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Poliovirus
Published in Patricia G. Melloy, Viruses and Society, 2023
The fundraising arm of the National Foundation for Infantile Paralysis, the March of Dimes, was able to successfully complete their mission of protecting America’s children from polio. During the Great Depression and even World War II, the foundation adapted and kept raising money to fight polio through an amazing marketing campaign. Impressively, the NFIP privately funded Salk’s vaccination trials, something that would be done today through significant collaboration with either national or international governmental partners. Certain aspects of disease fundraising, such as using “Poster Children,” was first used by the March of Dimes as well (Oshinsky 2005). The March of Dimes also affected the public’s awareness of and attention to one particular disease, polio, among many other diseases that can affect children. Their successful mission illustrated that public perception of a disease is critical to raising the political will and capital to tackle an expensive task like eliminating a disease. One modern fundraising comparison might be to the “Ice Bucket Challenge” campaign for amyotrophic lateral sclerosis (ALS), which swept the United States in 2014, raising $115 million dollars for ALS research (The ALS Association 2019). Now, imagine a sustained fundraising challenge happening from 1938 to 1955! After the Salk vaccine came out, the National Foundation for Infantile Paralysis changed its name to National Foundation and shifted its focus to birth defects and arthritis, continuing its mission to help America’s children. It is known today exclusively as the March of Dimes (Jacobs 2015; Rose 2010) (Figure 4.6).
Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive degeneration of motor nerve cells in the brain (upper motor neurons) and spinal cord (lower motor neurons). About 20% of familial ALS cases involve a mutation in the superoxide dismutase 1 (SOD1) gene (80). Different theories posit either the involvement of excessive glutamatergic neurotransmission, leading to calcium overload, and cell death, or the involvement of increased axonal membrane excitability, which could be caused by either increased persistent sodium or reduced delayed-rectifier potassium currents (81–84). In a recent study which conducted multi electrode array (MEA) and patch-clamp recordings on ALS hiPSC-derived neurons, it was observed that these neurons fired significantly more spontaneous APs relative to neurons derived from their isogenic control lines (85). By using gene targeting and homologous recombination techniques, the SOD1 mutation was corrected in the iPSC lines and the electrophysiological properties were recorded. The corrected neurons showed spiking rates similar to that of the isogenic control lines. Upon the application of retigabine, a specific activator of subthreshold KV7 (KCNQ) currents and a known anticonvulsant, the hyperexcitability phenotype of ALS motor neurons was rescued.
Progressive Neurological Diseases
Published in Amy J. Litterini, Christopher M. Wilson, Physical Activity and Rehabilitation in Life-threatening Illness, 2021
Christopher M. Wilson, Amy J. Litterini
The typical presentation of ALS symptoms includes persistent weakness and/or spasticity in one or more extremities, with initial presentation often unilateral. Difficulty with swallowing and/or speech may accompany the extremity symptoms. Bowel and bladder dysfunction may also be noted by individuals with ALS, and chronic constipation leads to increased risk for bowel obstruction. Prolonged immobility can also contribute to symptoms of pain for these individuals. Fasciculations are also seen, as well as cognitive and behavioral issues for some people. Risk factors for ALS which are consistently reported include older age, male gender, and tobacco use disorder.33
A Brazilian multicentre study on the clinical and epidemiological profiles of 1116 patients with amyotrophic lateral sclerosis and its phenotypic variants
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Christian Marques Couto, Elisa de Melo Queiroz, Renata Nogueira, Ana Paula Pires Duarte Küsel, Osvaldo J. M. Nascimento
Familial ALS cases represent up to 10% in most epidemiological studies (6). In our sample, 12.9% of the cases were FALS. The higher proportion of these cases might have been related to selection bias, as the admission of patients to our rehabilitation hospitals may have inspired their affected relatives to seek care. It is essential to note an even higher proportion of hereditary forms of ALS among patients with restricted phenotypes with predominantly lower motor neuron manifestations. Such a distribution is heavily influenced by ALS type 8, as a high prevalence of this subtype is well recognized in the states in Southeast Brazil, where it was originally described (38). Those patients may have classic ALS presentations but usually have predominantly lower motor neuron phenotypes and prolonged disease courses. Our large number of patients with mutations in VAPB is reflective of the prevalence and the relatively lower cost and ease of execution of this genetic test. Similar founder effects were also described for SOD1 p.D91A in a Scandinavian population and TARDBP p.A382T in a Sardinian population (39,40).
TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target
Published in Expert Opinion on Therapeutic Targets, 2022
Yara Al Ojaimi, Audrey Dangoumau, Hugo Alarcan, Rudolf Hergesheimer, Patrick Vourc’h, Philippe Corcia, Débora Lanznaster, Hélène Blasco
ALS remains a fatal disease with an average life expectancy of 2 to 5 years following the appearance of symptoms. There is still no effective treatment to reverse or stop the progression of ALS. The only two FDA-approved drugs, Rilutek® (Riluzole) and Radicava® (Edaravone), produce mild effects on slowing down disease progression. One of the major pathological consequences of TDP-43 pathology is the depletion of nuclear TDP-43 and its subsequent effects on alternative splicing and protein expression. Therefore, one of the main aims of targeting TDP-43 proteinopathy is to restore the lost nuclear functions of the protein. For this reason, the development of new therapeutic strategies such as antisense oligonucleotides (ASO) seemed promising, but clinical translation remains challenging [3–5]. Therefore, intense research is still being conducted to find reliable ALS biomarkers and innovative potential treatments targeting the most relevant pathophysiological factors that can alter the course of the disease. In this review, we will discuss the physiological role of TDP-43 and the subsequent effects of TDP-43 proteinopathy. We then present the advances made in the therapeutic strategies targeting TDP-43 pathology in ALS.
Genetic testing for amyotrophic lateral sclerosis in Canada – an assessment of current practices
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Kristiana Salmon, Nancy Anoja, Ari Breiner, Marvin Chum, Annie Dionne, Nicolas Dupré, Amanda Fiander, Daniel Fok, Amer Ghavanini, Sylvie Gosselin, Aaron Izenberg, Wendy Johnston, Sanjay Kalra, Geneviève Matte, Michel Melanson, Colleen O’Connell, Benjamin Ritsma, Kerri Schellenberg, Christen Shoesmith, Sandra Tremblay, Heather Williams, Angela Genge
Predictive testing practices were the most variable. Considerations for predictive testing in ALS have been previously published (18–21); however, there is a need for global input and further development, given the recent advances in ALS genetics. In addition, there is a lack of research surrounding the psychological impact of predictive testing for ALS (21). Seventy percent (19/27) of clinics indicated that they do not provide prospective follow-up to at-risk, asymptomatic family members who obtain positive predictive testing results. When these cases are referred to a medical genetics department for a consult (80%, 16/20 Figure 3(C)), it is unclear to ALS clinicians what, if any, follow-up is provided. As such, it can be extrapolated that there are families with known genetic etiologies for ALS that could be lost to follow-up. A first-of-its-kind clinical trial for pre-symptomatic SOD1 gene mutation carriers is ongoing (NCT04856982), emphasizing the urgent need for better predictive testing practices in ALS.