertation researcher or researchers as well as students carrying out their advanced studies.

Contact details

Santtu Heinonen
Helsinki University Hospital Children and Adolescents
santtu.heinonen(a)hus.fi

In HUS, pediatric clinical trials with medicinal products present increasingly more important part of the hospital’s high-quality, permanent activities, and that requires solid co-operation between professionals in various specialties.

For example, research provides crucial new information about the efficacy of medicines in the treatment of various diseases and about pediatric drug safety.

Docent Jaana Kallio and M.Sc. Pirkko Lepola are establishing pediatric clinical trial unit in the division of digital and innovation services at HUH Children and Adolescents. Some of the trials are researcher-initiated academic studies and some are funded by the pharmaceutical or biotech industry.

The EU regulation on medicinal products for pediatric use that came into force in 2007 increased the need for research. The regulation obliges pharmaceutical companies to study all new drugs for their use in children and adolescents as well, if the European Medicines Agency sees the products are necessary and needed for the pediatric population.

High-quality research

HUS directs resources to train research personnel, and all activities are guided by Good Clinical Practice guidelines.

To ensure high-quality research and applicability for children, expert teams evaluate and plan all studies.

Pediatric clinical trials can provide information about medicinal products such as their absorption and breakdown, elimination and excretion from the body (pharmacokinetic studies), efficacy and safety (clinical trials), and long-term effects (drug safety studies). In this way, it is possible to provide new innovative, safe and effective medicines also for children.

In the future, the implementation of clinical trials will include a separate youth panel where children and adolescents can express their opinions about, for example, the readability of trial information leaflets and about understanding the trial procedures involved in the study.

Importance of networking in pediatric clinical trials

HUS conducts pediatric clinical trials in collaboration with the Finnish investigators network for pediatric medicines (FinPedMed) together with similar Nordic (NordicPedMed) network, having a same aim to increase recruitment and participation in pediatric clinical trials in the future.

As required by the Paediatric Regulation, the pharmaceutical industry has already created over a thousand Paediatric Investigation Plans (PIP) approved by the Pediatric Committee of the European Medicines Agency.

– Only around 130 of these PIP trials have been carried out. The future trials would require the participation of over 200,000 children in Europe. This requires wide research networks, and we contribute to their development significantly, Jaana Kallio explains.

Common European c4c project

HUS researchers are participating in a project called c4c (Collaborative Network for European Clinical Trials for Children), which was launched in May 2018. It is funded by IMI2 (Innovative Medicines Initiative2).

– We are developing a Europe-wide network that is efficient and of high quality to act according to the ethical and regulatory guidelines, and fulfil all quality and safety requirements set for research. HUS acts as a national hub in the project. We are looking for methods that would allow a permanent and seamless network to develop. In this way, research would best serve the needs of pediatric drug treatment and would create new innovative, effective, and safe medicinal products for children at an accelerated pace, Kallio states.

Contact information

Jaana Kallio
Helsinki University Hospital, Children and Adolescents
jaana.kallio(a)hus.fi

Website

Clinical trials involving children

Professor Mikko Pakarinen’s research group studies congenital liver and gastrointestinal disorders in children. The researchers also examined the significance of congenital disease phenotype to the prognosis and to the onset of clinical symptoms.

In the research group, the expertise of experienced pediatric surgeons and pediatricians is combined with the expertise of young pediatric surgeons and pediatricians interested in the research topic. The group actively cooperates on a national level and with international research groups.

Pakarinen explains that networking has allowed the use of modern analytical methods in the study.

Knowledge of the pathophysiological and genetic mechanisms of liver and gastrointestinal disorders will help to develop the diagnostics, treatment and monitoring of the diseases, and to improve the treatment results.

– We are particularly interested in severe intestinal failure related liver damage, biliary atresia, and congenital development disorders of the biliary tract, liver and the intestine, Mikko Pakarinen explains.

These diseases continue to cause significant long-term morbidity. Some of them are also associated with high mortality rates.

New pharmaceutical treatments under investigation

The group is also about to create reliable markers for liver damage which are suitable for clinical use. They are required for the new medicinal investigations on pediatric liver and bile duct diseases in order to monitor the response to treatment.
Pakarinen’s group actively participates in international clinical multicentre studies looking for new pharmaceutical treatments.

– These studies have, for the first time, been able to pharmacologically improve the intestinal absorption function in patients with short bowel syndrome, and to reduce the need for intravenous nutrition.

According to Pakarinen, the progress made in the research has an immediate positive effect on the treatment of patients.

– At the same time, we have made progress in the identification of the pathophysiological mechanisms of biliary atresia and the liver damage related to severe intestinal failure. This will allow for the development of new and better treatments in the future.

Between 2014 and 2018, the group published 80 original articles. The group regularly reports on its research results in international congresses in the field.

The research group was formed gradually in the 21st century, and its activities were officially launched in 2009.

The group includes various senior researchers, dissertation researchers and fledgling researchers as well as students carrying out their advanced studies.

Contact details

Mikko Pakarinen
Helsinki University Hospital Children and Adolescents
mikko.pakarinen(a)hus.fi

A robotic exosuit enhanced walking coordination in children with cerebral palsy and improved gait efficiency by 15%. The results of longer periods of robotic training will be examined in the future.

Problems related to walking limit functional capacity, physical activity and inclusion and also decrease quality of life. Cerebral palsy is the most common cause of severe physical disability in children.

– We’re using wearable robotics to study children’s walking and its rehabilitation. Our research examines why children with physical disabilities walk in a certain way and whether robotic training could make their walking smoother, explains Juha-Pekka Kulmala, PhD (Sport Sciences).

The multidisciplinary research group currently includes two doctoral researchers in the field of biomechanics and a post-doctoral researcher in social psychology. Three-year funding from the Ministry of Education and Culture made it possible to establish the research group in 2021. The research group received five-year funding from the Academy of Finland, which enables a larger research group in September 2022.

Robotic exosuit made walking more efficient

Assistive robotics, such as exoskeletons and exosuit technology, is mainly used for therapy at this time. As the technology develops in the future, wearable robotics will also provide more help in daily movement.

A growing understanding of the neural and biomechanical reasons for deviant walking patterns will aid in the development of more effective forms of treatment. Rehabilitation robotics will be a reasonable option for improving walking ability in the future. A pilot study (Thurston et al. 2021) found that walking coordination in children with cerebral palsy can be guided with a robotic exosuit in a way that improves gait efficiency by 15%. Future research will investigate the impacts of longer periods of robotic training.

The background for this research project is Juha-Pekka Kulmala’s post-doctoral visit to Harvard Biodesign Lab in 2018. This facility is one of the leading research laboratories in wearable robotics. Soon after his visit, a first-generation exosuit ankle robot was purchased for HUS Motion Laboratory. Based on the results of Maxwell Thurston’s pilot project, it was possible to start the larger research project that is currently in progress.

Contact information

Juha-Pekka Kulmala, Biomechanics expert and researcher, PhD (Sport Sciences)
HUS Motion Laboratory, New Children’s Hospital
juha-pekka.kulmala@hus.fi

Links to research:
Thurston M, Kulmala JP, Nurminen J, Avela J. Beyond orthoses: Using an exosuit to enhance the walking pattern of patients with unilateral Cerebral Palsy. Gait & Posture 2021;90: 271-273.

Kulmala JP, Haakana P, Nurminen J, Elina Y, Niemelä T, Marttinen-Rossi E, Mäenpää H, Piitulainen H.  A test of the effort equalization hypothesis in children with cerebral palsy who have an asymmetric gait.  PLoS ONE 2022: 17(1): e0262042

Piitulainen H, Kulmala JP, Mäenpää H, Rantalainen T. The gait is less stable in children with cerebral palsy in normal and dual-task gait compared to typically developed peers. J Biomech. 2021;117:110244.

Under Docent of Pediatric Neurology Tuula Lönnqvist, the NEUROCHILD research group studies severe pediatric progressive brain diseases and neuromuscular diseases. The study of genetic causes and disease mechanisms aims at improving the diagnostics and treatment of the diseases.

