NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) : characterisation of a novel cerebropulmonary disease

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.Peer reviewe

Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy

The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBAS, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBAS variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.A1a371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg5SHis, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.A1a371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufml in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.A1a371Thr variant in trans with a loss-of-function allele in UBAS underlies a severe infantile-onset encephalopathy.Peer reviewe

Toimintamalli simulaatiosta sairaanhoitajan osaamisen varmistamiseksi LKS:n leikkaus- ja anestesiayksikössä

YAMK opinnäytetyöhön liittyvän kehittämistehtävän tavoitteena oli kehittää simulaation toimintamallia leikkaus- ja anestesiayksiköön kokonaisvaltaisemmin sopivaksi. Simulaatiotoimintamallin avulla saadaan laajennettua simulaatiotoimintaa ja sitä kautta kehitettyä sairaanhoitajien osaamista ja myös potilasturvallisuutta hoitotyössä. Opinnäytetyömme tarkoituksena oli kartoittaa leikkaus- ja anestesiayksikön sairaanhoitajien kokemuksia simulaatioista ja niiden kehittämisestä leikkaus- ja anestesiayksikössä. Toimintamallia voidaan käyttää esimiehen ja simulaatio-ohjaajan työkaluna uusien sairaanhoitajien perehdyttämisessä sekä osaamisen varmistamisessa leikkaus- ja anestesiayksikössä. Terveydenhuolto muuttuu nopealla tahdilla ja potilasturvallisuudesta ja sen jatkuvasta kehittämisestä on huolehdittava. Simulaation keinoin tapahtuva toimintojen ja toimintaprosessien harjoittelu on lisääntynyt ja tulee edelleen lisääntymään yhtenä koulutus- ja opetusmenetelmänä. Opinnäytetyömme perustuu design-tutkimukseen, jonka tarkoituksena on kehittää sekä teoriaa että käytäntöä. Design-tutkimuksessa edetään sykleittäin ja tässä työssä raportoimme yhden design-syklin. Syklin ensimmäisessä vaiheessa laadimme toimintamallin perustuen aikaisempaan tutkimukseen. Lisäksi kartoitimme sairaanhoitajien kokemuksia simulaatioharjoittelusta Lapin Keskussairaalan leikkaus- ja anestesiayksikössä kyselytutkimuksen avulla. Toisessa vaiheessa testasimme toimintamallia kuvaavaa tarkistuslistaa simulaatioharjoituksen aikana, jota arvioimme palautekyselyn avulla. Lopuksi esitämme toimintamallin, jota on kehitetty edelleen aineistonkeruun ja analysoinnin perusteella sekä lisäksi yksikköön luodun vuosikellomallin ja työntekijän perusohjeistuksen simulaatiokouluttamiselle. Tuloksien perusteella simulaatio on yksikön sairaanhoitajien mielestä hyvä keino oppia ja ylläpitää taitoja sekä kehittää hoitoprotokollia. Simulaatioita toivottiin järjestettävän useammin ja aiheiksi toivottiin erilaisia hätätoimenpiteitä, joita leikkaussalissa voi tulla eteen. Simulaatiomalli vastaa arvion mukaan aiemmin suunniteltua eli on tavoitteiden mukainen.This thesis is part of the Master ́s degree programme in nursing at the Lapland University of Applied Sciences. The aim of this thesis was to update an operat-ing model for simulations. This model is aimed to nurses at the operating theatre in the Lapland Central Hospital to develop and to maintain the skills and know-how of the nurses. The purpose of the thesis was to find out the nurses´ experi-ences and developmental expectations for the simulation in the operating thea-tre. The simulation can also increase patient safety in perioperative nursing. The knowledge base consisted of scientific research publications. The research method was a design research which is research strategy to improve both a the-ory and working life. Scientific publications were used as the source material in this thesis. The inquiry was created to find out nurses´ exceptions to developed simulation in the operating theatre at Lapland Central Hospital. The response rate of the inquiry was high (84 %). The material acquired in the inquiry was ana-lysed using a content analysis. Next, the simulation operating model was creat-ed. The model was piloted in work life and it feedback in the pilot. The operating model was improved based on the feedback. Most of the people who answer the inquiry thought that simulation learning is a very important and useful education and familiarization instrument in healthcare

Radiation-induced meningiomas: A shadow in the success story of childhood leukemia

While the prognosis of acute childhood leukemia has improved, long-term survivors are increasingly experiencing late effects of the treatment. Cranially irradiated survivors are predisposed to the development of CNS tumors. Our aim was to describe the incidence of secondary brain tumors and to define the significance of treatment-related risk factors and host characteristics in a cohort of childhood leukemia survivors. Our cohort consisted of 60 consecutive cranially irradiated adult survivors of childhood leukemia treated in Oulu University Hospital (Oulu, Finland); MRI of the brain was performed on 49. The sites of the tumors, their histology, and details of the leukemia treatment were determined. Of the 49 patients, 11 (22%) 1–8 years of age at the time of diagnosis developed meningioma later in life, while no other brain tumors were seen. In this cohort, the development of meningioma seemed to show undisputable linkage with long latency periods (mean, 25 years; range, 14–34 years) and an increasing incidence 20 years after the treatment (47%). Three patients had multiple meningiomas, two had recurrent disease, and one had an atypical meningioma. Age at the time of irradiation, gender, or cumulative doses of chemotherapeutic agents showed no significant association with the development of meningiomas. The high incidence of meningiomas in this study was associated with long follow-up periods. Although the cohort is small, it seems probable that the increasing incidence of meningioma will shadow the future of cranially irradiated leukemia survivors. Systematic brain imaging after the treatment is therefore justifiable

Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease

The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation