14 research outputs found
Reelin Associated With Restricted and Stereotyped Behavior Based on Principal Component Analysis on Autism Diagnostic Interview-Revised
TƤmƤ artikkeli ei ole avattavissa lehden sivuilta, koska linkit ja DOI vievƤt vƤƤrƤƤn artikkeliin samoin PDF sen ohessa. Kustantajalle ilmoitettu ja pyydetty korjausta.Abstract Background: Twin and family studies have indicated a strong genetic component in autism spectrum disorders, and genetic studies have revealed highly heterogeneous risk factors. The range and severity of the symptom presentation also vary in the spectrum. Thus, symptom-based phenotypes are putatively more closely related to the underlying biology of autism than the end-state diagnosis. Methods: We performed principal component analysis on Autism Diagnostic Interview-Revised algorithm for 117 Finnish families and 594 families from the Autism Genetic Research Exchange (AGRE). The resulting continuous component scores were used as quantitative phenotypes in family-based association analysis. In addition, K-means clustering was performed to cluster and visualize the results of the PCA. Unaffected siblings were included in the study. Results: The components were interpreted as Social Component (SC), communication component and Restricted and Stereotyped Behavior Component (RSBC). K-means clustering showed that, especially in SC, the range of the symptom severity was increased by the siblings. The association of neuroligin 1 with SC was increased, compared to a previous study where only the end-state diagnosis was used. In RSBC, the range of the symptom severity of siblings overlapped greatly with that of patients, which could explain why no association of reelin was found in previous studies in which only the end-state diagnosis was used, but a significant association of reelin with RSBC was now found in the Finnish families (Bonferroni-corrected p=0.029 for rs362644). Although, the Finnish sample is isolated and genetically very homogeneous, compared to the heterogeneous background of AGRE families, many single-nucleotide polymorphisms in reelin, showed modest association with RSBC in the AGRE sample, too. Conclusions: This study demonstrates how the quantitative phenotypes can affect the association analyses, and yields further support to the use of siblings in the study of complex neuropsychiatric disorders.Peer reviewe
Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3
Peer reviewe
MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction
Haematopoietic progenitor cells show special sensitivity to mitochondrial DNA (mtDNA) mutagenesis, which suggests that increased mtDNA mutagenesis could underlie anemias. Here we show that elevated mtDNA mutagenesis in mice with a proof-reading deficient mtDNA polymerase (PolG) leads to incomplete mitochondrial clearance, with asynchronized iron loading in erythroid precursors, and increased total and free cellular iron content. The resulting Fenton chemistry leads to oxidative damage and premature destruction of erythrocytes by splenic macrophages. Our data indicate that mitochondria actively contribute to their own elimination in reticulocytes and modulate iron loading. Asynchrony of this sequence of events causes severe mitochondrial anaemia by depleting the organism of red blood cells and the bone marrow of iron. Our findings account for the anaemia development in a progeroid mouse model and may have direct relevance to the anemias associated with human mitochondrial disease and ageing.Peer reviewe
Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions
AbstractMitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.</div
The Special Features of Organising an Association Event : Case: JyvƤskylƤ Booking
The commissioner of this thesis is JyvƤskylƤ Booking, a unit of JyvƤskylƤ Congress Centre Ltd. The aim was to give suggestions and development ideas for JyvƤskylƤ Booking for the future in the field or organizing events for associations. As JyvƤskylƤ Booking has started to provide event management and organizing services, these suggestions are to help them gain more customers and comprehensive service. This called for studying associations and their special characteristics as event organisers. The focus was on international association events mainly organized in the JyvƤskylƤ region.
The study was implemented as a qualitative study, in a theme interview form. Seven associations operating in Finland were individually interviewed with each interview lasting about one hour. The representatives of each association were given the main themes of the interview beforehand, and the interview itself was more conversational.
The interviews were recorded and then analyzed at a later stage of the thesis process. The main issues discovered from the study were divided into operational and marketing issues. Operational issues suggested ways to develop the services and operations of JyvƤskylƤ Booking to improve their event organizing competences. The marketing issues focused on recommendations for the marketing material of JyvƤskylƤ Booking aimed for associations as potential customers.
The thesis can be utilized by JyvƤskylƤ Booking in their efforts to develop their operations in the recently commenced event organizing branch. However, it should be remembered that these recommendations for services and marketing development are solely based on the needs and demands of the potential customers the commercial aspects of which were not considered. The thesis can also be used by others when needing information on the buying behaviour of associations and event organising characteristics.OpinnƤytetyƶn toimeksiantaja oli JyvƤskylƤ Booking, joka on JyvƤskylƤn Kongressikeskuksen yksikkƶ. TehtƤvƤnƤ oli antaa JyvƤskylƤ Bookingille ideoita ja ehdotuksia sen kehitystyƶhƶn tapahtuman jƤrjestƤmisen saralla. JyvƤskylƤ Booking on alkanut tarjota tapahtumien jƤrjestƤmisen ja toteuttamisen palveluita, joten nƤiden ehdotuksien tavoitteena oli saada JyvƤskylƤ Bookingille lisƤƤ asiakkaita sekƤ vƤlineitƤ kokonaisvaltaisten palveluiden tarjoamiseen. TƤmƤ vaati jƤrjestƶjen tutkintaa, sekƤ sen selvittƤmistƤ, mitkƤ ovat niiden erityisominaisuuksia tapahtumien jƤrjestƤjinƤ. Kohteena olivat kansainvƤliset jƤrjestƶtapahtumat, jotka jƤrjestetƤƤn JyvƤskylƤn alueella.
Tutkimus toteutettiin kvalitatiivisena teemahaastatteluna. SeitsemƤƤ Suomessa toimivaa jƤrjestƶƤ haastateltiin, ja jokainen haastattelu kesti noin tunnin ajan. Jokaiselle haastateltavalle lƤhetettiin haastatteluiden pƤƤteemat etukƤteen luettavaksi, mutta itse haastattelutilanne oli keskustelun omainen. Haastattelut nauhoitettiin ja analysoitiin opinnƤytetyƶprosessin myƶhemmƤssƤ vaiheessa.
Analysointitulokset jaettiin kahteen osaan: toiminnallisiin ja markkinoinnillisiin asioihin. Toiminnalliset ehdotukset kƤsittelivƤt JyvƤskylƤ Bookingin operatiivisia puolia, jotta se voisi kehittƤƤ tapahtumajƤrjestƤmispalveluitaan. Markkinointia koskeva osa sisƤlsi ehdotuksia JyvƤskylƤ Bookingille markkinointimateriaaleista, jotka voidaan kohdentaa jƤrjestƶille ja nƤin ollen potentiaalisille asiakkaille.
JyvƤskylƤ Booking voi hyƶdyntƤƤ tƤtƤ opinnƤytetyƶtƤ tulevaisuudessa vasta aloittamallaan tapahtuman jƤrjestƤmisen toimialalla. On kuitenkin muistettava, ettƤ nƤmƤ ehdotukset palveluiden ja markkinoinnin kehittƤmiseen pohjautuvat vain jƤrjestƶjen toiveisiin ja vaatimuksiin eikƤ kaikkia liiketoiminnallisia puolia ole huomioitu. TƤtƤ opinnƤytetyƶtƤ voivat hyƶdyntƤƤ muutkin, jotka etsivƤt tietoa jƤrjestƶjen ostokƤyttƤytymisestƤ sekƤ jƤrjestƶtapahtumien erityispiirteistƤ
FreeStyle Libre -sensorin potilasopas tyypin 1 diabeetikoille
Kudosverensokeria mittaava flash-sensorointi on yksi merkittƤvimmistƤ kehityksistƤ diabeteksen hoitoon liittyen. Haminassa sen kƤyttƶ on vasta aluillaan. Flash-sensorointi auttaa tyypin 1 diabeteksen hoidon suunnittelussa. Sensorin jatkuvan kƤytƶn on osoitettu parantavan hoitotasapainoa. OpinnƤytetyƶn tarkoituksena oli tuottaa FreeStyle Libre -sensorin potilasopas aikuisille tyypin 1 diabeetikoille, kehittƤƤ diabeteshoitajan tyƶtƤ ja edistƤƤ hoidon ohjausta. OpinnƤytetyƶn tavoitteena on saada asiakas sitoutumaan diabeteksen hoitoon, sekƤ hyƶdyntƤmƤƤn sensoria pitkƤllƤ aikavƤlillƤ. MitƤ parempi diabeteksen hoitotasapaino on, sitƤ vƤhemmƤn tulee kustannuksia ja kuormitusta terveydenhuollolle.