The research group has extensive competencies in pediatric neurology as well as strong competencies in molecular genetics, particularly in ataxia, mitochondrial disease and other neurometabolic and neuromuscular diseases, such as neuropathy.

The research was launched in the 1980s in conjunction with basic researchers, such as Anu Wartiovaara, and clinical partners such as Anders Paetau.

– Our partners include nationally esteemed experts in neural pathology, physiology and radiology. We engage in translational cooperation with basic researchers at the University of Helsinki, and internationally with the MCRN (Mitochondrial Clinical Research Network) and Christopher Carroll (St George’s, University of London), Tuula Lönnqvist explains.

New disease genes identified

The academic Neurogenomics project produces information on the usefulness of exome sequencing and cost-effectiveness in severe neurological diseases. The new research methods can be used to determine the order of the entire genome.

Lönnqvist explains that thanks to the new method, more and more patients with various rare diseases have already received an accurate diagnosis.

– Our goal is to use new gene technology applications to provide an accurate genetic diagnosis for as many diseases as possible and to identify their natural course. Determining the causes and the course of development of the diseases will help us to offer new types of experimental treatments and studies for patients in the future.

In international cooperation, new disease genes have already been identified, and new diagnostic methods, such as gene panels and serum markers, have already been developed.

Researchers have also examined the genetic background of one disease within the Finnish disease heritage, the infantile-onset spinocerebellar ataxia (IOSCA). IOSCA causes the early onset of difficulties related to movements, ataxia and a progressive degeneration of the peripheral nervous system and central nervous system.

– For the future of children with rare diseases, it is extremely important to diagnose the symptoms as accurately as possible. It allows them to receive individual and correct treatment and genetic counselling.

Contact details

Tuula Lönnqvist
Helsinki University Hospital Children and Adolescentstuula.lonnqvist(a)hus.fi

Pirjo Isohanni
Helsinki University Hospital Children and Adolescents
pirjo.isohanni(a)hus.fi

Professor Sampsa Vanhatalo’s multidisciplinary research group studies the early functional development of the brain at the Baby Brain Activity (BABA) Center. How do adverse experiences in infancy lead to neurodevelopmental disorders and how do treatments affect brain development?

Research carried out at BABA is already being utilised in the development of devices in several Finnish and international medical companies.

The collaboration project between various universities, which was launched in 2018, is already producing smart clothing for babies.

– We develop smart clothing, such as disposable EEG caps, pants for sleep monitoring and smart jumpsuits which are suitable for the diagnostics and treatment of infants. The Academy of Finland, the Foundation for Pediatric Research and the Finnish Brain Foundation support the project, Sampsa Vanhatalo says.

BABA is also regularly referred to as an international centre for the functional study of the brain. BABA researchers are involved in many international multicentre projects in Europe, the United States and Australia.

Sampsa Vanhatalo sought to accelerate the establishment of the BABA Center in Australia, Brisbane, Perinatal Research Center in University of Queensland. After returning to Finland, he established the BABA Center in connection with the Pediatric Research Center in 2013. It brings together the groups studying infant brain activity at the Helsinki University Hospital and at Helsinki University.

– We have developed methods to measure infant electroencephalography (EEG) as well as new types of mathematical analysis methods. Thanks to this, the Neonatal Intensive Care Unit can perform multichannel measurements of infant brains, or mathematically assess the dialogue between brain areas in newborn babies.

The research group has also developed methods for the automatic analyses of the EEG signal which are based on machine learning. New methods are already able to identify epileptic seizures from the EEG signal and to assess the functional maturity of the child’s cerebral cortex (Functional Brain Age).

Eye tracking camera to monitor development

Vanhatalo’s research group has started the first hospital -based infant eye tracking studies to assess cognitive development in infants.

The group wants to have an impact on clinical treatment practices by inventing new types of research methods and solutions.

– One of them is a method based on artificial intelligence to assess infant electroencephalography, in particular to monitor recovery from brain injury. It can be integrated into the Intensive Care Unit’s monitoring devices, or it may be used for studying new forms of medication and treatment.

The Vanhatalo research group is currently developing a cognitive test system for infants and preschool-age children which is based on eye tracking camera. It would also be suitable for extensive use outside of hospital settings.

Approximately 30 researchers and four research nurses are involved in BABA center research. The group members are physicians from various fields, engineers, physicians, mathematicians and psychologists and students in these fields.

Contact details

Sampsa Vanhatalo
Helsinki University Hospital Children and Adolescentssampsa.vanhatalo(a)helsinki.fi
www.babacenter.fi

The Neo-Neuro research network of seven independent and multidisciplinary groups, led by Professor Leena Haataja, examines the impact of risk and protective factors on long-term neurological prognosis in children at the fetal and neonatal stage.

Fetal and neonatal risk factors affecting the long-term neurological prognosis of children include prematurity, brain hemorrhages, lack of oxygen and inflammation. Protective factors include genetic mechanisms and early interaction between child and parents.

– Based on accumulating research evidence, the prognostic information we are able to provide to the parents of newborn babies at developmental risk is as accurate as possible, project leader Leena Haataja explains.

Neo-Neuro develops methods for assessing the functional ability of children in order to be able to diagnose children with neurological issues as early as possible.

– With the sensitive and validated methods we have developed for this purpose, we are able to target the support and rehabilitation measures requiring social resources to children at the greatest developmental risk, Haataja says.

She explains that according to studies, rehabilitation which starts before the age of six months can result in significantly better independent functional abilities in children with cerebral palsy than rehabilitation that starts later.

Quality control for rehabilitation and intervention studies requires the national unification of research and treatment processes.

– We also develop methods which allow for the active consideration of the views of children with neurological disabilities during rehabilitation. Rehabilitation which the child finds relevant and goal-oriented is also theoretically the most effective in bringing about positive long-term changes.

Long-term monitoring of small premature infants

The Neo-Neuro network has received international attention for the extensive long-term monitoring study on risk and protective factors in the development of very low birthweight premature infants (PIPARI), for the HINE method developed for the early identification of cerebral palsy and for the integration of the evaluation methods for cerebral palsy, which are based on research evidence, to clinical work with patients.

– There has also been widespread interest in a study based on national data which showed that on the level of the population, the low Apgar score in newborn babies is linked to subsequent severe chronic neurological diseases.

Haataja explains that the next major objective is to develop motion analysis methods based on machine learning. In the future, they could be used in studies supplementary to clinical diagnostics during the first year of children’s lives, and in studies on the effectiveness of rehabilitation.

The project leader has eleven PhD students currently preparing their dissertation, four of whom are involved in a project for monitoring the development of premature babies, two in projects carried out at the BABA Center (BAby Brain Activity) and five in independent research groups of three to ten people which have been formed around the subject of each graduate’s ongoing dissertation.

The cooperation between the research projects is implemented through the guidance received by students preparing their dissertations and by postdoc researchers, joint research projects and co-financing. The Neo-Neuro network has been constructed over the past 18 years.

The cooperation projects represent several medical specialities (pediatric neurology, pediatrics, neonatology, neuroradiology, clinical neurophysiology, gynecology).

The research network also includes psychologists and neuropsychologists, physical therapists, an occupational therapist, physicists, engineers, statisticians and nurses.

Contact details
Leena Haataja
Helsinki University Hospital Children and Adolescents
leena.haataja(a)hus.fi

Links
www.utu.fi/pipari

Prediction of neuromotor outcome in infants born preterm at 11 years of age using volumetric neonatal magnetic resonance imaging and neurological examinations. Dev Med Child Neurol 2016; 58:721-27.

Multiprofessional evaluation in clinical practise: establishing a core set of outcome measures for children with cerebral palsy. Dev Med Child Neurol 2017; 59: 322-28.

Low Apgar scores at both one and five minutes are associated with long-term neurological morbidity. Acta Paediatr. 2018 Jun;107(6):942-951.

The research group of Pediatric Neurologist Tarja Linnankivi maps out gene mutations causing epilepsy. The group is also searching for ways to more rapidly identify CRMCC, a rare disorder affecting multiple organs. The studies used the most recent methods of genetic research.

