Bakgrund: ALS är en obotlig neurologisk sjukdom som leder till försvagning av muskler efter en nedbrytande process i nervsystemet. Det finns en ärftlig komponent, men i många fall går det inte att fastställa orsaken bakom sjukdomens uppkomst. Att diagnostiseras med en obotlig sjukdom där kroppsliga funktioner avtar samtidigt som de kognitiva förmågorna och känseln består innebär ofta ett stort lidande för patienterna. Att beskriva patienters erfarenheter av sjukdomen kan öka förståelsen och skapa en möjlighet att närma sig lidandet. Syfte: Syftet var att beskriva patienters upplevelse av att leva med ALS. Metod: Studien är en litteraturöversikt som baserades på 15 vetenskapliga artiklar. Dessa återfanns i databaserna Pubmed och CINAHL. Artiklarna granskades med hjälp av Sophiahemmets Högskolas formulär för kvalitetsgranskning och analyserades genom en integrerad analys. Resultat: Ur analysen framträdde tre kategorier: “Upplevelsen av maktlöshet”, “Upplevelsen av att vara en börda” och “Upplevelsen av att anpassa sig till en ny tillvaro”. I resultatet framkom att patienter med ALS upplevde ett lidande som de själva beskrev i olika termer, men likaså återgav de positiva erfarenheter och hur dem utvecklade strategier för att hantera sin nya tillvaro. Slutsats: Denna litteraturöversikt beskriver hur patienter med ALS hanterar sin verklighet, vilket till viss del skiljer sig åt. Lidandet som patienterna upplever kan bli del av personlig utveckling, samtidigt som risken finns att hela livsperspektivet påverkas negativt om patienterna fastnar i lidandet. Sjuksköterskan har en viktig roll i att lindra patienters lidande och litteraturöversikten upplyser om hur ett personcentrerat förhållningssätt, som bland annat innefattar lyhördhet till hur patienterna upplever sin tillvaro, kan bidra till detta. / Background: ALS is an incurable neurological disease that leads to muscle deterioration following a degrading process in the nervous system. There is a hereditary component, but in many cases it is not possible to determine the cause behind the onset of the disease. Being diagnosed with an incurable disease in which bodily functions decline at the same time as the cognitive abilities and tactile sense remains often results in great suffering for the patients. Describing patients' experiences of the disease can increase understanding and create an opportunity to approach suffering. Aim: The aim was to describe patients' experiences of living with ALS. Method: The study is a literature review based on 15 articles. These were found in the databases PubMed and CINAHL. The articles were reviewed with the use of Sophiahemmets Högskola's form for quality review and were analyzed through integrated analysis. Results: From the analysis three categories appeared: “The experience of powerlessness”, “The experience of being a burden” and “The experience of adapting to a new existence”. The results showed that patients with ALS experienced suffering that they themselves described in different terms, but they also portrayed positive experiences and how they developed strategies to manage their new situation. Conclusions: This literature review describes how patients with ALS manage their reality, which differs to some extent. The suffering that the patients experience may be part of personal development, while there is a risk that the entire life perspective will be adversely affected if the patients become stuck in the suffering. The nurse plays an important role in relieving patients suffering and the literature review informs how a person-centered approach, which includes, among other things, responsiveness to how patients experience their lives, can contribute to this.

