Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects between 14,000 to 15,000 Americans. The upper and lower motor neurons degenerate, which eventually causes muscle paralysis, atrophy, and ultimately death from respiratory failure. It has a high treatment cost as well as a high toll on the patient and their families and friends. Currently, there are only two drugs approved by the FDA for the treatment of ALS: riluzole and edaravone. Research is constantly being conducted to understand and develop further treatment modalities, however, many drugs have failed to demonstrate significant improvement in phase III trials. One of the pathophysiology that these drugs, including riluzole, target is excitotoxicity of the motor neurons. This review will briefly expand upon the different trials that were conducted targeting the excitotoxicity pathway. Although they may have not been successful in prolonging survival in ALS patients, we can learn from these studies and build upon them.

Bakgrund: Amyotrofisk lateralskleros (ALS) är en allvarlig sjukdom som leder tilldöden för den som drabbas eftersom det inte finns någon behandling. Sjukdomen innebäratt motoriska nervceller som styr skelettmusklerna och som finns i hjärnan, hjärnstammenoch ryggmärgen dör. Detta leder till att musklerna som inte får nervimpulser förtvinar.Syftet: Syftet med denna litteraturstudie var att sammanställa och beskriva upplevelserav att leva med ALS hos personer som diagnostiserats med sjukdomen.Metod: Beskrivande litteraturstudie. 12 vetenskapliga artiklar med kvalitativ ansatsanvändes i resultatet.Huvudresultat: Resultatet visade att sjukdomen påverkade det dagliga livet för personermed ALS i form av upplevelsen av förlorad autonomi, upplevelsen av lidande i form avnegativa känslor och upplevelsen av hopp och hopplöshet. Personerna använde sig avolika coping-strategier för att hantera sjukdomen. En personcentrerad kommunikationfrån vårdens sida efterlystes av personerna med ALS samt en önskan att vårdpersonaleninte skulle vara negativa. För att återfinna en mening i livet beskrev personerna att det varviktigt att ha ett eget liv med egen vilja och egna intressen. Även förändringar i familjenoch i livssituationen uppstod hos personer med ALS.Slutsatser: Personers upplevelser av att leva med ALS visade stora förändringar ochutmaningar i det dagliga livet. Fysiska och psykiska förändringar som medförde olikaförluster hanterades av personerna med hjälp av olika strategier för att upprätthållalivskvaliteten. För att få en mening i livet var det viktigt för personerna att ha kvarintressen och få stöd från familjen och närstående. Det var även viktigt att vårdpersonalenarbetade på ett personcentrerat sätt.Nyckelord: ALS, personer, upplevelser

The human VAMP-associated protein B (hVAPB) has been shown to cause a range of motor neurodegenerative diseases, including amyotrophic lateral sclerosis 8 (ALS8) and spinal muscular atrophy (SMA). However, the molecular mechanisms underlying VAPB-induced neurodegeneration remain elusive. We sought to address this question by identifying VAPB interacting proteins, which may be affected by the disease causative mutations. Using a combination of biochemical and genetic approaches in Drosophila, we confirmed the evolutionarily conserved phosphoinositide phosphatase Sac1 (Suppressor of Actin 1), as a DVAP binding partner and showed that the two proteins colocalise in the endoplasmic reticulum. We also show that DVAP function is required to maintain normal levels of phosphoinositides (PIs) and that downregulation of either Sac1 or DVAP at the larval neuromuscular junction (NMJ) affects a number of synaptic processes, including axonal transport, synaptic growth, microtubule integrity and localisation of several postsynaptic components. We found that double knock down of DVAP and Sac1 induces no further increase in the severity of the mutant phenotypes when compared to either single mutant alone. This, together with the similarity in mutant phenotypes, indicates that the two genes function in a common pathway. In flies carrying the ALS8 mutation (DVAP-P58S), we observed reduced viability, locomotion defects and early death in surviving adults, closely matching the phenotypes of both DVAP and Sac1 downregulation. Additionally, transgenic expression of DVAP-P58S in the motor system elicits synaptic defects similar to those of either Sac1 or DVAP loss-of-function, including an increase in the levels of PtdIns-4-Phosphate (PI4P), the substrate of Sac1. Consistent with these observations, we found that Sac1 is sequestered into DVAP-P58S mediated aggregates and that downregulation of PI4P in neurons rescues the neurodegenerative and the synaptic phenotypes associated with DVAP-P58S transgenic expression. Together our data unveil a previously unknown function for Sac1 in neurodegeneration and synaptic function, as well as provide evidence for a dominant negative mechanism for phosphoinositide-mediated ALS8 pathogenesis. We also highlight a causative role for increased PI4P levels in VAPB-P56S induced neurodegeneration.

