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Background: Childhood brain tumor (BT) survivors have an increased risk of treatment-related late effects, which can reduce health-related quality of life and increase morbidity. This study aimed to investigate lumbar disc degeneration in magnetic resonance imaging (MRI) in adult survivors of radiotherapy-treated childhood BT compared to age and sex-matched population controls. Methods: In this cross-sectional comparative study, 127 survivors were identified from hospital registries. After a mean follow-up of 20.7 years (range 5–33.1), 67 survivors (mean age 28.4, range 16.2–43.5) were investigated with MRI and compared to 75 sex-matched population-based controls. Evaluated MRI phenotypes included Pfirrmann grading, intervertebral disc protrusions, extrusions, and high-intensity-zone-lesions (HIZ). Groups were also compared for known risk factors of lumbar intervertebral disc (IVD) degeneration. Results: Childhood BT survivors had higher Pfirrmann grades than controls at all lumbar levels (all p < 0.001). Lumbar disc protrusions at L4-5 (p = 0.02) and extrusions at L3-4 (p = 0.04), L4-5 (p = 0.004), and L5-S1 (p = 0.01) were significantly more common in the BT group compared to the control. The survivor cohort also had significantly more HIZ-lesons than the controls (n=13 and n=1, p=0.003). Age at diagnosis was associated with lower degree of IVD degeneration (p < 0.01). Blood pressure correlated with IVD degeneration (P < 0.05). Conclusions: Signs of early disc degeneration related to tumor treatment can be seen in the IVDs of survivors. Disc degeneration was more severe in children treated in adolescence.

Background: The role of cytokines in the pathogenesis of febrile seizures (FSs) is unclear, and information regarding cytokine production outside of FS episodes is scarce. Methods: In our controlled follow-up study of patients with FSs, we compared the levels of 12 serum cytokines after the patients’ first FSs, during febrile episodes without FSs, after recurrent FSs, during healthy periods after FSs, and between patients and controls. Results: Two-hundred fifty-one patients with first FS participated in the study, of whom 17 (mean age 1.6 years, SD 0.7) with recurrent FSs completed the protocol as required by the sample size calculations. The mean IL-1RA level was higher after the first FSs (2580 pg/mL, SD 1516) than during febrile episodes without FSs (1336 pg/mL, SD 1364, P = 0.006) and healthy periods after FSs (474 pg/mL, SD 901, P = 0.001). IL-1RA levels were also higher during first (2580 pg/mL) and recurrent FSs (2666 pg/mL, SD 1747) in comparison with febrile controls (746 pg/mL, SD 551) (P < 0.001 and P = 0.001, respectively), but there was no difference in the IL-1RA between febrile episodes without FSs and febrile controls. Conclusions: Patients with FSs produce stronger inflammatory reactions during febrile episodes with FSs compared with febrile episodes without FSs and febrile controls.

Purpose: Growth failure is common in radiotherapy-treated long-term survivors of pediatric brain tumors, but studies on longitudinal growth in this patient group are lacking. Here, the aim was to assess the changes in growth patterns before and after brain tumor diagnosis, the adult height, and the risk factors for compromised growth. The incidence and treatment practices of growth hormone deficiency were analyzed. Methods: A cohort of 73 survivors of childhood brain tumor (median age 27.2 years, range 16.2 to 43.8 years) was studied after a median follow-up period of 20.4 years from diagnosis (IQR 14.9 to 22.9 years). Patients were treated in five university hospitals in Finland between 1970 and 2008. Growth curves, final height, and patient- and disease-related risk factors for compromised growth during different growth periods were analyzed. Laboratory analyses for IGF-1 and IGFBP-3 were performed at the follow-up. Results: Growth failure was evident at diagnosis, with a mean height decline of −0.6 SDS (standard deviation score) from birth (95% CI −1.15 to −0.05). Mean height SDS decline after the diagnosis was −1.09 SDS (95%CI −1.51 to −0.66). At follow-up, 37% of the study subjects (27/73) had true short stature (height < −2 SDS). The mean height deficit corrected for target height was −1.9 SDS (95% CI −1.45 to −2.40). Growth failure was associated with the age at diagnosis, corticosteroid dose, radiotherapy modality and mean dose of irradiation in the thalamic area. Low IGF-1 level (below −2.0 SDS) was found in 32% (23/72), and untreated growth hormone deficiency in 40% (29/72) of the subjects. Conclusions: Longitudinal growth impairment was common in radiotherapy-treated survivors of childhood brain tumor, resulting in compromised adult height. Loss of growth potential was evident already at diagnosis and further accelerated by the treatments. At young adulthood, unrecognized growth hormone deficiency was common.