The group operating in the Epilepsy Unit of New Children’s Hospital examines the genetic factors related to epilepsy in a joint project with the research group of Professor Anna-Elina Lehesjoki (Folkhälsan Research Center and Helsinki University). The cooperation began as early as the 1990s, when the first epilepsy genes were identified.

The study gathers information on the nature, treatment response and prognosis for epilepsies caused by various gene defects.

Linnankivi’s research group is oriented towards an active international cooperation, which is particularly important when studying rare epilepsy syndromes. Among other things, the group is involved in the world’s largest genetic epilepsy research project, the EPI25 study.

– The more than 60 children involved in the research project have been assigned a specific genetic diagnosis. It is important to determine the genetic cause, since it may affect the selection of the correct pharmaceutical treatment of epilepsy or other form of treatment, and it may also allow for accurate genetic counselling. In the long term, understanding the genetic backgrounds creates potential for developing targeted treatments for various forms of the disease, Tarja Linnankivi says.

The mystery of CRMCC

Linnankivi’s research group also delves into the mystery of CRMCC (cerebroretinal microangiopathy with calcifications and cysts), a rare disorder affecting multiple organs.

The disorder with abnormalities of the micro blood vessels of the brain and the retina involves the development of calcifications and cavities in the brain.

In Finland, CRMCC is more prevalent than elsewhere in the world. The symptoms and findings related to the disorder have been mapped out since the early 21st century.

– Subsequently, it has been discovered that the disorder affects multiple organs. In addition to the findings in the brain and the eyes, it is associated with a fetal growth defect, and abnormal skeletal structure, intestinal bleeding and blood count abnormalities, Linnankivi explains.

The research group discovered the CTC1 gene defect causing the disorder in 2012, simultaneously with a British research group.

The disorder is recessively hereditary and is often manifested in childhood, but milder forms of the disorder, in which the symptoms begin in adulthood, have also been discovered.

– Several manifestations of the disorder, such as blood count abnormalities as well as liver and kidney malfunctions, are not yet well known, and in these terms, our research continues.

Studies completed by the Linnankivi group help identify CRMCC more rapidly, which allows for better prevention of the damage caused, such as the loss of vision. The long-term goal is to slow down the progress of the disorder.

The CRMCC project includes experts in pediatric neurology, many other pediatric fields and imaging. There is also close cooperation with the research group of Professor Tero Kivelä from the Department of Ophthalmology (Eye Diseases) , and in terms of adult patients, with the research group of Hematologist, Docent Ulla Wartiovaara-Kautto. The research group of Professor Anna-Elina Lehesjoki (Folkhälsan Research Center and Helsinki University) is in charge of molecular genetic studies.

Contact details

Tarja Linnankivi
Helsinki University Hospital Children and Adolescentstarja.linnankivi(a)hus.fi

Links to genetic studies on epilepsy:

Defining the phenotypic spectrum of SLC6A1 mutations. Epilepsia. 2018 Feb;59(2):389-402. doi: 10.1111/epi.13986.

Dravet syndrome: New potential genetic modifiers, imaging abnormalities, and ictal findings. Epilepsia. 2013 Sep;54(9):1577-85. doi: 10.1111/epi.12256.

SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain  Neurology. 2010 Oct 19;75(16):1454-8. doi: 10.1212/WNL.0b013e3181f8812e.

Links to CRMCC studies:

Cerebroretinal microangiopathy with calcifications and cysts. Neurology 2006;67;1437-1443.

Cerebroretinal microangiopathy with calcifications and cysts: characterization of the skeletal phenotype. Am J Med Genet A. 2011 Jun;155A(6):1322-8. doi: 10.1002/ajmg.a.33994.

Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am J Hum Genet. 2012 Mar 9;90(3):540-9. doi: 10.1016/j.ajhg.2012.02.002.

The research group of project leader Mari Videman has a strong desire to understand the development of the infant brain. Their ambition is to reveal how fetal exposure to medication affects the developing brain and the child’s subsequent development.

The research group uses methods of clinical neurophysiology, child neurology, psychiatry, psychology, and mathematics, to examine the effects of antiepileptic medication and antidepressants on the function of the infant brain.

The AED (AntiEpileptic Drug) project has found that the electrical activity of newborn brain exposed to antiepileptic medication differs from the brain activity of control children. Furthermore, the neurocognitive development of the children is affected by the exposure to antiepileptic medication. The developmental differences can be detected already in infancy.

-Our findings are in line with the current guidelines of the treatment of epilepsy during pregnancy. The antiepileptic medication is important for the health of both the mother and the baby, but the safety of the medication should be considered carefully when planning pregnancy, Videman explains.

The research group is part of the international EURAP register study (International Registry of Antiepileptic Drugs and Pregnancy), which involves 42 countries and more than 700 partners.

The NCEP, Neurocognitive Extension Protocol, is a follow-up study assessing the long-term neurocognitive effects of the fetal exposure to antiepileptic medication by the age of six to seven years.

The RaMaVa research project enlightens the effects of fetal exposure to SRI (Serotonin Reuptake Inhibitor) medication. The research group has detected that the electrical brain activity of the newborns exposed to antidepressants differ from the brain activity of the unexposed newborns. The effects were mild, and their importance to the subsequent development is still unknown.

– Our findings confirm the current view of the treatment of depression during pregnancy and have been included in the Current Care recommendations. The treatment of depression during pregnancy is important for the health of both the mother and the baby. During pregnancy, therapy and other non-medicinal treatments take precedence, but in severe cases of depression, medication may be necessary.

The findings of the research group increase information on the factors affecting the development and function of the infant brain. In addition, the objective of the research group is to develop new, non-invasive, methods to predict developmental challenges already during the neonatal period or in infancy, and to enable early support to those who require it.

Ongoing follow-up studies

Follow-up studies examine whether the changes to the electrical activity of the brain detected during the neonatal period are related to subsequent particularities in learning abilities or development. One of the goals is to find biological markers related to neurocognitive development by measuring the electrical activity of the brain at the age of six years.

– We believe that in the future, the research data will help to select safer medications for women with epilepsy or depression planning a pregnancy. The studies may reveal mechanisms underlying learning processes, and assist to develop assessment methods to be used as a diagnostics tool to detect children in risk for learning difficulties.

The Videman research group is part of the international BaBa (BAby Brain Activity) research centre at Helsinki University Hospital. The group cooperates closely with the Aalto University engineering sciences and the Department of Psychology at the University of Tampere. The group has been active since 2010.

Contact details

Mari Videman
New Children’s Hospital, Helsinki University Hospital
mari.videman(a)hus.fi

Links

http://www.babacenter.fi/index.php

Kirsi Mikkonen and Tarja Linnankivi, who are specialized in pediatric neurology, examine epilepsy with onset during the first year of children’s lives, its causes and its effects on the children’s development. The research aims to produce new information on the ability to anticipate or prevent the onset of epilepsy in high-risk infants.

The research group consists of experts in pediatric neurology, clinical neurophysiology, neonatology, ophthalmology, radiology, molecular genetics and pediatric neuropsychology. The group is also involved in national and international cooperation.
The first part of the project was launched in 2017.

Researchers will monitor children who developed epilepsy in their infancy until the age of two years. The potential genetic cause of epilepsy is examined using the latest research methods. Researchers monitor the development of infants and search for new methods which could be used to identify the children with development-related risks at a very early stage. The study also produces information on the prevalence of adverse effects on the visual field caused by vigabatrin medication.

Can a serious illness be prevented?

The project examining the prevention of infantile spasms was launched in 2018. In the project, children will be monitored until the age of seven.

– We perform EEG examinations to monitor the electrical activity of the brain in children who are known to have an increased risk of developing infantile spasms. We will examine whether the onset of the infantile spasms can be prevented by means of vigabatrin medication and whether preventive treatment improves the subsequent development of these children. We will also determine whether vision-related adverse effects can be detected in the school-age children who received vigabatrin treatment in their infancy, the researchers explain.

Contact details

Kirsi Mikkonen
Helsinki University Hospital / Pediatric Neurology
kirsi.h.mikkonen(a)hus.fi

Tarja Linnankivi
Helsinki University Hospital / Pediatric Neurology
tarja.linnankivi(a)hus.fi

Professor Eeva Aronen’s research group explores the various factors affecting children’s mental health. The aim is to improve the prevention of child psychiatric disorders, their assessment, diagnostics and treatment methods.

The research group includes persons with background in medicine, psychology, pedagogy, biology and pharmacology. The group was formed in different research projects during the last five years.

– Children’s mental health is based on the developing brain and positive interactive experiences. The environment affects the development of the brain during pregnancy and throughout the child’s growth and development. It is important to promote children’s mental health, since we know that the course of development during childhood often predicts good health or illnesses during adulthood, Eeva Aronen states.

The studies examine the importance of sleep, stress and executive functions to children’s mental health. The group also studies conduct disorders in children and develops an intervention model for the treatment of disruptive behaviour. The use of psychiatric medication in children is also studied.

The impact of sleep and stress on behaviour

Results on the impact of sleep and stress on behaviour, mood, and executive functions in school children and child psychiatric patients have already been received.

– We have also reported results of the impact of skills related to executive functions, such as attention, working memory, inhibition capacity, to psychiatric symptoms in school children, and results of the impact of sleep and stress-related experiences on the psychiatric symptoms in children and adolescents.

The subject for further studies has already been determined.

– In our studies, we discovered that children below school age on whom a child psychiatric assessment was performed had many deficiencies in executive functions and sleep problems that had an impact on children’s symptoms. In school-aged children, negative experiences, and stress assessed by questionnaires or heart rate variability were significant for the child’s symptoms.

Aronen says that these findings encourage the group to further develop new assessment and treatment methods for executive functions in children, to study the impact of child and parent stress on a child’s mental symptoms, and to develop new forms to support the treatment and prevention of psychiatric disorders in children.

Contact details

Eeva Aronen
Helsinki University Hospital Children and Adolescents
eeva.aronen(a)hus.fi

Links to studies

Teivaanmäki S, Huhdanpää H,  Kiuru N, Aronen ET,  Närhi V, Klenberg L. Heterogeneity of executive functions among preschool children with psychiatric symptoms European Child & Adolescent. Psychiatry 2020.

Maasalo K, Lindblom J, Kiviruusu O, Santalahti P, Aronen ET.  Longitudinal associations between inhibitory control and externalising and internalising symptoms in school-aged children. Development and Psychopathology 2020;1–13.

Vuori M, Martikainen JE, Koski-Pirilä A, Sourander A, Puustjärvi A, Aronen ET, Chudald R, Leena K. Saastamoinen L. Children’s Relative Age and ADHD Medication Use: A Finnish Population-Based Study. Pediatrics 2020:146.

Varimo E, Saastamoinen L, Rättö H, Mogk H, Aronen ET. New Users of Antipsychotics among Children and Adolescents in 2008-2017: a Nationwide Register Study. Front. Psychiatry 2020;11:316.

Huhdanpää H, Moralez-Munoz I, Aronen ET, Pölkki P, Saarenpää-Heikkilä O, Kylliäinen A, Paavonen JE. Prenatal and Postnatal Predictive Factors for Child´s Inattentive and Hyperactive Symptoms at age 5 years:  The Role of Early Family-related Factors. Child Psychiatry & Human Development. 2021;52:783–799.

Karjalainen P, Kiviruusu O, Santalahti P, Aronen ET.  Parents’ perceptions of a group-based parenting program in families with child protection and other family support services in a real-life setting. Child & Family Social Work. 2020; 1-12.

Karjalainen P., Santalahti P., Aronen E.T. & Kiviruusu O. Parent- and teacher-reported long-term effects of parent training on child conduct problems in families with child protection and other support services: a randomized controlled trial. Child Adolesc Psychiatry Ment Health. 2021;15:7.  

Backman H, Laajasalo T, Jokela M, Aronen ET. Parental warmth and hostility and the development of psychopathic behaviors: A longitudinal study of young offenders. Journal of Child and Family Studies. 2021;30:955-965.

Varimo E, Aronen ET, Mogk H, Rättö H, Saastamoinen LK. Antipsychotic Treatment Duration in Children and Adolescents: A Register-Based Nationwide Study. J Child Adolesc Psychopharmacol. 2021;6:421-429.

Vuori M, Sourander A, Aronen ET, Kronström K, Saastamoinen LK. Relative Age and the Use of Second-Generation Antipsychotics from 7 to 17 Years of Age: A Population-Based Register Study. J Child Adolesc Psychopharmacol. 2021 Oct 7.

Seesjärvi E, Puhakka J, Aronen ET, Lipsanen J, Mannerkoski M, Hering A, Zuber S, Kliegel M, Laine M, Salmi J. Quantifying ADHD symptoms in open-ended everyday life contexts with a new virtual reality tool. Journal of Attention Disorders, in press.

Docent Juulia Paavonen’s research group studies sleep in small children, and the development of sleep patterns and sleep quality. Few long-term studies on sleep in small children have been made, though sleep problems are very common in small children.

The aim of researchers is to improve the screening and treatment of pediatric sleep disorders.

– We attempt to find out how common sleep disorders are in children and what factors affect their prevalence. We want to develop the screening and treatment for pediatric sleep disorders, Juulia Paavonen says.

Sleep is also being studied in terms of children’s early psychosocial development. Researchers are also interested in finding out how sleep disorders may predict the disordered regulation of attention or behaviour later in life.

According to the study, sleep disorders are very common in early childhood and are slowly reduced towards the age of two years.

New information has been received on the connection between families’ daily customs and habits and better quality of sleep. For instance, regular evening routines seem to be beneficial to children at a very early stage.

Occasionally, sleep disorders are related to genetic features or temperamental features.

– However, the family’s habits are important. All children with sleep-related problems can be helped to sleep better by focusing on the type of daily life which would best support good sleep patterns for these particular children, Juulia Paavonen states.

The parents may be reassured by the study results which indicate that waking up at night in early childhood is not related to poorer cognitive development at the age of two years.

Are there differences in sleep patterns between boys and girls?

In an epidemiological study, Paavonen’s group focuses on examining the prevalence of various sleep disorders and the risk factors affecting them. The group will produce information on the prevalence of sleep disorders (difficulties falling asleep, waking up at night, amount of sleep) in girls and boys during the first two years of their lives.

Subsequently, a long-term study will examine for which types of pediatric sleep disorders treatment should be available as early as possible and which types of sleep disorders are temporary.

Families with children may be reassured by the fact that sleep disorders are common and usually improve over time. The purpose of research data is also to reassure families by finding out what can be considered the normal development of sleep patterns in children, since they may have incorrect views which are not based on research information. These views often include extreme examples of children who sleep extremely well or very poorly.
Research data also supports the work of child health clinics in identifying children’s symptoms and counselling families. Based on the research results, fact sheets, treatment instructions and materials for families and professionals will be produced in good time, for instance on the Mental Hub’s website.

– Researchers find it very encouraging to hear how many families have been satisfied with their possibility of participating in a study they consider important. They have often found time to answer our long questionnaires. This unique material will provide us with valuable information on many factors affecting children’s welfare.

Juulia Paavonen’s research group includes PhD students, postdoc researchers and students preparing their thesis.

The group includes physicians specialising and specialised in pediatrics, psychiatry, child psychiatry, child neurology, and gynecology as well as Bachelors in Medicine carrying out their basic studies. It also includes researchers in psychology and social psychology. The group actively collaborates with experts in many fields.

The group was formed gradually after 2010 when the collection of the material and networking with researchers in the field was launched. The dedicated researchers would also welcome researchers in nutrition or health care or students completing their advanced studies.

Contact details

Juulia Paavonen
Helsinki University Hospital Children and Adolescents
juulia.paavonen(a)hus.fi

Links to studies

www.thl.fi/child-sleep

Sleep Difficulties in Infancy Are Associated with Symptoms of Inattention and Hyperactivity at the Age of 5 Years. A longitudinal study. J Dev Behav Pediatr. 2019 Jun 3. doi: 10.1097/DBP.0000000000000684

Parental reports showed that snoring in infants at three and eight months associated with snoring parents and smoking mothers. Acta Paediatr. 2019 Feb 21. doi: 10.1111/apa.14758.

The role of parental circadian preference in the onset of sleep difficulties in early childhood. Sleep Medicine, 2018 Nov 24. doi: https://doi.org/10.1016/j.sleep.2018.10.039 

Silja Kosola, the first Nordic docent in adolescent medicine, studies the transition of adolescent patients from children’s hospital to adults’ treatment units. Her team also examines the significance of health checks conducted by school doctors, and school doctors’ approach to school absenteeism. 

Silja Kosola’s research team collaborates with researchers from many different fields, such as various medical specialists as well as specialists in nursing science and social sciences.

– We believe that collaborative research builds a common understanding of the needs of adolescents in health care and, thus, benefits adolescent patients, says Silja Kosola.

The main research topic of the team is the transition of adolescent patients from children’s hospital to adults’ treatment units. Kosola became fascinated with the subject during her doctoral thesis, which she wrote when participating in Professor Pakarinen’s research team.

– While studying the long-term outcomes of pediatric liver transplantation, I noticed that the transition phase has been challenging everywhere and that there is a need for essential research data on the topic.

Good transitional care is currently one of the key topics of interest in adolescent medicine and the subject of the Bridge over troubled water study carried out in collaboration by two parties: the New Children’s Hospital and the Pediatric Research Center in Helsinki and the Royal Children’s Hospital and the Centre for Adolescent Health in Melbourne. In Melbourne, research is led by Professor Susan Sawyer.

The 253 Finnish participants have now been recruited, but in Australia recruitment continues. The adolescents will be monitored for three years, and data will be collected annually from the adolescents themselves and from patient records. Data will also be gathered on the costs of care. The aim is to publish the research protocol this year.

Practical research to support health care

The research team will also study the significance of health checks conducted by school doctors and the role of school doctors in addressing school absenteeism.

Research has significantly improved treatment results in many pediatric diseases. Kosola’s research team is looking for answers to very practical questions. How to maintain the treatment results as the patients reach adulthood? Which has a bigger effect on the transition: the severity of illness or a sense of self-efficacy? What kind of support do young patients need to cope?

– We aim to provide research data to support the health care system. Adolescents have been marginalized for too long: they have a greater need for autonomy than children, but they cannot take full responsibility for their treatment in the same ways as adults.

Kosola began assembling her research team after returning from her post doc research stay at Melbourne’s Royal Children’s Hospital in 2016. The project received a significant boost in 2019, when the Finnish Medical Foundation awarded Kosola a large grant for setting up a research team.

Contact information:

Docent Silja Kosola
silja.kosola (a) helsinki.fi

Docent Kristiina Aalto is in charge of an extensive research project focusing on the various areas of pediatric rheumatology, monitoring the effectiveness of medication, quality issues, patient experiences as well as clinical and register studies.

The research focuses on the development of treatment strategies, the assessment of the impact of treatment as well as networking internationally with other hospitals, clinics and specialities. The prognosis of pediatric rheumatism is examined in conjunction with the Rheumatology Clinic for adults.

The research group also examines the advantages and disadvantages of biological medication as well as the fluency of the process of transferring pediatric rheumatology patients on their way to becoming adult patients.

– Our long-term studies have indicated that pediatric rheumatism causes a significant disease burden. Many pediatric rheumatology patients also suffer from chronic inflammation, a decreased functional capacity and some level of disability in adulthood. Our aim is to update this information, Kristiina Aalto explains.

The long-term monitoring of pediatric rheumatism began at the end of the 1990s with the studies made by Visa Honkanen and Pekka Lahdenne. The research is continued by Kristiina Aalto and Suvi Peltoniemi.

Importance of long-term monitoring

The purpose of long-term monitoring (BART study) is to examine how the prognosis of the disease correlates with the onset age of the disease and other features at the early stages of the disease. The study examines training, employment, support received from society, potential physiotherapy and quality of life. The BART study has also produced the largest amount of research results.

In Finland, the Department of Eye Diseases (research on iritis), the Triangle Hospital (transition study), the Department of Oral and Maxillofacial Diseases (the jaw joint project) and gastroenterologists (intestinal disorders) are involved in the joint Nordic BART study.

The pediatric rheumatism research group considers it important to be able to extensively use the national pediatric rheumatism register, for instance for the assessment of biological medicinal products. The project involves all university hospitals and most central hospitals.

The aim is to create a disease-specific quality register in conjunction with the Rheumatology Clinic for adults and to include in it data from the registers of the National Institute for Health and Welfare, the Social Insurance Institution of Finland and the HILMO Care Register for Health Care. In the future, biobank may also be used in it.

Rehabilitation needs for pediatric rheumatology patients

The collaborative study of the Orton Foundation, the Triangle Hospital and HUS’s Children’s Hospital assesses the transfer of pediatric rheumatology patients to the adult ward by mapping out features such as the impact of medication, disability or incapacity for work.

As for the SANDRA study, it monitors the well-being of the patients and the implementation of treatment by means of mobile phones.

The JADAS multicentre study examines the disease activity of pediatric rheumatism. The aim is to turn the disease activity indicator into a tool which can be used easily for purposes such as considering the adequacy of medication. There are also ongoing studies on the use of biological medicinal products in the treatment of pediatric rheumatism.

Results on all studies have been published in international medical publications (PuBMed) in international congresses for pediatric rheumatology and rheumatology.

Contact details

Kristiina Aalto
Helsinki University Hospital Children and Adolescents 
kristiina.aalto(a)hus.fi 

Website

http://bartinfo.net/nosper/

ORALPEDHEART is a randomized controlled intervention trial to explore the effect of early counselling on oral health in children with heart diseases.

We have learned from previous studies that children with severe congenital heart diseases experience notably more problems with their oral health than healthy children do.

HUS’s pediatric dentistry and cardiology join forces in a cooperation project to study if early repetitive counselling has an effect on the child’s oral health, dental fear, and need for dental restoration such as fillings.

The trial also explores the background factors in oral health and the needs for maintaining oral health.

Support for the entire family

This multiprofessional cooperation study may have a significant social and academic effect.

The interdisciplinary team of five includes a doctor in pediatric dental care, a pediatric cardiologist, and a doctoral student in oral health, among other professionals. The team was founded in 2016.

Currently, the whole team works under one roof in the New Children’s Hospital. The cardiologist and one of the pediatric dentists have known each other since they were students.

They aim to study the effect of support and information on oral health in children with heart diseases: Is there a difference in oral care habits between healthy children and children with heart diseases, and do heart children experience more dental fear? The study also explores oral health related quality of life, and the effect of tube feeding (PEG) on orofacial dysfunctions, i.e. problems with the muscles of the mouth and the face.

“Children with severe congenital heart diseases have more caries than the healthy control group, even though they have received prophylactic additional fluoride treatments. This is why counselling and support should be offered even earlier than before, that is before the children experience symptoms, such as caries,” says Principal Investigator My Blomqvist.

Oral bacteria may be harmful for children with heart diseases. When these bacteria enter the bloodstream, they may cause endocarditis, which is an infection of the valves and inner surface of the heart. Endocarditis can occur due to dental procedures, but the risk is also present at home when brushing the teeth if the child has plenty of bacteria entering the bloodstream.

The oral health in children with heart diseases has been studied before but from a different point of view. Intervention studies have emphasized enhanced caries prevention in older age groups in children whose caries bacteria have already colonized the mouth.
“ORALPEDHEART study provides support and information for the families with heart children already before the caries process begins. Our method is a recurring motivational interview. If the method proves useful, we may utilize it also in other patient groups with a high risk for caries.”