Bakgrund: Amyotrofisk lateral skleros (ALS) är en nervsjukdom som leder till kroppslig pares och slutligen döden, oftast har patienten ett bibehållet intellekt tillsammans med full sensorisk funktion. När en patient drabbas av en svår sjukdom kan det innebära att livsvärlden förändras drastiskt och de existentiella dimensionerna blir tydligare. Syfte: Belysa ALS-patienters upplevelser med fokus på de existentiella dimensionerna. Metod: Studien genomfördes genom att göra en litteraturöversikt på ett systematiskt sätt. Författarna sökte vetenskapliga empiriska artiklar via databaserna Cinahl, Psychinfo, Pubmed och Swepub. För att bredda sökningarna använde sig författarna av snowballsökning och manuell sökning. Sökningarna resulterade i åtta kvalitetsgranskade kvalitativa artiklar vilka sedan användes i studien. Innehållsanalysen av de valda artiklarna skedde med en induktiv ansats, artiklarna kvalitetsgranskades även av författarna med hjälp av en granskningsmall. Resultat: Två teman och fem kategorier identifierades i analysprocessen: Meningslöshet- Förnekelse, Existentiellt lidande och Rädsla. Meningsfullhet- Information/Kommunikation och Hanterbarhet. Slutsats: Genom tydlig kommunikation ges större möjlighet att få förståelse för sin sjukdom, att känna hopp och kunna leva i nuet. Trots den svåra sjukdomen och ett ökat omvårdnadsbehov kan patienterna ändå känna en meningsfullhet i livet.

No description available.

It is my discovery of the mandala that has had the most significant influence on me as an artist. The mandala, Sanskrit word for circle or center, is found in a majority of my pieces, either literally or symbolically. My interest in and subsequent use of the mandala began twenty years ago and continues to this day. The mandala is a primordial image found in the macrocosm of the universe, the microcosm of nature, and in the psyche of man. The circle has been used throughout the world in image and architecture as a sacred symbol since the beginning of time.

In this study, we used a custom made quadrifilar needle electrode and multichannel electromyography (EMG) software tool to decompose EMG signals and investigate the behavior of motor unit discharge rate (MUDR) of concurrently active motor units in patients with amyotrophic lateral sclerosis (ALS). Decomposition is a technique used to break down the complex EMG signal into its constituent motor units. A motor unit is a single alpha motor neuron and all the muscle fibers it innervates. ALS is a progressive degenerative disorder of both the upper and lower motor neurons. We recorded four differentially amplified EMG signals from the first dorsal interosseous (FDI) muscle of six ALS patients (four with predominant lower motor neuron pathology and two with predominant upper motor neuron pathology) and seven control subjects. Recordings were made from force contractions of 20 and 50% of maximum voluntary contraction (MVC). All control subjects were between the ages of 40 and 70 years and were examined by a practicing physiatrist for exclusion criteria including neuromuscular disorders or any medications that might affect muscle activity. We observed differences in initial firing rates and variability of active motor units between control subjects and ALS patients. Furthermore we observed differences in firing rates and variability of active motor units between ALS patients with predominant upper motor neuron pathology and ALS patients with predominant lower motor neuron pathology. Initial motor unit firing rates for control subjects were 16.22 +/- 2.06 Hz at 20% MVC and 19.79 +/- 1.66 Hz at 50% MVC. As expected, initial motor unit firing rates from patients with predominant lower motor neuron pathology were higher than those of control subjects; 18.87 +/- 4.73 Hz at 20% MVC and 24.28 +/- 5.01 Hz at 50% MVC. ALS patients with predominant upper motor neuron pathology, as expected, had initial motor unit firing rates that were lower than those observed in control subjects; 9.22 +/- 1.68 Hz at 20% MVC and 12.83 +/- 2.26 Hz at 50% MVC. Motor unit firing rate time series in ALS patients with predominant upper motor neuron pathology showed decreased variability, 0.99 +/- 0.17 Hz at 20% MVC and 1.70 +/- 0.52 Hz at 50% MVC, when compared to control subjects, 2.37 +/- 0.67 at 20% MVC and 4.20 +/- 1.00 at 50% MVC. Variability of motor unit firing rate time series in ALS patients with predominant lower motor neuron were high, 3.38 +/- 1.2 Hz at 20% MVC and 4.07 +/- 1.56 Hz at 50% MVC, compared to control subjects. At 50% MVC, motor unit substitution was observed in ALS patients with predominant upper motor neuron pathology despite the contractions lasting just a few seconds. Motor unit action potentials (MUAPs) recorded from patients were polyphasic when compared to those from control subjects, as is characteristically found in practice.