Purpose: Survivors of childhood brain tumors (BT) are at high risk for long-term physical and psychological sequelae. Still, knowledge about health-related quality of life (HRQL) and associated factors in this population is sparse. This study investigated HRQL and its predictors in long-term survivors of childhood BT Methods: Survivors of childhood BT (mean age=28.1 years, SD=6.8, n=60) underwent clinical examination and neurocognitive examination, and completed self-rating questionnaires assessing HRQL (RAND-36) and depressive symptoms (Beck Depression Inventory-II). Socio-demographic information was gathered via a questionnaire. Tumor- and treatment-related information was collected from medical records. Control group data were collected from age-matched controls (n=146) without a history of cancer, randomly selected from the local population registry. Multiple linear regression models were used to investigate predictors of HRQL; separate models were ftted for each domain of the RAND-36. Results: Male survivors (mean age=27.0, SD=6.0, n=39) reported signifcantly lower HRQL than male controls in the domains of physical functioning, general health, vitality, social functioning, and role limitations-emotional. Female survivors (mean age=30.2 years, SD=7.6, n=21) reported comparable levels as female controls in all domains except physical functioning. A higher burden of late efects, not working/studying, being diagnosed with BT during adolescence, and reporting current depressive symptoms were signifcant predictors of lower HRQL. Conclusions: Our results highlight that male survivors of childhood BT are at particular risk of impaired HRQL. Also, results point to the close relation between symptoms of depression and impaired HRQL in survivors of childhood BT which should be acknowledged by long-term follow-up care.

Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients’ immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in

Aim: To investigate the usefulness of the National Emergency X-Radiography Utilization Study (NEXUS) II head trauma decision rule in clinical practice for paediatric patients in a tertiary university hospital serving as the only paediatric hospital in the area. Methods: We compared how doctors evaluated and examined patients with head injury during two time periods, before and after the introduction of NEXUS II decision rule. Multiple implementation strategies were used as follows: education, tutoring and written instructions for the use of NEXUS II. Results: Two hundred and forty-four head injury patients visited the hospital before and 385 after the introduction of the NEXUS II decision rule. The number of hospital admissions (56%) and the mean duration of hospitalisation (2.5 days) remained the same during the two periods. In the NEXUS II evaluated group, there was a decrease of 40% in the number of hospital admissions. NEXUS II was applied in only 62 (16%) cases. The number of head imaging procedures remained the same. No patients with a clinically significant head injury were missed with the NEXUS II evaluation. Conclusion: NEXUS II was ineffective as our implementation failed. When used, NEXUS II reduced expenses in our study population by decreasing the number of hospital admissions.

Background: Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy. Methods: Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients’ files. Results: Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16–43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts. Conclusions: Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.

Various genetic aetiologies — including mitochondrial diseases, chromosomal disorders, and other monogenic diseases — are involved in status epilepticus (SE), a common neurologic emergency occurring in children and adults that exhibits high rates of morbidity and mortality. The exact frequency of mitochondrial SE is currently undefined. Furthermore, patients with pathogenic variants of POLG1 encoding mitochondrial DNA polymerase gamma have an increased risk of acute liver failure (ALF) induced by the common antiepileptic drug, valproic acid (VPA), which is problematic due to these patients also often experiencing drug-resistant seizures. Overall, the role of liver transplantation (LT) in VPA-ALF due to mitochondrial disease has been controversial. In the present work, large retrospective cohort studies were conducted for two main purposes: (1) to determine the genetic aetiologies of SE among Finnish paediatric and adult patients by specifically focusing on the common mitochondrial genetic defects associated with an increased risk of SE and (2) to examine whether common POLG1 p.Q1236H and p.E1143G variants are connected to liver or pancreatic toxicity upon exposure to VPA monotherapy. This thesis also describes the characteristics of VPA-ALF associated with the pathogenic POLG1 variant p.W748S and the prognosis of LT in a retrospective case series. Mitochondrial diseases explained 4.5% of SE cases in the study cohort. Patients with mitochondrial SE suffered from refractory SE significantly more often than patients with other forms of genetic or non-genetic SE. Additionally, mortality rates were higher in patients with mitochondrial or chromosomal disorders compared with the other groups, reflecting the severity of the underlying condition and the higher frequency of refractory SE. POLG1 variants p.Q1236H and p.E1143G could not be identified as risk factors for VHT or pancreatic toxicity, implying that VPA treatment might be suitable for patients harbouring t, Tiivistelmä Useita perinnöllisiä syitä, kuten mitokondriotauteja, kromosomihäiriöitä ja muita geenimuutoksia on tunnistettu status epilepticuksen (SE) eli pitkittyneen epileptisen kohtauksen taustalla. SE on yleinen neurologinen hätätilanne, johon liittyy merkittävää oheissairastavuutta ja kuolleisuutta sekä lapsilla että aikuisilla. Mitokondriotauteihin liittyvän SE:n tarkkaa esiintyvyyttä ei tiedetä. Potilailla, joilla on patogeenisia variantteja mitokondrioiden DNA-polymeraasia koodaavassa tuman POLG1-geenissä, on todettu kohonnut riski yleisesti käytetyn epilepsialääkkeen valproaatin (VPA) aiheuttaman akuutin maksavaurion kehittymiselle. Tämä tekee lääkehoidon valinnasta ongelmallista, koska näillä potilailla on usein epilepsialääkkeille resistenttejä kohtauksia. Maksansiirron merkitys akuutin maksavaurion hoidossa mitokondriotauteja sairastavilla potilailla on ollut kiistanalainen. Tutkimuksen tavoitteena oli selvittää SE:n perinnöllisiä syitä suomalaisilla lapsi- ja aikuispotilailla retrospektiivisesti kerätyssä laajassa potilasaineistossa. Tutkimuksessa keskityttiin yleisimpiin mitokondriaalisiin perinnöllisiin muutoksiin, joiden on aiemmin todettu liittyvän SE:n lisääntyneeseen riskiin. Tutkimuksen toisena päätavoitteena oli selvittää väestössä yleisten POLG1-geenin muutosten eli varianttien p.Q1236H ja p.E1143G yhteyttä maksatoksisuuteen tai haimatoksisuuteen VPA-monoterapian aikana. Lisäksi tutkittiin VPA:n aiheuttaman maksavaurion kliinisiä erityispiirteitä patogeeniseen POLG1-varianttiin p.W748S liittyen sekä mutaatiostatuksen vaikutusta maksansiirron jälkeiseen ennusteeseen. Mitokondriotaudit selittivät 4,5 % SE-tapauksista tämän väitöskirjatyön potilasaineistossa ja näillä potilailla SE pitkittyi hoitoresistentiksi tai erittäin resistentiksi merkitsevästi muita potilasryhmiä useammin. Kuolleisuus oli suurin potilailla, joilla todettiin mitokondriotauti tai kromosomihäiriö, liittyen todennäköisimmin vakavaan taustasairauteen ja hoitoresistentin SE:n suu