My Blomqvist wishes to emphasize that the aim of the study is to improve oral health in children with heart diseases but also to develop oral health care recommendations. Families would benefit from support and practical instructions.

ORALPEDHEART currently enrols children with heart diseases.

Contact information

My Blomqvist, DDSc, Dental Specialist
my.blomqvist@hus.fi
https://oralpedheart.webnode.fi

The project by docent Emmi Helle, MD, MSc (Econ), studies structural congenital heart defects. Researchers are looking for the causes of these heart defects with complicated heredity by examining genes and environmental factors.

Emmi Helle launched a research project in Finland after returning from her postdoc studies at Stanford University in the United States in 2017.

– We are currently concentrating on structural defects affecting the left side of the heart. These include hypoplastic left heart syndrome (HLHS), aortic stenosis, coarctation of the aorta, and the bicuspid aortic valve. The heredity of congenital heart defects is complicated.

Although variants in a few known genes are known to cause congenital heart defects alone, in the majority of cases it is likely that these defects develop due to a combination of genetic and environmental factors, Emmi Helle states.

The research group has collected a study cohort of approximately 200 Finnish patients. Gene variants causing heart defects are being sought by exome sequencing. In addition, the group has performed genome-wide association analyzes related to heart defects in the FinnGen project.

– We are studying disease mechanisms by using induced pluripotent stem cells (iPS) produced from patients’ skin cells. We differentiate iPS cells into myocardial cells and vascular endothelial cells. The aim is to determine the contribution of individual gene variants to the onset of structural heart defects, Helle continues.

It is known that several factors during pregnancy, such as abnormalities in maternal glucose metabolism and maternal overweight, are risk factors for congenital heart failure in the offspring. Helle’s group also conducts a registry study, which uses Finnish national registries to find out the connection between diseases and medications in pregnancy and congenital heart defects in a national research cohort that includes all children born in Finland in 2006-2016 and their mothers.

The Pediatric Academic track funding has played a significant role in the progress of Helle’s project. The research is done in collaboration with Academy of Finland Research Fellow Riikka Kivelä from the University of Helsinki. Kivelä’s group develops new methods to enable the modelling of diseases by means of stem cells. Researchers are particularly interested in co-culture cell models.

The other partners include Professor Timo Otonkoski’s laboratory at the University of Helsinki, Professor Eero Kajantie’s group at Finnish Institute for Health and Welfare (THL), Professor James Priest’s laboratory at the University of Stanford in California and the University of Washington Center for Mendelian Genomics in Seattle.

Contact details

Emmi Helle
Helsinki University Hospital, University of Helsinki
emmi.helle(a)hus.fi

Links to studies

https://www.helsinki.fi/en/researchgroups/congenital-heart-disease

https://tuhat.helsinki.fi/portal/en/persons/emmi-helle(96acecb6-c170-4e26-852c-ba9ace93a1a8).html

Pediatric cardiologist Taisto Sarkola’s group develops methods based on ultrasound to study the cardiovascular structure and function of children at risk for long-term cardiovascular disease. The group is looking for solutions to monitor and prevent atherosclerosis in families at risk.

The development of adult cardiovascular diseases begins in childhood and possibly as early as the fetal stage. This process is affected by heredity, childhood diseases and vascular disorder as well as by various environmental factors.

In children, cardiovascular diseases which cause symptoms mainly present at birth. These malformations may impact the development of the cardiovascular system during growth and maturation, and Sarkola’s group studies these as well.

Researchers develop new non-invasive methods based on high-resolution ultrasound for the diagnostics of vascular diseases such as vasculitis in children and adults.

During the previous five years, a translational research group has been formed to study the development of blood vessels and heart in children. In addition to the principal investigator, the group includes PhD students, postdoc researchers and students completing advanced studies.

The group actively collaborates with the Dental Unit at the Children’s Hospital in the intervention project for promoting oral health in children with significant heart malformations (ORALPEDHEART). The group also collaborates with pediatric diabetologists in the MOHA project – a motivational interview intervention study to improve blood sugar levels and cardiovascular health in adolescents with type 1 diabetes. In conjunction with oncologists, the long-term effects of cancer treatments are assessed in the HSCT study.

Solutions are also being sought for the monitoring and prevention of early atherosclerotic changes in families at risk. Together with the Folkhälsan research centre, Taisto Sarkola’s group is involved in projects for the prevention of cardiovascular diseases in the setting of obesity, maternal gestational and pre-gestational diabetes, and hypertension (RADIEL and SIVELU studies).

– The collaboration with Folkhälsan is important and it has significantly contributed to the activities of our research group, Sarkola explains.

Contact details

Taisto Sarkola
Children’s Hospital, Helsinki University Hospital
taisto.sarkola(at)helsinki.fi

A research team headed by Associate Professor Laura Madanat-Harjuoja, MD, PhD, will focus on cancer predisposition in cancer presenting at a young age and will investigate the use of liquid biopsy in monitoring and early detection of primary tumors and recurrence in children and adolescents at increased risk of cancer.

“There is relatively little information regarding the application of liquid biopsy in monitoring of pediatric cancer patients. So far, liquid biopsy has only been used in a clinical setting in breast, lung and colorectal cancer in adults,” says Laura Madanat-Harjuoja.

Dr. Laura Madanat-Harjuoja recently returned from the US where she worked as a post-doctoral researcher at Dana-Farber Cancer Institute/Harvard University. Her post-doctoral work led to a publication in the Journal of Clinical Oncology that showed that not only could circulating tumor DNA be identified in the blood and urine samples of patients with Wilms tumor, but that prognostically relevant copy number alterations could be identified in their blood. Some blood samples contained genetic mutations that were not detected in  the biopsied tumor tissue. According to Dr. Madanat-Harjuoja, this is because a tumor biopsy represents only one part of the tumor. The advantage of liquid biopsy is that it captures DNA that is released into the bloodstream from the entire tumor.

“What this means is that circulating tumor DNA detected in the blood of patients can give us an information on several tumors in the same patient in the case of metastatic cancer, for instance. Liquid biopsy also appears to be a promising tool for identifying tumor heterogeneity.” says Dr. Madanat-Harjuoja.

Identifying and monitoring individuals with cancer susceptibility

The research team uses nationwide population-based registry data, through which they have successfully identified more than 9,000 individuals who developed cancer in childhood and their 58,000 - and second -degree relatives, allowing for the identification of individuals and families with cancer predisposition. Medical record abstraction revealed that only one in three of these phenotypically high risk families showed signs of a known cancer susceptibility syndrome, which indicates that there are as yet unidentified cancer susceptibility syndromes. A total of 44 families in which two children developed cancer under the age of 21 were unidentified. Blood sample collection has been completed and the next step is to investigate potential new cancer susceptibility syndromes through exome sequencing.

The study also involves evaluating an optimum monitoring program for individuals with a cancer susceptibility syndrome. A further purpose is to find out whether liquid biopsy could be used for cancer screening in this at-risk group.

“For instance, at the moment children with Li Fraumeni syndrome are monitored with full body MRI scans multiple times a year. This requires the children to be anesthetized and produces a lot of false positives. Liquid biopsy could provide a more specific and non-invasive method for cancer screening,” says Madanat-Harjuoja.

The Finnish Cancer Registry, the Dana-Farber Cancer Institute and the Karolinska Institutet are research partners in the study.

Professor of Cell Therapy and Transfusion Medicine, Kim Vettenranta, MD, PhD, and his group study the use and applicability of targeted cell therapies among children with cancer and severe immunological diseases. The group also targets the introduction of immunological donor tolerance through haploidentical stem cell transplantation among recipients of living-donor kidney transplants. Both groups cooperate with the Finnish Red Cross Blood Service.

Vettenranta’s group studies so-called natural killer cells (NK cells) in allogeneic stem cell transplantation as well as their applicability in modern, targeted cell therapies.

– We take particular interest in the possibility of using NK cells produced from the cord (CB) or peripheral blood of third parties in patients with leukemia or other cancers, also without the allogeneic bone marrow transplantation, Vettenranta explains.