Palliativ vård innebär att förbättra livskvalitet för personer med livshotande kronisk sjukdom och dess närstående. De fyra hörnstenar som den palliativa vården vilar på är symtomkontroll, kommunikation, teamarbete och närståendestöd. Sjuksköterskor inom palliativ vård har till uppgift att tillsammans med teamet förebygga, observera, behandla och lindra symtom för både patient och närstående. Amyotrofisk lateralskleros är en motorneuronsjukdom som påverkar kroppens alla muskler. Nedsatt andningsfunktionen hos personer med ALS leder till hypoventilation vilket kan behandlas med ventilatorstöd med noninvasiv ventilator via näseller helmask och trakeostomiansluten invasiv ventilator. Sjuksköterskan har ett ansvar att stödja personen med ALS att bevara sin autonomi, värdighet och livskvalitet samt stödja närstående som ofta även är vårdare. Behandling för att ersätta livsnödvändiga funktioner, såsom andning, som ges i syfte att bevara liv vid ett livshotande tillstånd innebär en livsuppehållande behandling. Rätten att neka behandling är lagstadgad i Sverige likaväl som rätten att avsäga sig pågående behandling. Studiens resultat diskuteras mot Katie Erikssons teorier om vårdlidande. Syftet med studien var att undersöka sjuksköterskors erfarenheter av avslutande av ventilatorbehandling för personer med amyotrofisk lateralskleros inom palliativ vård Metoden som använts var en intervjustudie med kvalitativ ansats. Tio sjuksköterskor intervjuades med avseende på deras erfarenheter av att avsluta ventilatorbehandling. En kvalitativ analys med induktiv ansats användes för att få fram både latent och manifest data. Resultatet presenteras under två teman. I temat att göra resan från oro och rädsla till trygghet beskrivs att sjuksköterskorna inför att avsluta ventilatorbehandling kunde känna rädsla och oro men att avslutet i de allra flesta fall uppfattades ett värdigt avslut där sjuksköterskan lindrade lidande. Vidare presenteras faktorer som kan minska erfarenheten av oro och rädsla. Under detta tema återfinns kategorierna att praktiskt förbereda inför avslut, att stänga av ventilatorbehandling samt förberedelse och bearbetning. I temat att balansera de egna känslorna som uppstår framkommer sjuksköterskans känslor av ansvar och hur de förhöll sig till detta ansvar. I detta tema belyser sjuksköterskorna vad de upplever är vårdens helhetsansvar, att det finns ett informationsansvar samt att de känner ett personligt ansvar mot personen som vill avsluta ventilatorbehandling. Under detta tema finns kategorierna teamarbete på olika nivåer, att förhålla sig till ansvar och målet med vården. Slutsatser som kan dras är bland annat; att närvara vid avslut av livsuppehållande ventilatorbehandling kan skapa känslor av oro och rädsla men förberedelser och planering kan göra erfarenheten positiv. Det finns en trygghet i rutiner och att använda redan befintlig erfarenhet för att sjuksköterskor ska känna sig trygga i avslutssituationen. / Palliative care means to improve quality of life for people with a life-threatening chronic illness and their family. The four cornerstones on which palliative care rests are symptom control, communication, team work and support for family. Nurses in palliative care have the task, together with the palliative team, to prevent, observe, treat and alleviate symptoms for both patient and their family members. The need for palliative care to be adapted for people with neurological disease, which includes amyotrophic lateral sclerosis (ALS), has only been noticed in recent years. For people with ALS, there can be advantages with an early contact with palliative care providers. Nurses in palliative care has a challenge to support the person with ALS in order to preserve autonomy, dignity and quality of life, and to support relatives. Amyotrophic lateral sclerosis is a collective term for several motor neuronal diseases where the most common form is classical amyotrophic lateral sclerosis. Reduced respiratory function in people with ALS lead to hypoventilation, which van be treated with ventilator support. Treatment may be either non-invasive ventilator via nasal or whole mask and with invasive ventilation via tracheostomy. Life-sustaining treatment means to replace vital functions, such as breathing, to preserve life in a life-threatening condition. The right to refuse treatment is statutory in Sweden as well as the right to renounce ongoing treatment. The results of the study are discussed against Katie Eriksson's theories of suffering of care. The aim of the study was to investigate nurses' experiences of withdrawal of ventilator treatment for patients with amyotrophic lateral sclerosis in palliative care. The method used was an interview study with qualitative approach. Ten nurses were interviewed for their experience regarding withdrawal of ventilator treatment. A qualitative analysis with inductive approach was used to obtain both latent and manifest data. The result is presented under two themes. In the theme of making the journey from worry and fear to security, it is described that the nurses before withdrawal of ventilator treatment could feel fear and anxiety, but that in most cases the conclusion was perceived as a worthy termination of treatment where the nurse alleviated suffering. Furthermore, factors are presented that can reduce the experience of concern and fear. Under this theme are the categories to practically prepare for withdrawal, to turn off ventilator treatment and preparation and processing. In the theme of balancing their own feelings that arise, the nurse's feelings of responsibility emerge and how they relate to this responsibility. In this theme, the nurses highlight what they feel is the overall responsibility of caregivers, that there is an information responsibility and that they feel a personal responsibility towards the person who wants to terminate the ventilator treatment. Under this theme are the categories team work at different levels, to relate to responsibility and the aim of the care. Conclusions that can be drawn include; attending withdrawal of life-sustaining ventilator treatment can create feelings of concern and fear, but preparation and planning can make the experience positive. Security can be found in routines and using already existing experience, which can make nurses feel safe in the withdrawal situation.