Background: Childhood brain tumors (CBTs) are the most common solid tumors in childhood. CBT survivors have a high risk of several late-effects, including cerebrovascular disease (CVD), neurocognitive impairment, secondary neoplasms, and low bone mineral density; however, only a few studies have clinically investigated the late-sequelae in young-adult CBT survivors. Aim: To determine the prevalence of CVD, neurocognitive impairment, secondary neoplasms, and bone mineral density in a national cohort of radiotherapy-treated long-term survivors of CBT. Subjects and Methods: Radiotherapy-treated CBT survivors diagnosed between 1970–2008 were selected based on the following inclusion criteria: follow-up ≥5 years since the cessation of therapy and age of ≥16 years at the time of the study. Survivors were clinically and neuropsychologically examined, and investigated by magnetic resonance imaging (MRI), bone mineral densitometry, and laboratory analysis. Results: We included 74 survivors after a mean follow-up time of 18.9 ± 6.1 years. The mean age at follow-up was 28.4 ± 6.8 years and at diagnosis 8.3 ± 4.3 years. At the 20-year follow-up, the cumulative prevalence of CVD, along with small- and large-vessel disease was 52%, 38%, and 16%, respectively. Ischemic infarcts or transient ischemic attacks were diagnosed in 11% of the survivors, lacunar infarcts in 10%, and cerebral hemorrhage in 3%. White matter lesions (WMLs) were noted in 49% of the survivors. Higher blood pressure was associated with CVD, large-vessel disease, WMLs, and lacunar infarcts. Survivors had lower cognitive performance in all neuropsychological domains than controls. Mean verbal intelligence quotient was 89 ± 14 and mean performance intelligence quotient 87 ± 19. Executive functions (Z-score -5.0 ± 5.3 SD) and processing speed (Z-score -4.3 ± 5.4 SD) were extensively impaired. Executive functions and processing speed were associated with everyd, Tiivistelmä Taustaa: Suomessa sairastuu vuosittain 46–60 lasta aivokasvaimeen, joka on lapsuusiän yleisin, kiinteä kasvain. Selviytyneillä on todettu lisääntynyt hoitojen myöhäisvaikutuksien riski. Kuitenkin nuorten aikuisten haittavaikutuksia on toistaiseksi tutkittu melko vähän. Tutkimuksen tarkoitus: Tarkoituksena oli selvittää sädehoidon jälkihaittoina esiintyvien sairauksien, kuten aivoverisuonisairauksien, älyllisten ongelmien, sekundaaristen kasvainten ja luustonhaurastumisen yleisyyttä ja riskitekijöitä suomalaisessa, kansallisessa kohortissa. Aineisto ja Menetelmät: Tutkimukseen kutsuttiin kaikki Suomessa lapsuusiällä aivokasvaimen sairastaneet aikuiset, jotka oli hoidettu sädehoidolla vuosina 1970–2008. Tutkittavat olivat yli 16-vuotiaita ja hoitojen päättymisestä oli yli 5 vuotta. Osallistuneille tehtiin kliininen ja neuropsykologinen tutkimus, pään magneettikuvaus, luustontiheysmittaus ja laboratoriotutkimuksia. Tulokset: Tutkimukseemme osallistui 74 nuorta aikuista 18,9 ± 6,1 vuotta hoitojen päättymisen jälkeen. Tutkittavat olivat iältään 28,4 ± 6,8-vuotiaita osallistuessaan, ja 8,3 ± 4,3-vuotiaita diagnoosihetkellä. Aivoverisuonisairaus todettiin 52% tutkimukseen osallistuneella 20 vuoden seurannan jälkeen, pienten suonten tauti oli 38 %:lla ja suurten suonten tauti 16 %:lla. Aivoinfarktin oli sairastanut 9 % tutkituista, lakuunainfarktin 10 % ja aivoverenvuodon 3 % tutkituista. Valkean aivoaineen muutoksia todettiin 49 %:lla magneettikuvauksessa. Korkea verenpaine lisäsi aivoverisuonisairauden, suurten suonten taudin, valkoisen aivoaineen muutoksien sekä lakuunainfarktien riskiä. Selviytyjien keskimääräinen kielellinen älykkyysosamäärä oli 89 ± 14 ja ei-kielellinen 87 ± 19. Suurimmat vaikeudet todettiin toiminnanohjauksessa (Z-luku −5,0 ± 5,3 SD) ja prosessointinopeudessa (Z-luku −4,3 ± 5,4 SD). Toiminnanohjauksen ja prosessointinopeuden vaikeudet olivat yhteydessä arkielämän haasteisiin. Sekundaaristen aivokalvokasv