In his opinion, it is particularly fascinating to determine whether cord blood units may be used to produce an NK product which is employable in pediatric patients in the treatment of acute myeloid and lymphoblastic leukemia with a poor prognosis. In adults, this is studied not only for lymphoblastic leukemia but also for multiple myeloma.

Does the future in cancer care lie with CAR-equipped cell therapy?

A cure for pediatric cancers with a particularly poor prognosis, neuroblastoma and sarcomas, is also being sought.

The aim of the group and its cell therapy and research programme is to produce genetically manipulated CAR-NK cells for both adult and pediatric patients in close collaboration with the Finnish Red Cross Blood Service (FRCBS) laboratory. The group includes some of Finland’s leading experts in HLA and NK cells.

The other focus of interest in the group is tolerance provided by a haploidentical stem cell transplant in pediatric patients receiving a kidney transplant from their parent at a very early age. The joint venture includes the renal disease and transplantation group of Professor Hannu Jalanko and Docent Timo Jahnukainen as well as Docent Samppa Ryhänen from the group for blood and oncological diseases and stem cell transplantations of the Children’s Hospital.

– We would like to develop a treatment avoiding the risks involved in the long-term immunosuppressive therapy following renal transplantation. Again, the tolerance and immunity are studied in close collaboration with the Blood Service researchers.
In their PhD projects, two future pediatricians from Kim Vettenranta’s previous research group study the immunological complications and recovery related to childhood allogeneic stem cell transplants.

Contact details

Kim Vettenranta
University of Helsinki, the Children’s Hospital, the Finnish Red Cross Blood Service
kim.vettenranta(a)hus.fi

Professor Markku Heikinheimo’s research group and its collaboration network study several developmental and endocrinological diseases and cancers. They are interested in the gene regulation, particularly in GATA transcription factors essential in the development and function of a multitude of organs.

The group is currently searching for insights into two pediatric liver diseases, biliary atresia and hepatoblastoma. The group also studies gonadal diseases, such as ovarian and testicular diseases, infertility, and germ cell tumours.

Heikinheimo’s group studies the pathogenesis of these diseases and searches for new follow-up markers as well as new therapeutic tools using translational approaches. Gene regulation, which is the key interest of the group, plays an important role during cell growth and development.

– We are particularly interested in factors regulating gene expression, i.e. proteins called transcription factors. These include GATA proteins, and we attempt to shed more light on their interactive networks as well as target genes, Professor Heikinheimo explains.

Towards new therapies to treat severe diseases

Studies use animal models, cell cultures, and comprehensive patient samples as well as clinical data. The initial objective is to have a more profound understanding of the pathophysiology of diseases and to improve their diagnostics and monitoring. In the future, the goal is to develop new therapies for these rare diseases.

In earlier work, the group has examined the role of GATA factors in development of adrenal glands, digestive tract and gonads as well as in several developmental disorders and cancers.

For example, Heikinheimo’s group has shown that the GATA6 protein is involved in the pathological differentiation of hepatic cells in biliary atresia. Biliary atresia is a severe congenital developmental disorder of the extrahepatic bile ducts of the liver.

Next, the group will study this phenomenon with an animal model using mice. In another project, the changes in gene expression in biliary atresia patients will be studied more extensively.

– We will also examine three cancers. In hepatoblastoma, we have elucidated the role of GATA proteins in programmed cell death and in the epithelial-mesenchymal transition. In an ongoing study on ovarian granulosa tumours we clarify the hormonal dependence, mechanisms of metastases and tendency to recur, Heikinheimo says.

In collaboration with researchers at the Washington University in St. Louis, the gene regulation of pediatric germ cell tumours has also been examined.

Extensive cooperation network as the strength of the research group

The research group established by Markku Heikinheimo in the mid-1990s has already included 20 doctoral candidates. In the current group consisting of approximately ten people, some members have the basic physician’s training, and some are biologists. The group includes experienced postdoctoral researchers as well as doctoral students and undergraduate students.

The physicians in the group are specialising or have completed their training to become paediatricians, gynecologists, laboratory physicians, neurologists, oncologists and radiologists.

One of the group’s strengths lies in its close collaboration with other specialities such as physiology, pathology, gynecology, and pediatric surgery, with researchers from the various faculties of the University of Helsinki, Finnish and foreign universities as well as research institutes.

– Since the establishment of our group, our most important partner has been the research group of Professor David B. Wilson at Washington University in St. Louis. Many of our researchers have either visited St. Louis or worked there for longer periods of time while preparing their dissertations.

Contact details

Markku Heikinheimo
Helsinki University Hospital Children and Adolescents
markku.heikinheimo(a)helsinki.fi

Website

https://www.helsinki.fi/en/researchgroups/developmental-and-tumor-biology-research-group

Links to studies
TUHAT research portal

Twitter
@MarkkuHeikinhe1

There are several ongoing studies at the Children’s Hospital from small premature babies to infants. Professor Sture Andersson’s group studies the treatment results for small premature babies by means of machine learning.

The treatment of small premature babies is complicated and expensive. The Children’s Hospital has already documented data on more than two thousand small premature babies in digital format.

– By using big data technology, events putting small premature babies at risk of complications can be identified. We are developing algorithms based on artificial intelligence to increasingly predict these complications, Sture Andersson explains.

The research results are obtained by combining information on the clinical monitoring of small premature babies, imaging studies (such as central nervous system MRI) and various registers (Small premature babies, Hilmo, Kela). This requires both clinical competencies and knowledge of IT and artificial intelligence technologies.

– The digital data system for the Neonatal Intensive Care Unit at the Children’s Hospital has material on small premature babies which has been documented in detail and is extensive on an international level. In addition, Finland’s comprehensive register activities allow for monitoring patients, Andersson says.

The objective of the research is to develop the quality of treatment and to adopt new diagnostic methods.

The group was launched in 2012 and it cooperates with Aalto University and the HUS IT Department. Between 1999 and 2013, the group examined the predictability of sepsis in premature babies in conjunction with IBM.

How much vitamin D do babies need?

Professor Sture Andersson and Professor Outi Mäkitie’s research group examines the effects of vitamin D, particularly on the bones of infants, on the growth of children, on their immunity and infections as well as their mental development.

– Vitamin D affects most of our cells, and it has significant impacts on bones, on immunity and growth, particularly in childhood. We try to establish the sufficient vitamin D level for resulting in positive health effects in infants, Sture Andersson states.

In a clinical trial (VIDI), 975 healthy children received either 10 micrograms or 30 micrograms of vitamin D per day from the age of two weeks to the age of two years. The study found that 10 micrograms of vitamin D was equally effective for the development of the bones and for restricting the number of infections as a larger daily dose.

In the future, researchers will statistically examine the effect of vitamin D on allergies, vaccine response, virus and bacteria colonies and children’s mental development in the same cohort.

– In Finland, the normal vitamin D supplement of 10 micrograms from the age of two weeks to the age of two years is sufficient, and thus a larger supplement is not beneficial to children.

So far, nine publications have been completed in the project, and a follow-up of the cohort will start in 2019.

The research group, which was launched in 2010, includes competencies in neonatology, pediatric endocrinology, infectious diseases, nutrition and genetics.

Fluid transport in the airways

In a unique study, Professor of Neonatology Sture Andersson and Pediatric Cardiologist Olli Pitkänen-Argillander’s research group examines the transport of fluid in neonates’ airways and its contribution to pulmonary edema after heart surgery in actual patients.
Previously, such physiological events have mainly been studied on cell platforms or on animals.

Andersson and Pitkänen-Argillander and a translational research group introduce basic researchers’ findings to the study of patients and healthy people. They began to study fluid transport in the airways of newborns as early as the late 1990s. At that stage, humans are only adapting to breathe air after living in the uterus.

Fetal fluid must be removed from the lungs of newborn babies.

Under Pediatric Cardiologist Pitkänen-Argillander, the group began to examine in the 2010s the contribution of fluid transport in the airways to the onset of pulmonary edema and recovery from it after pediatric heart surgery. Docent Otto Helve has further expanded the study on fluid transport in the airways to pediatric infectious diseases. In addition, there is research cooperation with neonatologists, pulmonary physicians and cardiac anesthesiologists from the Children’s Hospital.