Indiana University-Purdue University Indianapolis (IUPUI) / The main, underlying cause of neurodegenerative disease is the progressive loss of neuronal structure or function, whereby central and/or peripheral nervous system circuitry is severely and irreversibly damaged, resulting in the manifestation of clinical symptoms and signs. Neurodegenerative research has revealed many similarities among these diseases: although their clinical presentation and outcomes may differ, many parallels in their pathological mechanisms can be found. Unraveling these relationships and similarities could provide the potential for the discovery of therapeutic advances such that a treatment for one neurologic disease may also be effective for several other neurodegenerative disorders. There is growing awareness that due to the complexity of pathophysiological processes in human disease, specifically targeting or inactivating a single degenerative process or a discrete cellular molecular pathway may be ineffective in the treatment of these multifaceted disorders. Rather, potential therapeutics with a multi-target approach may be required to successfully and effectively control disease progression. Recent advances in neurodegenerative research involve the creation of animal disease models that closely mimic their human counterparts. The use of both toxin- exposure and genetic animal models in combination may give insight into the underlying pathologic mechanisms of neurodegenerative disorders (target identification) leading to the development and screening of prospective treatments and determination of their neuroprotective mechanism (target validation). Taken together, ideal candidates for the treatment of neurodegenerative disease would need to exert their neuroprotective effect on multiple pathological pathways. Previous studies from this laboratory and collaborators have shown that the naturally-occurring compound, caffeic acid phenethyl ester (CAPE), is efficacious for the treatment against neurodegeneration. Because of its versatile abilities, CAPE was chosen for this study as this compound may be able to target the pathogenic pathways shared by two different animal models of neurodegeneration and may exhibit neuroprotection. In addition, adipose-derived stem cell conditioned media (ASC-CM), a biologically-derived reagent containing a multitude of neuroprotective and neurotrophic factors, was selected as ASC-CM has been previously shown to be neuroprotective by using both animal and cell culture models of neurodegeneration.

Fused in sarcoma (FUS) is an RNA binding protein involved in DNA repair and RNA metabolism, including mRNA transcription, splicing, transport and translation. FUS is genetically and pathologically associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To explore the mechanisms by which pathogenic mutations in FUS cause neurodegeneration in ALS-FUS, we generated a series of FUS knock-in mouse lines that express the equivalent of the ALS-associated mutant proteins FUSP525L and FUSΔEX14 at physiological levels from the FUS locus. We demonstrate that heterozygous mutant FUS mice show progressive, age-dependent loss of vulnerable subpopulations of spinal motor neurons. While ALS-associated mutations in FUS lead to partial loss of function, we provide genetic evidence that the motor neuron phenotype observed is a consequence of a dose-dependent gain of function, associated with the insolubility of FUS and related RNA binding proteins (RBPs). Furthermore, we show that motor neuron degeneration is driven by cell autonomous mechanisms, associated with mutant FUS-independent inflammatory changes. In this faithful mouse model of ALS-FUS, we demonstrate that an antisense oligonucleotide (ASO) targeting the FUS transcript (ION363) results in the efficient silencing of both wild type and mutant FUS alleles, and that postnatal reduction of FUS protein levels in the brain and spinal cord delays disease onset in this mouse model of ALS-FUS. In a first-in-human trial of ION363, we demonstrate that repeated, intrathecal injections of this candidate therapeutic in an ALS patient with a FUSP525L mutation leads to the efficient silencing of both wild type and mutant FUS in the central nervous system, and a reduction in the burden of FUS aggregates that are a pathological hallmark of ALS-FUS. In mouse genetic and human clinical studies, we provide evidence in support of a therapeutic strategy by which silencing of the FUS gene may be used to prevent or delay disease onset in pre-symptomatic carriers of pathogenic FUS mutations, or to slow disease progression in symptomatic ALS- and FTD-FUS patients. In addition, we use this newly generated model to investigate the role of potential modifiers of FUS toxicity, including hnRNP U and UPF1, and study the role of chronic neuroinflammation in the disease progression that could lead to the development of novel therapeutics to provide immediate clinical benefit to patients with ALS-FUS.

