Hyperthyroidism and Papillary Thyroid Carcinoma in Thyrotropin Receptor D633H Mutant Mice

Background: Constitutively active thyrotropin receptor (TSHR) mutations are the most common etiology of non-autoimmune hyperthyroidism (NAH). Thus far, the functionality of these mutations has been tested in vitro, but the in vivo models are lacking. Methods: To understand the pathophysiology of NAH, we introduced the patient-derived constitutively active TSHR D633H mutation into the murine Tshr by homologous recombination. Results: In this model, we observed both subclinical and overt hyperthyroidism depending on the age, sex and copy number of the mutated allele. Homozygous mice presented hyperthyroidism at 2 months of age, while heterozygous animals showed only suppressed TSH. Interestingly, at 6 months of age, thyroid hormone concentrations in all mutant mice were analogous to wildtypes, and they showed colloid goiter with flattened thyrocytes. Strikingly, at one-year of age nearly all homozygous mice presented large papillary thyroid carcinomas (PTC). Mechanistically, this PTC phenotype was associated with an overactive thyroid and strongly increased stainings of proliferation, pERK, and NKX2-1 markers, but no mutations in the “hot-spot” areas of common oncogenes (Braf, Nras, Kras) were found. Conclusions: this is the first study to reveal the dynamic age-, sex- and gene dosage-dependent development of NAH. Furthermore, we show that a constitutively active TSHR can trigger a malignant transformation of thyrocytes

Open Innovation Maturity in Companies

Using open innovation approach instead of closed innovation approach improves productivity. To successfully implement the open innovation approach in a company, it is important to evaluate its maturity and readiness to use this approach. The aim of this study is to explore the open innovation maturity and readiness of Finnish and Greek companies. Hence, this study follows a quantitative approach and uses a 13-item survey to explore the open innovation maturity levels. A total of 81 participants from different companies and with different expertise and backgrounds participated in the survey. In addition to the survey, to examine the open innovation maturity of the companies the maturity model for open innovation which consist of five levels with level 5 depicting the highest maturity level was used. The aim was to examine the open innovation maturity of the companies participating in the study. Based on the results, the studied companies were found to mainly achieve level 3 regarding open innovation thinking. More attention and effort should be given to achieve levels 4 and 5. Due to the importance of achieving maturity levels 4 and 5 and their complexity, the need for companies to understand the significance of strategic thinking and for aligning their general strategy with their innovation strategy was highlighted. Additionally, it was evident that to achieve higher levels of maturity, open innovation approaches should be followed and changes in the organizational management should be implemented. Concluding we claim that for companies to adopt an effective open innovation culture, it is essential to integrate appropriate models, methods, and practices starting from lower maturity levels.© 2023 Pekka Makkonen, Kerstin Siakas, Georgios Lampropoulos. Published by Academic Publishing.fi=vertaisarvioitu|en=peerReviewed

The Effects of Presleep Slow Breathing and Music Listening on Polysomnographic Sleep Measures - a pilot trial

Knowledge on efficient ways to reduce presleep arousal and, therefore, improve sleep, is scanty. We explored the effects of presleep slow breathing and music listening conditions on sleep quality and EEG power spectral density in young adults in a randomized, controlled trial with a crossover design. Participants’ (N = 20, 50% females) sleep was measured on two consecutive nights with polysomnography (40 nights), the other night serving as the control condition. The intervention condition was either a 30-minute slow breathing exercise or music listening (music by Max Richter: Sleep). The intervention and control conditions were placed in a random order. We measured heart rate variability prior to, during and after the intervention condition, and found that both interventions increased immediate heart rate variability. Music listening resulted in decreased N2 sleep, increased frontal beta1 power spectral density, and a trend towards increased N3 sleep was detected. In the slow breathing condition higher central delta power during N3 was observed. While some indices pointed to improved sleep quality in both intervention groups, neither condition had robust effects on sleep quality. These explorative findings warrant further replication in different populations.Peer reviewe

Screening for Mutations in Isolated Central Hypothyroidism Reveals a Novel Mutation in Insulin Receptor Substrate 4

Background Central hypothyroidism (CeH) is a rare condition affecting approximately 1:16 000- 100 000 individuals. Congenital forms can harm normal development if not detected and treated promptly. Clinical and biochemical diagnosis, especially of isolated CeH, can be challenging. Cases are not usually detected in neonatal screening, which, in most countries, is focused on detection of the more prevalent primary hypothyroidism. Until now, five genetic causes for isolated CeH have been identified. Here we aimed to identify the genetic cause in two brothers with impaired growth diagnosed with CeH at the age of 5 years. We further evaluated the candidate gene variants in a large genetic database. Methods Clinical and biochemical characterization together with targeted next-generation sequencing (NGS) was used to identify the genetic cause in a family of two brothers presenting with CeH. Screening of insulin receptor substrate 4 (IRS4) variants was carried out in the FinnGen database. Results A novel monoallelic frameshift mutation c.1712_1713insT, p.Gly572Trp fs*32 in the X-linked IRS4 gene was identified by NGS analysis in both affected males and confirmed using Sanger sequencing. Their mother was an unaffected carrier. In addition to the declined growth at presentation, central hypothyroidism and blunted TRH test, no other phenotypic alterations were found. Diagnostic tests included head MRI, thyroid imaging, bone age, and laboratory tests for thyroid autoantibodies, glucose, insulin and glycosylated hemoglobin levels. Examination of the IRS4 locus in FinnGen (R5) database revealed the strongest associations to a rare Finnish haplotype associated with thyroid disorders (p = 1.3e-7) and hypothyroidism (p = 8.3e-7). Conclusions Here, we identified a novel frameshift mutation in an X-linked IRS4 gene in two brothers with isolated CeH. Furthermore, we demonstrate an association of IRS4 gene locus to a general thyroid disease risk in the FinnGen database. Our findings confirm the role of IRS4 in isolated central hypothyroidism.Peer reviewe