– Fluid transport is mainly based on the transport of osmotic water, brought about by sodium ions, towards the extracellular matrix, and further on to blood and lymph circulation. We examine the respiratory epithelial channel transporting sodium ions by performing ion flow measurements on the mucosa and by means of gene technologies, Pitkänen-Argillander explains.

Significant gene findings

In the early 21st century, the group was at the forefront of finding the gene encoding the ENaC channel in the respiratory epithelium. The research group has also already shown that in prematurely born babies and babies suffering from neonatal respiratory distress syndrome (RDS), fluid transport in the airways is undeveloped, and that a pulmonary ultrasound assessment indicates that the pulmonary fluid is removed more slowly after a cesarean section than after vagina oral delivery.

Babies with congenital cyanotic heart defect have an increased risk of pulmonary edema after heart surgery. After heart surgery, the amount of pulmonary fluid can be assessed not only by means of thoracic imaging but also by means of pulmonary ultrasound.

Fascinating research questions

Among other things, researchers would like to examine whether pulmonary ultrasound could be used to assess pulmonary fluid in clinical work with patients.

The group is also searching for an answer on the role of inflammation mediators in the airways in conditions after heart surgery. How do gender differences manifest themselves in the gene expression of key transportation channels? It is known that boys are more at risk of neonatal breathing difficulties.

A pilot study examines fluid transportation and its abnormalities in the airways of infants with the RS virus infection. And what is the role of Cl ion channels in the removal of pulmonary fluid after birth?

– Since pulmonary ultrasound examinations are rapid and easy, we hope that in the future, they could be part of daily work in the intensive care units for newborns and older children, Pitkänen-Argillander says.

The research group currently includes a dissertation researcher, postdoc researchers and a senior researcher. An experienced laboratory assistant works at the Biomedicum laboratory.

Contact details

Sture Andersson
Children’s Hospital, University of Helsinki
sture.andersson(a)hus.fi

Olli Pitkänen-Argillander
Children’s Hospital, University of Helsinki
olli.pitkanen-argillander(a)hus.fi

Links to studies

Assessment of extravascular lung water by ultrasound after congenital cardiac surgery. Pediatr Pulmonol. 2017 Mar;52(3):345-352. doi: 10.1002/ppul.23531.

Chronic Hypoxemia in Children With Congenital Heart Defect Impairs Airway Epithelial Sodium Transport. Pediatr Crit Care Med. 2016 Jan;17(1):45-52. doi: 10.1097/PCC.0000000000000568.

Lung Ultrasound and Static Lung Compliance during Postnatal Adaptation in Healthy Term Infants. Neonatology. 2015;108(4):287-92. doi: 10.1159/000438453. 

Duration of gestation and mode of delivery affect the genes of transepithelial sodium transport in pulmonary adaptation. Neonatology. 2015;107(1):27-33. doi: 10.1159/000363729.

Delayed lung liquid absorption after cesarean section at term.  Neonatology. 2013;104(2):133-6. doi: 10.1159/000351290. 

Expression of the epithelial sodium channel in airway epithelium of newborn infants de-pends on gestational age. Pediatrics. 2007 Dec;120(6):1311-6. 

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Postdoc researcher Antti Kyrönlahti studies the rare biliary atresia and pediatric stem cell transplantation.

Research requires good collaborative relationships. In Professor Markku Heikinheimo’s research group, Kyrönlahti has formed good partnerships in Finland and abroad. His postdoc periods in Frankfurt and St. Louis have accelerated the creation of networks abroad.

The biliary atresia uses a messenger RNA sequencing material which is unique on an international level and which is already being analysed.

In conjunction with Professors Markku Heikinheimo and Mikko Pakarinen, who have carried out extensive research into biliary atresia, Kyrönlahti examines why connective tissue accumulates in the liver of pediatric patients after a successful Kasai operation.

Biliary atresia is treated surgically with the Kasai operation, which improves short-term clinical outcomes by alleviating cholestasis. Unfortunately, inflammation and progressive liver fibrosis persist after the Kasai operation, resulting in cirrhosis and deterioration of liver function. Fibrotisation of the liver due to biliary atresia is the most common cause of liver transplantations in small children.

– If we could identify the factors causing the fibrotisation of the liver, the accumulation of connective tissue after the Kasai operation, we could develop new medication for these patients. It might reduce the need for liver transplantation in the future, Antti Kyrönlahti says.

In biliary atresia patients, Kyrönlahti’s group has already identified two signal transmission routes which appear to be overly active even after the Kasai operation. The researchers are currently examining the connection between these signal routes and the fibrotisation of the liver.

Research into haploidentical stem cell transplantation

In another project, Antti Kyrönlahti and Docent Eliisa Kekäläinen, who is involved in the Helsinki University research programme for immunobiology, study the restoration of immune system after haploidentical stem cell transplantation.

They are about to launch a collaboration project with the Frankfurt University Hospital. Professor of Cell Therapy and Transfusion Medicine Kim Vettenranta plays an important role in enabling the project.

Kyrönlahti has visited Frankfurt with the support of the Finnish Pediatric Research Foundation in order to acquire deeper knowledge on haploidentical stem cell transplantation and to plan the details of the collaboration project.

In haploidentical stem cell transplantations, the transplants are treated before implanting them in the patient. In the technique most commonly used for pediatric patients, a large number of the mature T and B cells are removed from the transplants.

– The haploidentical stem cell transplantation technique is still relatively new. However, it seems that patients have far fewer graft-versus-host reactions due to the transplant, which may, in the worst case, result in significant issues after an otherwise successful stem cell transplantation. This is why we need new information about the onset of the graft-versus-host reaction, Kyrönlahti explains.

Contact details

Antti Kyrönlahti
Helsinki University Hospital Children and Adolescents
antti.kyronlahti(a)hus.fi

A research group led by Kaija-Leena Kolho attempts to discover the causes of rapidly increasing cases of inflammatory bowel diseases and biomarkers that can be used to predict the onset and development of the diseases.

Inflammatory bowel diseases (IBD) are the most important subject of research in pediatric gastroenterology. Nearly one percent of the current population of Finland has been diagnosed with IBD. The reasons behind the rapid increase in the occurrence of the disease are unknown.

Approximately one out of three patients are diagnosed with a severe form of the disease that requires expensive medications that affect the body’s immune system.

According to professor Kolho’s research, the use of antibiotics in early childhood increases the risk of pediatric Crohn’s disease. The data of Kela’s drug purchase register were used in the study.

Currently, the group is studying the long-term effects of antibiotics on children’s gastrointestinal microbiome, or normal flora.

HELMi research on the development of microbiome

In cooperation with docent Anne Salonen, PhD Katri Korpela and professor Willem de Vos, Kaija-Leena Kolho is studying the development of the microbiome of small children in the HELMi research project (Healthy Early Life Microbiota). The project was initiated in 2016.

The effect of the intestinal microbiome and the factors that shape it on the child’s health and well-being are studied in the project. The aim is to determine the variability in a healthy microbiome and to identify the changes that might indicate a risk of the onset of the disease.

More than 1,000 families with a pregnant mother have been recruited into the study. 96% of these families participated in the study when their child reached the age of three months, and 92% were still included in the study when their child reached the age of one year.

The first phase of the HELMi research project ends in March 2020. The research protocol has been published: BMJ Open Cohort profile: Finnish Health and Early Life Microbiota (HELMi) longitudinal birth cohort. 2019 Jun 27;9(6):e028500.

“We also study other pediatric gastrointestinal disorders with a particular attention on long-term coping,” says Kaija-Leena Kolho.

This clinical, translational research is carried out in cooperation with several research units both in Finland and internationally. Members of the research group have written several dissertations and there are dissertations in progress, while some students are completing their advanced studies.

Contact information

Kaija-Leena Kolho
kaija-leena.kolho@helsinki.fi
+358 (0)50 566 1442