Bakgrund: I Sverige insjuknar cirka 220–250 personer av Amyotrofisk Lateralskleros (ALS) per år. Sjukdomen innebär att nervceller som styr skelettmusklerna förtvinar och slutligen dör vilket leder till svåra symtom. Idag finns inget botemedel utan insatserna riktas till symtomlindring och livslängden är cirka två till tre år. Sjuksköterskor som vårdar personer med ALS upplevde svårigheter att balansera både den sjukes och anhörigas vilja/upplevelser samtidigt.   Syfte: Att beskriva upplevelser om hur det är att vara anhörig till personer som lever med Amyotrofisk lateralskleros (ALS). Metod: En deskriptiv litteraturstudie bestående av 14 vetenskapliga artiklar med kvalitativ ansats som söktes i databasen Medline via PubMed. Huvudresultat: Känslor som maktlöshet och sorg uppstod hos de anhöriga samt en känsla av att vara fängslad till personen med ALS och hemmet. Anhöriga genomgick en livsomställning och hittade olika hanteringsstrategier för att klara av situationen. Förändrade roller i familjen medförde starkare och svagare familjerelationer samtidigt som kärleken blev mer komplex. Anhöriga fick en negativ bild av vården och lyfte bristen på information, istället verkade stödet från det sociala nätverket vara mer betydelsefullt.  Slutsats: Anhöriga till personer med ALS kände sig maktlösa och sorgsna men dem hittade hanteringsstrategier som underlättade vardagen. Anhöriga sökte stöd inom det sociala nätverket då vården ofta var en besvikelse. Dem lyfte ett behov av bättre informationshantering från vården och önskade att den skulle vara familjecentrerad. Denna litteraturstudie kan komma att bidra till ett ökat perspektiv hos anhöriga, personer med ALS och vården. / Background: 220–250 people get diagnosed with Amyotrophic Lateral Sclerosis (ALS) every year in Sweden. The disease entails that the nerve cells controlling skeletal muscles degenerate and die creating severe symptoms. Today, there is no cure, so the resources focus on symptom-management, the average lifespan after diagnosis is two to three years. Nurses caring for people with ALS struggled with balancing the will/experience of the person with ALS and the close relatives concurrently.  Aim: Describe experiences of being a close relative to people living with Amyotrophic Lateral Sclerosis. Method: Descriptive literature study based on 14 scientific articles with qualitative approach searched on the database Medline via PubMed. Main results: Emotions such as feeling powerless and grief was identified, they felt imprisoned to the person with ALS and their home. Close relatives went through life-changing events and found coping strategies. Changed family roles created stronger and weaker family relationships and love got complex. Close relatives got a negative picture of the health-system and highlighted the lack of information, instead they valued the support from their social networks. Conclusion: Close relatives to people with ALS felt powerless and grief but found coping strategies that eased their situation. Close relatives soughed support within the social network since the health-system disappointed. They highlighted needs for better information management from the health-system and whished for it to be family-focused. This literature study may create wider perspectives among close relatives, people with ALS and the health-system.