Oxidative stress has a degenerative effect on neuronal health. Mutations in the copper zinc superoxide dismutase (SOD1), an important antioxidant, have been found in patients suffering from amyotrophic lateral sclerosis (ALS). Classical EMS induced mutations to SOD1 in Drosophila show similar loss of motor coordination and shortened lifespan seen in humans. A study of newly created human ALS point mutants along with the classic alleles show similar phenotypes in their neurodegeneration. I examined markers of oxidative stress, neuronal health and behavioral phenotypes throughout the lifecycle of aging flies. Larvae were largely found to be unaffected by mutations in SOD1, with no measured increase in ROS level over wild type (WT) flies. Mutant pupae were found to have two major defects in their circadian eclosion rhythm and their fundamental ability to eclose from the pupal casing. Adults showed the classic reduced lifespan and motor abilities. To further examine the health on non-glutamatergic synapses electroretinograms (ERGs) were recorded at different levels of survivorship indicated by Kaplan-Meier Survival curves. These ERGs show that the histaminergic synapses they record have greater degeneration in aging SOD1 mutants than in WT flies. This is true for their chronological age as well as their biological age. There was coinciding disruption of the photo transduction pathway of the photoreceptors that coincided with degeneration at the synapse. This demonstrates the separate degenerative effect of high levels of oxidative stress impart separate for the normal aging process.

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the progressive degeneration of motor neurons. Although there has been some progress in the identification of genes linked to inherited cases of ALS, the etiology of this disease remains largely unknown. Clinical progression of motor neuron diseases is associated with the degeneration of the axon preceding cell death. Elucidating novel mechanisms important for motor axon maintenance will help gain greater insight into disease pathogenesis. Here, I report that mutations in ras-opposite (rop), which encodes the Drosophila homologue of mammalian Sec1/Munc18, cause progressive degeneration of motor axons while sensory axons are largely unaffected. While mutations in mammalian munc18-1 have been linked to degeneration of the spinal cord, the mechanisms by which this occurs are unknown. Using Drosophila, I found that RNAi-induced knockdown of rop leads to severe motor deficits in adult flies. In addition, I discovered that motor axon degeneration in rop mutants could be delayed by overexpression of the neuronal maintenance factor Nmnat. Interestingly, I found that Rop is localized with Nmnat at the neuromuscular junction and that Rop physically interacts with Nmnat in vivo. These data indicate a novel role for Rop in motor axon maintenance and provide insight into the pathogenesis of neurodegenerative diseases targeting motor neurons, such as ALS.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease with no cure. TAR-DNA binding protein 43 (TDP-43) is the major component of the cytoplasmic inclusions characteristic of ALS. Transgenic Drosophila lines expressing wild-type, mutant and splice variants of human TDP-43 were generated. I find that ubiquitous expression of all TDP-43 transgenes, except for TDP-43∆C-term, is sufficient to cause lethality. I also show that eye-specific expression of a TDP-43∆N-term splice variant, which localizes diffusely to the cytosol, results in increased cell toxicity suggesting an association between cytosolic localization and toxicity. Consistent with this model, I find that the TDP-43∆N-term splice variant is capable of recruiting full length TDP-43 into the cytoplasm, and I suggest this may represent an initiating event in TDP-43-linked ALS. Altogether, my results seem to indicate that exclusion of TDP-43 from the nucleus rather than its presence in aggregates is linked to increased cytotoxicity and lethality in ALS.