Screening for Mutations in Isolated Central Hypothyroidism Reveals a Novel Mutation in Insulin Receptor Substrate 4

Background: Central hypothyroidism (CeH) is a rare condition affecting approximately 1:16 000- 100 000 individuals. Congenital forms can harm normal development if not detected and treated promptly. Clinical and biochemical diagnosis, especially of isolated CeH, can be challenging. Cases are not usually detected in neonatal screening, which, in most countries, is focused on detection of the more prevalent primary hypothyroidism. Until now, five genetic causes for isolated CeH have been identified. Here we aimed to identify the genetic cause in two brothers with impaired growth diagnosed with CeH at the age of 5 years. We further evaluated the candidate gene variants in a large genetic database.MethodsClinical and biochemical characterization together with targeted next-generation sequencing (NGS) was used to identify the genetic cause in a family of two brothers presenting with CeH. Screening of insulin receptor substrate 4 (IRS4) variants was carried out in the FinnGen database.Results: A novel monoallelic frameshift mutation c.1712_1713insT, p.Gly572Trp fs*32 in the X-linked IRS4 gene was identified by NGS analysis in both affected males and confirmed using Sanger sequencing. Their mother was an unaffected carrier. In addition to the declined growth at presentation, central hypothyroidism and blunted TRH test, no other phenotypic alterations were found. Diagnostic tests included head MRI, thyroid imaging, bone age, and laboratory tests for thyroid autoantibodies, glucose, insulin and glycosylated hemoglobin levels. Examination of the IRS4 locus in FinnGen (R5) database revealed the strongest associations to a rare Finnish haplotype associated with thyroid disorders (p = 1.3e-7) and hypothyroidism (p = 8.3e-7).ConclusionsHere, we identified a novel frameshift mutation in an X-linked IRS4 gene in two brothers with isolated CeH. Furthermore, we demonstrate an association of IRS4 gene locus to a general thyroid disease risk in the FinnGen database. Our findings confirm the role of IRS4 in isolated central hypothyroidism</p

Kelan monimuotoisen perhekuntoutuksen kehittämistyö : Palveluntuottajien näkökulma

Kelan Lasten perhekuntoutuksen kehittämishankkeissa (LAKU- ja Etä-LAKU-hankkeet) on kehitetty monimuotoista perhekuntoutusta 5–12-vuotiaille lapsille ja heidän perheilleen. Kehittämistyötä on toteutettu vuosina 2012–2018, minkä jälkeen kuntoutuspalvelu jalkautetaan soveltuvin osin Kelan valtakunnalliseen kuntoutustoimintaan. Kehittämistyön aikana on saatu paljon arvokasta tietoa niin asiakkailta, palveluntuottajilta kuin yhteistyökumppaneiltakin. Tieteellisen seurantatutkimuksen keskeiset tulokset julkaistaan erillisessä raportissa. Tässä raportissa kuvataan lyhyesti hankkeen taustaa sekä kuntoutuksen sisältöä. Pääpaino on kuitenkin palveluntuottajien kirjoittamissa teksteissä, jossa he kuvaavat omin sanoin työryhmän, asiakkaiden sekä yhteistyötahojen kokemuksia LAKU- ja Etä-LAKU-kuntoutuksesta. Lapsen kuntoutuksessa on tärkeää ottaa mukaan koko perhe sekä arjen toimintaympäristö, kuten koulu ja päiväkoti. Tämä mahdollistui LAKU-kuntoutuksessa. Yhteistyö hoitavan tahon kanssa oli joissakin tapauksissa haasteellista mm. aikataulujen suhteen, mutta toteutui pääasiassa hyvin. Kuntoutus sisältää joustavuutta niin käyntikertojen rakenteessa kuin sisällössäkin. Sitä toivottiin kuitenkin jatkossa lisää, koska perheiden haasteet ovat erilaisia. LAKU- ja Etä-LAKU-kuntoutukseen kuuluivat perheiden kuntoutusviikonloput, joita pidettiin toimivina. Niissä korostui erilaiset ryhmätoiminnat sekä erityisesti vertaistuki. Asiakkaat toivoivat enemmän kuin kaksi viikonloppua kuntoutusprosessin aikana, mutta palveluntuottajien näkemyksen mukaan määrä oli riittävä. Etä-LAKU-hankkeessa kuntoutus tapahtui pääasiassa perheen kotona niillä paikkakunnilla, joissa etäisyydet ovat pitkiä ja palveluita vähän. Malli haastoi työntekijät, mutta myös antoi paljon. Perheet olivat tyytyväisiä ja hyvin sitoutuneita kotona tehtävään kuntoutukseen. Asiakasperheet, yhteistyökumppanit että työntekijät kokivat LAKU- ja Etä-LAKU-kuntoutuksen pää-sääntöisesti hyödylliseksi ja lapsen sekä perheen toimintakykyä parantavaksi kuntoutusmuodoksi. Yhtenäisenä toiveena oli, että kuntoutus jatkuisi Kelan vakiintuneena toimintana hankkeiden jälkeen

Greenhouse gas emissions in Finland 1990-2014 : National inventory report under the UNFCCC and the Kyoto protocol

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