Novel genetic aetiologies for epileptic encephalopathies and movement disorders have been discovered by using next-generation sequencing methods. The phenotypic and genotypic variability in these conditions is very wide. The aim of this study was to discover novel genetic causes and phenotypes of childhood-onset drug-resistant epilepsy and epileptic or developmental encephalopathies that occur separately or together with movement disorders, and familial movement disorders. Furthermore, the use of whole-exome sequencing (WES) as a diagnostic tool in clinical practice was evaluated. Altogether, 12 children with undefined aetiology, who fulfilled the inclusion criteria, were included in the study. GABRG2 gene was identified as a genetic cause of epileptic encephalopathies. Novel GABRG2-associated phenotypes included progressive neurodegeneration, epilepsy in infancy with migrating focal seizures, and autism spectrum disorder. New pathogenic variants, GABRG2 p.P282T and p.S306F, were discovered. The pathogenic NACC1 variant caused focal epilepsy, developmental disability, bilateral cataracts, and dysautonomia. The novel phenotype associated with the NACC1 p.R298W variant included hyperkinetic movement disorder. SAMD9L was found to be the genetic cause for the familial movement disorder. The phenotype associated with the novel SAMD9L p.I891T variant was very variable. Neuroradiological findings included cerebellar atrophy and periventricular white matter changes. After publication of these results, SAMD9L was reported to be one of the most common genetic aetiologies of childhood bone marrow failure and myelodysplastic syndrome. The pathogenic homozygous MTR variant was found to cause early-onset epileptic encephalopathy that occurred together with movement disorder and haematological disturbances. Drug resistant seizures responded to cofactor and vitamin treatments. Whole-exome sequencing for 10 patients with drug-resistant epilepsy or epileptic or developmental, Tiivistelmä Uusien sekvensointimenetelmien käyttöönotto on mahdollistanut epileptisten enkefalopatioiden ja liikehäiriöiden uusien geneettisten syiden löytymisen. Näissä sairausryhmissä geenien ja ilmiasujen vaihtelevuus on suurta. Tutkimuksen tarkoituksena oli löytää uusia geneettisiä syitä ja ilmiasuja lapsuusiällä alkavissa vaikeahoitoisissa epilepsioissa ja epileptisissä tai kehityksellisissä joko itsenäisesti tai yhdessä liikehäiriön kanssa esiintyvissä enkefalopatioissa sekä perheittäin esiintyvissä liikehäiriöissä. Lisäksi selvitettiin eksomisekvensoinnin käyttökelpoisuutta kliinisessä diagnostiikassa näiden potilasryhmien kohdalla. Tutkimukseen osallistui yhteensä 12 sisäänottokriteerit täyttävää lasta, joiden sairauden syy oli jäänyt tuntemattomaksi. GABRG2-geenin mutaatiot aiheuttivat epileptisiä enkefalopatioita, joiden uutena ilmiasuna oli etenevä taudinkuva, johon liittyivät aivojen rappeutuminen, migroiva imeväisiän paikallisalkuinen epilepsia sekä autismikirjon häiriö. Tutkimuksessa löydettiin uusia GABRG2-mutaatioita: p.P282T ja p.S306F. NACC1-geenin mutaatio aiheutti epilepsian, kehitysvammaisuuden, molemminpuolisen kaihin ja autonomisen hermoston toiminnan häiriön. Hyperkineettinen liikehäiriö oli uusi NACC1 p.R298W -mutaatioon liittyvä ilmiasu. SAMD9L-geenin mutaatio aiheutti perheessä esiintyvän liikehäiriön. Neurologinen ja hematologinen ilmiasu olivat hyvin vaihtelevia. Aivojen kuvantamislöydöksiin sisältyi pikkuaivojen rappeutumista ja valkoisen aivoaineen muutoksia aivokammioiden ympärillä. Näiden tutkimustulosten julkaisemisen jälkeen SAMD9L-geenin mutaatioiden on todettu olevan yksi yleisimmistä perinnöllisistä luuytimen vajaatoiminnan ja myelodysplasian syistä. Homotsygoottinen MTR-geenin mutaatio aiheutti varhain alkaneen epileptisen enkefalopatian, liikehäiriön ja hematologisen häiriön. Kofaktori- ja vitamiini hoidot vähensivät epileptisiä kohtauksia, joihin tavanomainen lääkitys ei tehonnut. Geneettiset syyt ja ilmiasut ovat epileptisis