Toimeksiantajana oli Haminan kaupungin perusterveydenhuollon diabeteshoitajat. Tavoitteena oli laatia loppuasiakkaiden sekƤ diabeteshoitajien tarpeita vastaava selkeƤ opas, jota diabeteshoitajat voivat jakaa asiakkailleen sensoroinnin alkaessa. OpinnƤytetyƶ toteutettiin kehittƤmistehtƤvƤnƤ, jossa teoreettinen viitekehys kerƤttiin kirjallisuuskatsauksen keinoin ja toiminnallinen osuus eli potilasopas toteutettiin kehittƤmistutkimuksena. Teoreettinen tausta koostuu tyypin 1 diabeteksesta ja sen hoidosta, hoitotasapainosta ja siihen liittyvistƤ hƤiriƶistƤ, hoidon ohjauksesta sekƤ potilasoppaan laatimisesta. Potilasopas tehtiin yhteistyƶssƤ diabeteshoitajien kanssa ja siitƤ tehtiin yhteensƤ 3 eri versiota. Opas esitestattiin ja muokattiin vastaamaan mahdollisimman hyvin loppuasiakkaiden sekƤ diabeteshoitajien tarpeita.
Potilasoppaan kenttƤtyƶn vaiheet olivat suunnittelu- sekƤ toteutusvaihe. SisƤltƶ jaettiin kolmeen eri osioon: ātƤrkeƤƤā, āhuomioiā ja āvinkkejƤā. Kuvasimme nƤmƤ kokonaisuudet omilla vƤreillƤ ja symboleilla. TƤrkeƤƤ-osio on kuvattu punaisella liikennevalolla, huomioi-osio keltaisella liikennevalolla ja vinkkejƤ-osio vihreƤllƤ liikennevalolla. Potilasoppaassa on lisƤksi kuvia, esimerkiksi FreeStyle Libre ālaitteen eri osista ja symboleista. Potilasopasta kƤytetƤƤn diabeteshoitajan hoidon ohjauksessa, jossa tyypin 1 diabetesta sairastava potilas aloittaa ensimmƤistƤ kertaa flash-sensoroinnin FreeStyle Libre ālaitteella. Jatkokehityskohteeksi ehdotamme tutkimusta, jossa selvitettƤisiin potilasoppaan vaikutuksia tyypin 1 diabeetikon omahoidon sitoutumiseen. LisƤksi jatkossa voitaisiin tutkia FreeStyle Libre -sensorin kƤyttƤjien omahoitoon sitoutumista laajemminkin.Flash glucose monitoring system is a new method to manage type 1 diabetes. It helps to control the disorder and continuous use of flash monitoring has proved to improve the therapeutic equilibrium of type 1 diabetes. FreeStyle Libre is one of the brands in the flash sensor markets and it belongs to Abbott product family.
The purpose of this thesis was to create a FreeStyle Libre -sensor guide for patients with type 1 diabetes. The guide will be aimed at patients who are starting flash monitoring for the first time and it will help nurses to give instructions. The patients will receive essential information about the interstitial glucose reference values as well as how to sensor glucose with FreeStyle Libre, when to measure capillary glucose from blood and when to measure ketone bodies. This illustrated guide was produced in collaboration between two students and two diabetes nurses.