Ataxin-2 is an RNA-binding protein that is involved in many crucial cellular processes such as R-loop regulation, mRNA stability, TOR signaling regulation, and stress granule formation. Ataxin-2 is highly conserved, found in organisms ranging from Saccharomyces cerevisiae to Caenorhabditis elegans and Homo sapiens. Recently, ataxin-2 has been linked to the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). ALS is a fatal disease that causes loss of motor neurons. In addition to ataxin-2 interacting with known ALS risk factor proteins, research into the relationship between ataxin-2 and ALS shows that polyglutamine expansions in ataxin-2 are gain-of-function mutations that lead to overactivity of ataxin-2 and probable neurodegeneration. In fact, targeting ataxin-2 using gene silencing techniques dramatically slows the progression of ALS in both mice and man.The Grose laboratory has characterized a serine-threonine kinase, PAS kinase as upstream kinase and putative activator of ataxin-2. We hypothesize that knockdown of PAS kinase could, therefore, have similar effects to directly downregulating ataxin-2 and its cellular functions. Characterization of Ataxin-2 has revealed that its gain or loss of function lead to distinct cellular phenotypes. One study concluded that lowering ataxin-2 levels reduced the size and number of stress granules in mammalian cells, which was observed through microscopy. Another study found that activation and overexpression of ataxin-2 lead to reduced mTOR levels because of its sequestration to stress granules. Lastly, preliminary data obtained by the Grose laboratory suggests that yeast deficient in Pbp1 (the yeast homologue of ataxin-2) have altered cell cycles.This project describes the cellular readouts used to determine if PAS kinase downregulation confers the same cellular phenotypes as ataxin-2 downregulation. First, we found that PAS kinase does influence ataxin-2 abundance in mammalian cells. Using yeast as a model, we found that Pbp1 influences the cell cycle through its binding partners, causing a reduction in the percentage of cells in the G2 phase compared to the G1 phase. PAS kinase conferred an opposite change, most likely due to the activity of other PAS kinase substrates. Additionally, we found that Pbp1 deficiency is synthetically lethal when in conjunction with deficiency of any one of its cell cycle-related binding partners. The cellular changes cause by Pbp1 deficiency highlight not only the importance of ataxin-2 in the cell, but also the importance of understanding the effects of downregulation of ataxin-2.

Bakgrund Amyotrofisk lateralskleros är en dödlig sjukdom som påverkar såväl den drabbade som anhöriga. Anhöriga har en betydande roll då de ofta vårdar den närstående i hemmet, och på grund av sjukdomens progression kan det bli en omfattande livsförändring. Sjuksköterskor ska utgå ifrån ett palliativt personcentrerat förhållningssätt där anhöriga behöver praktiskt och emotionellt stöd. En anhörig som vårdar en person med långvarig sjukdom ska erbjudas stöd för att minska belastning och förbättra livssituationen. Syfte Syftet var att beskriva anhörigas erfarenheter av att ge stöd till en person med Amyotrofisk lateralskleros. Metod En litteraturöversikt med elva vetenskapliga artiklar användes. Artiklarna hämtades från databaserna Cinahl Complete och PubMed. Artiklarna analyserades med stöd av Fribergs analysmodell. Resultat Tre teman identifierades i resultatet: (1) Inre känslor, (2) Förändringar inom familjen och (3) Hälso- och sjukvårdspersonalens påverkan. Två underteman framkom: Förändrade familjerelationer och Förändrade roller. Sammanfattning Litteraturöversikten visade att det fanns ett behov av information och stöd från sjukvården och övriga anhöriga. Att vara anhörigvårdare medförde en känslomässig påverkan på grund av hög belastning och ansvarskänslor. Sjukdomen bidrog till förändringar inom familjen så som förändrade familjerelationer och nya roller och anhörigvårdare upplevde olika utmaningar som att bibehålla en normal vardag och åsidosätta sina egna behov. / Background Amyotrophic lateral sclerosis is a deadly disease that affects both the person affected by illness and their relatives. Relatives have a significant role as they often provide care for the person at home, and due to the progression of the disease there can be an extensive life change. Nurses shall focus on a palliative person-centered care where relatives need practical and emotional support. A relative who cares for a person with a long-term illness must be offered support to reduce the burden and improve the living situation. Aim The aim was to describe relatives’ experiences of providing support to a person with Amyotrophic Lateral Sclerosis Method Literatur review with eleven scientific articles were used. The articles were retrieved from the databases Cinahl Complete and PubMed. Friberg’s analysis model were used to analyze the articles. Results Three themes were identified in the result: (1) Inner feelings, (2) Changes within the family and (3) The impact of health care professionals. Two sub-themes emerged: Changed family relationships and Changed roles. Summary The literature review showed that there was a need of information and support from the healthcare system and other relatives. Family caregivers experienced an emotional impact due to high workload and feelings of responsibility. The disease contributed to changes such as changing family relationships and new roles, and family caregivers experienced various challenges such as maintaining a normal everyday life and overriding their own needs.

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