Purpose: Long-term side effects of the treatments are common in survivors of irradiated pediatric brain tumors. Ionizing radiation in combination with surgery and chemotherapy during childhood may reduce vertebral height and bone mineral density (BMD), and cause growth failure. The aim of this study was to evaluate the late consequences of tumor treatments on vertebrae in survivors of childhood brain tumors. Methods: 72 adult survivors (mean age 27.8 years, standard deviation 6.7) of irradiated childhood brain tumor were studied by spinal magnetic resonance imaging (MRI) for vertebral abnormalities from the national cohort of Finland. Patients were treated in five university hospitals in Finland between the years 1970 and 2008. Subject height and weight were measured and body mass index (BMI) was calculated. The morphology and height/ depth ratio of the vertebrae in the middle of the kyphotic thoracic curvature (Th8) and lumbar lordosis (L3) were examined. Vertebrae were analyzed by Genant’s semiquantative (SQ) method and spinal deformity index (SDI) was calculated. BMD was measured by using dual X-ray absorptiometry. Results: 4.2% (3/72) of the patients had undiagnosed asymptomatic vertebral fracture and 5.6% (4/72) of patients had radiation- induced decreased vertebral body height. Male patients had flatter vertebrae compared with females. Patient age at the time of irradiation, BMI and irradiation area correlated to vertebral morphology differentially in males and females. BMD had no association with the vertebral shape. Patients who had received craniospinal irradiation were shorter than the general population. Conclusion: Childhood brain tumor survivors had a high number of vertebral abnormalities in young adulthood. Irradiation was associated with abnormal vertebral morphology and compromised final height. Male gender may predispose vertebrae to the side effects of irradiation.

Studies of trophic-level material and energy transfers are central to ecology. The use of isotopic tracers has now made it possible to measure trophic transfer efficiencies of important nutrients and to better understand how these materials move through food webs. We analyzed data from thirteen 15N-ammonium tracer addition experiments to quantify N transfer from basal resources to animals in headwater streams with varying physical, chemical, and biological features. N transfer efficiencies from primary uptake compartments (PUCs; heterotrophic microorganisms and primary producers) to primary consumers was lower (mean: 11.5%, range:100%). Total N transferred (as a rate) was greater in streams with open compared to closed canopies and overall N transfer efficiency generally followed a similar pattern, although was not statistically significant. We used principal component analysis to condense a suite of site characteristics into two environmental components. Total N uptake rates among trophic levels were best predicted by the component that was correlated with latitude, DIN:SRP, GPP:ER, and % canopy cover. N transfer efficiency did not respond consistently to environmental variables. Our results suggest that canopy cover influences N movement through stream food webs because light availability and primary production facilitate N transfer to higher trophic levels.

Mitochondrial DNA depletion and deletions are related to mutations in the nuclear genes responsible for replication and maintenance of mitochondrial DNA (mtDNA). The POLG1 gene encodes the enzyme responsible for replication of mtDNA. A particular feature of the POLG1 mutations is an increased risk of acute liver failure (ALF) upon exposure to sodium valproate (VPA), but the pathomechanism is not resolved. The present work studies the molecular genetic aetiology and clinical phenotypes associated with mtDNA depletion and deletion. Another objective was an investigation of clinical phenotypes in POLG1 mutations and disentangling the pathomechanism of VPA-induced ALF in POLG1 mutations. Mitochondrial toxicity of VPA was examined using HepG2 cells as an experimental in vitro model. In this work, mtDNA depletion was associated with severe neonatal-onset encephalopathy. Furthermore, mtDNA depletion was found in muscle dystrophy as a secondary finding to muscle degradation. Multiple mitochondrial DNA deletions were found in two patients with Kearns-Sayre syndrome suggesting a genetic origin of the disease. POLG1 p.R722H mutation has been previously reported as a neutral polymorphism, but we found evidence suggesting that POLG1 p.R722H could be a pathogenic mutation in a homozygous or compound heterozygous state. We identified retrospectively five patients, who required liver