The thesis was composed as a design-based study. The literature review provided basic information concerning on type 1 diabetes, therapeutic equilibrium, co-morbidities, patient guidance and requirements of a good user guide. The actual field-work for the thesis study consisted of planning and implementing the guide and it was conducted in a continuous cycle. There were three different designs of the guide before the final product was approved. It was important that the guide met every need that were specified. The contents were separated to three sections, āimportantā, ānoticeā and ātipsā. These sections were also illustrated with traffic sign symbols red, yellow and green. Ideas for further development and studies could include for example the effects of guidance on patientsā self-treatment and the commitment to self-treatment among patients with type 1 diabetic in general
RadioloÄ£iskais izmeklÄjums pediatriskiem pacientiem ar skoliozi
Nosaukums: RadioloÄ£iskais izmeklÄjums pediatriskiem pacientiem ar skoliozi Autore: Saara Anni Susanna Suomalainen, medicÄ«nas studente Darba vadÄ«tÄjs: Dr. med. Paulis LaizÄns un Dr. med. JÄnis Upenieks PriekÅ”vÄsture : Skolioze ir sÄnu novirze, kas pÄrsniedz 10 grÄdus no normÄla mugurkaula, mÄrot pÄc rentgenogrammas, un tÄpÄc, ka sÄnu lÄ«kne ir saistÄ«ta ar skriemeļu rotÄciju lÄ«knes iekÅ”ienÄ, rodas trÄ«sdimensiju deformÄcija. IdiopÄtiskÄ skolioze bÄrnu populÄcijÄ ir sadalÄ«ta trÄ«s vecuma grupÄs - zÄ«daiÅu, bÄrnu un pusaudžu. RadiogrÄfiskais novÄrtÄjums ir galÄ«gÄs diagnozes pÄ«lÄrs. Labi uzÅemtos rentgenogrammÄs var novÄrtÄt segmentÄcijas anomÄliju raksturojumu, izliekumu veidu un to elastÄ«bu, kÄ arÄ« slimÄ«bas progresÄÅ”anu un ÄrstÄÅ”anas uzraudzÄ«bu. MÄrÄ·i: AttÄldiagnostikas radioloÄ£iskais un kvalitatÄ«vais izvÄrtÄjums pirms- un pÄcoperÄcijas periodÄ operÄtiem idiopÄtiskÄs skoliozes pacientiem, kÄ arÄ« salÄ«dzinÄt bÄrnu un pusaudžu atŔķirÄ«bas. MÄrÄ·is bija tos salÄ«dzinÄt ar iepriekÅ” publicÄtajiem datiem un atrast rezultÄtu, kas ietekmÄtu turpmÄkos ÄrstÄÅ”anas ieteikumus. MateriÄli un metodes: 52 idiopÄtiskas skoliozes pacientu radioloÄ£iskÄs attÄldiagnostikas retrospektÄ«va analÄ«ze, kas 2016.-2020. GadÄ tika hospitalizÄti operatÄ«vai ÄrstÄÅ”anai Latvijas BÄrnu slimnÄ«cÄ, ieskaitot. Respondenti sastÄvÄja no septiÅiem nepilngadÄ«gajiem un 45 pusaudžiem. RadioloÄ£iskie attÄli tika analizÄti datamed.lv PACS sistÄmÄ un ar leÅÄ·a lineÄlu tiem, kuriem pirms un pÄc operÄcijas nebija rentgena. PrimÄrÄ datu analÄ«ze tika veikta Microsoft Office Excel un statistiskÄ analÄ«ze IBM SPSS programmatÅ«rÄ. RezultÄti: Pirms un pÄc operÄcijas attÄldiagnostikas kvalitÄtei bija bÅ«tiski trÅ«kumi. GandrÄ«z pusei gadÄ«jumu bija lieliska pÄcoperÄcijas attÄlveidoÅ”ana, kad tikai 25% gadÄ«jumu pirmsoperÄcijas attÄlveidoÅ”ana bija lieliska. PirmsoperÄcijas MR tika veikts piecos no septiÅiem gadÄ«jumiem bÄrnu grupÄ (71,4%) un 28 reizes no 45 gadÄ«jumiem pusaudžu grupÄ (62,2%). Skriemeļu rotÄcija bija augstÄka krÅ«Å”u kurvja rajonÄ pusaudžiem nekÄ pusaudžiem (p = 0,002), bet jostas rotÄcijÄ nebija statistiskas nozÄ«mes. VidÄjais pirmsoperÄcijas Koba leÅÄ·is 1 bija plaÅ”Äks bÄrniem, 59,14 grÄdi, nekÄ pusaudžiem 47,49 grÄdi ar statistisku nozÄ«mÄ«gumu (p = 0,008). Pusaudžiem fiksÄto lÄ«meÅu vidÄjais rÄdÄ«tÄjs bija nedaudz mazÄks, taÄu statistikas atŔķirÄ«bas starp vecuma grupÄm nebija (p = 0,674). VidÄjÄ galvenÄs lÄ«knes korekcija grÄdos bija bÄrnu grupÄ 33,71 un pusaudžiem 25,72, taÄu statistikas nozÄ«mÄ«bas salÄ«dzinÄjumÄ ar grupÄm nebija (p = 0,068). SecinÄjums: GalvenÄs lÄ«knes pirmsoperÄcijas pakÄpe bija izteiktÄka bÄrniem nekÄ pusaudžiem. GalvenÄs lÄ«knes vidÄjÄ korekcija grupÄs neatŔķīrÄs, un hospitalizÄcijas ilgums bija lÄ«dzÄ«gs. Skeleta vecums operÄcijas laikÄ pusaudžiem bija daudz augstÄks nekÄ pusaudžiem. JÄuzlabo pirmsoperÄcijas un pÄcoperÄcijas attÄldiagnostikas kvalitÄte, papildinot to ar Lenke klasifikÄciju. Pirms operÄcijas MRI jÄveic visiem agrÄ«nÄ sÄkuma skoliozes pacientiem.Title: Radiological Assessment of Pediatric Scoliosis Patients. Author: S. Suomalainen, med.stud. Supervisor: MD Laizans & MD Upenieks. Background: Scoliosis is a lateral deviation >10 degrees of the normal spine measured on a radiograph and because the lateral curve is associated with rotation of the vertebrae within the curve, a 3D deformity occurs. Idiopathic scoliosis in pediatric population is divided to three age groups - infantile, juvenile and adolescent. The radiographic evaluation is the pillar for definitive diagnosis. In well-taken radiographs, the characterization of the segmentation abnormalities, the type of the curvatures and their flexibility can be assessed as well as disease progression and treatment monitoring. Objectives: Radiological assessment of pre- and postoperative imaging results of the operative treatment of the idiopathic pediatric scoliosis and the quality of the imaging. Comparison of juveniles and adolescents differences and comparison to previously published data and find a result, that would have an impact on further treatment recommendations. Materials & methods: Retrospective analysis of radiological imaging of 52 idiopathic scoliosis patients hospitalized for operative treatment in Childrenās Hospital of Latvia during 2016-2020 including. Population consisted of 7 juveniles and 45 adolescents. The radiological images were analyzed in datamed.lv PACS and with angle ruler in those, who didnāt have the pre- and postoperative X-rays in the system. The primary data-analysis was done in MSO Excel and statistical analysis in IBM SPSS. Results: The quality of pre- and postoperative imaging had major shortcomings. Almost half of the cases had excellent post-operative imaging, when preoperative imaging was excellent in only 25% of cases. Preoperative MRI was taken in 5 out of 7 cases in the juveniles (71.4%) and 28 times out of 45 of cases in the adolescents (62.2%). The vertebral rotation was higher grade in thoracic region in juveniles than in adolescents (p=0.002), but there was no statistical significance in lumbar rotation. The mean preoperative Cobb angle 1 was more extensive in juveniles, 59.14 degrees, than in adolescents 47.49 degrees (p=0.008). The Risser grade was higher in operated juveniles than in adolescents (p=0.04). The adolescents had slightly smaller mean of fixed levels, but there was no statistical difference between the age groups (p=0.674). The mean correction of the major curve in degrees was in juveniles 33.71 and in adolescents 25.72, but there was no statistical significance in comparison of the groups (p=0.068). Conclusions: The preoperative degree of major curve was more pronounced in juveniles than adolescents. The mean correction of the major curve didn't differ in the groups and the duration of hospitalization was similar. The quality of pre- and postoperative imaging should improve by adding Lenke classification. Preoperative MRI should be taken in juvenile patients