transplant after VPA-induced ALF. All five patients harboured POLG1 mutations supporting the evidence of POLG1 mutations as a risk factor for VPA-induced ALF. Previously, patients with POLG1 mutations have been considered unsuitable for liver transplantation, but we found that homozygous POLG1 mutations and adolescent or adult-onset disease predicted a good outcome following liver transplantation. In vitro studies on HepG2 cells showed that VPA disturbs mitochondrial respiration. Our results expand the phenotypes and molecular genetic features in mitochondrial DNA depletion and deletion syndro, Tiivistelmä Mitokondrion DNA:n (mtDNA) kahdentumisesta ja ylläpidosta vastaavien tuman geenien mutaatiot voivat johtaa mtDNA:n määrän vähenemiseen (depleetioon) ja katkoksiin (deleetioihin). MtDNA:n kahdentumisesta vastaavaa entsyymiä koodaa tuman POLG1-geeni. POLG1-mutaatioihin liittyy kohonnut riski sairastua natriumvalproaatin (VPA) aiheuttamaan akuuttiin maksavaurioon. Tutkimuksen tavoitteena oli tutkia mtDNA:n depleetion ja deleetioiden molekyyligeneettistä etiologiaa ja kliinisiä taudinkuvia. Tutkimuksessa selvitettiin myös POLG1-mutaatioihin liittyviä taudinkuvia ja POLG1-mutaatioihin liittyvän akuutin maksavaurion patomekanismia. VPA:n vaikutusta mitokondrioiden toimintaan tutkittiin in vitro HepG2-solumallissa. Tutkimuksessa todettiin mtDNA:n depleetion liittyvän vaikeaan varhain alkavaan aivosairauteen. Depleetio todettiin myös sekundaarisena merosiini-negatiivisessa lihasdystrofiassa. Kahdella Kearns-Sayren syndroomaa sairastavalla potilaalla todettiin multippelit mtDNA:n deleetiot, mikä viittaa syndrooman geneettisen alkuperään. POLG1 p.R722H-mutaatiota on aiemmin pidetty neutraalina polymorfiana, mutta tutkimuksen tulokset viittasivat siihen, että homotsygoottisena tai yhdistelmäheterotsygoottisena mutaatio on tautia aiheuttava. Helsingin yliopistollisen sairaalan elinsiirtorekisteristä tunnistettiin retrospektiivisesti viisi potilasta, jotka olivat saaneet maksansiirteen VPA:n aiheuttaman maksavaurion vuoksi. Kaikilla viidellä potilaalla todettiin POLG1-geenin mutaatio, mikä vahvistaa käsitystä geenin yhteydestä VPA:n aiheuttamaan maksavaurioon. POLG1-mutaatioita on pidetty vasta-aiheena maksansiirrolle, mutta tutkimuksessa todettiin homotsygoottisena esiintyvän POLG1-mutaation ja nuoruusiällä tai varhaisella aikuisiällä alkaneen taudin liittyvän parempaan maksansiirron jälkeiseen ennusteeseen. HepG2-solumallilla tehdyt tutkimukset osoittivat VPA:n haittaavan mitokondrioiden solyhengitystä. Tutkimuksen tulokset tuovat lisätietoa mtDNA:n depleetioon ja

The purpose of the present work was to investigate whether children with non-lesional temporal lobe epilepsy (TLE) have deficits in neuropsychological performance and whether the possible deficits can be investigated using functional magnetic resonance imaging (fMRI). In this population-based study, 21 children aged 8–15 with non-lesional TLE and a normal intelligence quotient were evaluated and compared with 21 healthy, age- and gender-matched controls. Neuropsychological assessments, clinical examinations, electroencephalography (EEG) and structural and functional MRI were performed on all the subjects. Three fMRI methods were used: resting-state regional homogeneity, resting-state functional connectivity and task-induced blood oxygenation level-dependent activation. The patients with non-lesional TLE showed good neuropsychological performance on average, although the girls were found to have significant problems in several neuropsychological tests. The deficits were not restricted to elements of performance involving the classical temporal lobe memory system but were also found in tests requiring frontal and parietal lobe functioning. Early onset of epilepsy and duration of epilepsy had significant negative effects on neuropsychological performance. All the fMRI methods detected significant functional differences between the TLE patients and the healthy controls, not only in the temporal lobes but also in broad networks extending to the frontal, parietal and thalamic areas. These differences seemed to differ markedly in