Chemical Free Cleaning, Microfiber cloths and Cleanability
This paper describes two studies, one in laboratory and another in hospital entranc area. The
aim of laboratory research was not to clean surfaces completely but obtain results with a
standardized method and compare cleanability. This research was conducted in laboratory to
study cleanability of two different kind of laminate surface. In the hospital study the aim was
to compare different kind of cleaning clothes and theirs cleaning results in different contact
areas. There was a small difference in cleanability measurement between different waters but
overall, the results did not differ much. Used microfiber cleaning cloths cleaned surfaces
poorly compared to the new ones as expected. Depending on the dirt one must make choices
what kind of microfiber cleaning cloth is best for different types of dirt. The hospital study
results will be ready in spring 2022
Latausinfratukien vaikuttavuuden arviointi : Loppuraportti
Loppuraportissa analysoidaan Energiaviraston myƶntƤmƤn julkisen latausinfran tuen sekƤ Asumisen kehittƤmis- ja rahoituskeskuksen (Ara) myƶntƤmƤn asuinkiinteistƶjen yksityisen latausinfran tuen kohdentumista sekƤ tukien vaikutuksia ajoneuvokantaan ja henkilƶautoliikenteen pƤƤstƶihin.
Yksityisen latausinfran tuki on kohdistunut voimakkaasti sisemmille kaupunkialueille. Tilastollisen analyysin mukaan ladattavien autojen mƤƤrƤ on lisƤƤntynyt nopeammin tukea hakeneissa tilastoruuduissa verrattuna mahdollisimman samankaltaisiin, tukea hakemattomiin vertailuruutuihin. Kyselytutkimuksen perusteella tuen vaikutus oli etenkin aikaistaa investointeja. Skenaariomallinnuksen mukaan vuoteen 2022 mennessƤ myƶnnettyjen tukien vaikutus pƤƤstƶihin on korkeintaan 88 tuhatta tonnia CO2-ekvivalenttia, jolloin pƤƤstƶvƤhennyksen hinta on vƤhintƤƤn 370 ā¬/tCO2-ekv.
Julkisen latausinfran tuki on kohdistunut hyvin laajalle alueelle. Maakuntatasolla tarkasteltuna hankkeiden osuudet seuraavat vahvasti liikennemƤƤrien osuutta. Tuettujen hankkeiden mƤƤrƤ vastaa suurta osaa etenkin julkisista teho- ja suurteholatauspisteistƤ. Tilastollisen analyysin mukaan lyhyempi etƤisyys julkisten teholatauspisteiden vƤlillƤ pƤƤvƤylien varrella on positiivisesti yhteydessƤ vƤyliƤ kƤyttƤvien kotitalouksien todennƤkƶisyyteen hankkia sƤhkƶauto.TƤmƤ julkaisu on toteutettu osana valtioneuvoston selvitys- ja tutkimussuunnitelman toimeenpanoa (tietokayttoon.fi). Julkaisun sisƤllƶstƤ vastaavat tiedon tuottajat, eikƤ tekstisisƤltƶ vƤlttƤmƤttƤ edusta valtioneuvoston nƤkemystƤ
Fibroblast Growth Factor 21 Drives Dynamics of Local and Systemic Stress Responses in Mitochondrial Myopathy with mtDNA Deletions
Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISRmt) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISRmt progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISRmt (ATF5, mitochondria) one-carbon cycle, FGF21, and GDF15). The local progression to 2nd metabolic ISRmt stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondria! unfolded protein response marks the 3rd ISRmt stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.Peer reviewe