location between the TLE patients depending on the interictal EEG findings. Neuropsychological performance results were supported by the fMRI findings, implying that TLE should be regarded as a widespread disruption of the brain networks and not just malfunction of a single region in the brain within these networks. This needs to be taken into consideration when evaluating learning abilities among TLE patients even at an early stage in ep, Tiivistelmä Tutkimuksen tarkoituksena oli selvittää onko lapsilla, jotka sairastavat tuntemattomasta syystä aiheutuvaa ohimolohkoepilepsiaa, neuropsykologisia ongelmia ja aiheuttavatko mahdolliset ongelmat aivojen toiminnallisessa magneettikuvauksessa nähtäviä muutoksia. Tähän väestöpohjaiseen tutkimukseen otettiin 21 tuntemattomasta syystä ohimolohkoepilepsiaa sairastavaa normaaliälyistä 8–15-vuotiaista lasta ja verrattiin heitä 21 terveeseen, ikä- ja sukupuolivakioituun kontrollihenkilöön. Kaikille tutkimukseen osallistuneille tehtiin neuropsykologinen tutkimus, kliininen tutkimus, aivosähkökäyrä sekä rakenteellinen ja toiminnallinen aivojen magneettikuvaus. Toiminnallisessa magneettikuvauksessa käytettiin veren happipitoisuudesta riippuvaista (engl. blood oxygenation level-dependent) kontrastia kuvantamaan levossa aivojen paikallista homogeniteettia (engl. regional homogeneity) ja toiminnallista kytkennällisyyttä (engl. functional connectivity) sekä kognitiivisten tehtävien herättämiä aktivaatio-vasteita. Tuntemattomasta syystä ohimolohkoepilepsiaa sairastavien lasten neuropsykologinen suoriutuminen oli keskimäärin hyvää, vaikkakin tytöillä oli nähtävillä tilastollisesti merkitseviä ongelmia useissa eri testeissä. Ongelmat eivät rajoittuneet pelkästään klassisiin ohimolohkoalueen muistitoimintoihin, vaan niitä havaittiin myös otsa- ja päälakilohkojen toimintoja edellyttävissä testeissä. Varhainen sairastumisikä ja epilepsian kesto heikensivät suoriutumista tilastollisesti merkitsevästi osatesteissä, joissa tarvittiin näönvaraisen hahmottamisen taitoja, psykomotorista nopeutta ja työmuistia. Ohimolohkoepilepsiaa sairastavien ja terveiden kontrollien aivoissa löydettiin toiminnallisia eroja kaikilla toiminnallisen magneettikuvauksen menetelmillä. Eroja ei todettu ainoastaan ohimolohkoissa, vaan niitä löytyi myös otsa- ja päälakilohkoon sekä tyvitumakealueelle ylettyvissä laaja-alaisissa hermoverkostoissa. Epilepsiapotilailla erojen paikantuminen riippui kohtaustenv

Objective: We studied the prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children in a defined population in Notthern Ostrobothnia, Finland. Methods: Children with diagnoses commonly associated with mitochondrial diseases were ascertained. Blood DNA from 522 selected children was analyzed for 3243A>G. Children with the mutation were clinically examined. Information on health history before the age of 18 years was collected from previously identified adult patients with 3243A>G. Mutation segregation analysis in buccal epithelial cells was performed in mothers with 3243A>G and their children whose samples were analyzed anonymously. Results: Eighteen children were found to harbor 3243A>G in a population of 97,609. A minimum estimate for the prevalence of 3243A>G was 18.4 in 100,000 (95% confidence interval, 10.9-29.1/100,000). Information on health in childhood was obtained from 37 adult patients with 3243A>G. The first clinical manifestations appearing in childhood were sensorineural hearing impairment, short stature or delayed maturation, migraine, learning difficulties, and exercise intolerance. Mutation analysis from 13 mothers with 3243A>G and their 41 children gave a segregation rate of 0.80. The mothers with hetetoplasmy greater than 50% tended to have offspring with lower or equal heteroplasmy, whereas the opposite was true for mothers with heteroplasmy less than or equal to 50% (p = 0.0016). Interpretation: The prevalence of 3243A>G is relatively high in the pediatric population, but the morbidity in children is relatively low. The random genetic drift model may be inappropriate for the transmission of the 3243A>G mutation. © 2007 American Neurological Association.