You are here: start » group_2_presentation_3_-_als

Differences

This shows you the differences between two versions of the page.

--- group_2_presentation_3_-_als [2016/03/27 00:40]
monachd
+++ group_2_presentation_3_-_als [2018/01/25 15:18] (current)
@@ Line 16: / Line 16: @@
 <style justify>
-Migraines are one of the oldest documented illness being described as early as 1200 BCE by the Egyptians. Arataeus of Cappadocia is however the one credited with the discovery of migraines after having extensively described unilateral headaches with aura. Migraines have plagued humans throughout our history with little progress made in the area of treatment and cures. Several treatments have been tried with no avail, including hot irons, bloodletting, inserting garlic into incisions made in the temple and applying opium and vinegar solutions directly to the skull. Some have even gone as far as to perform surgeries such as lobotomies on migraine sufferers. Trepanation involves making a hole in the skull to let out evil spirits that presumably were causing the migraine. It is possibly the oldest surgery in history and may date as far back as 6500 BCE.
+Jean- Marie Charcot (1825-1893) noted the first reports of the characteristics of ALS in 1874, and named the fatal syndrome based on what he found.  He was a noted French neurologist who explained how the central nervous system works and who has been called “the Father of Neurology”. (Rowland, 2001)
-The first known use of medication that has shown some success is use of ergotamine in the 1930s. Ergotamine constricts blood vessels in the brain and has been shown to provide pain relief in some individuals. Many drugs have been researched and experimented with since with little success. The first and currently only class of drugs developed and used solely for the treatment of migraines are Triptans, which were developed in the early 1990s (American Migraine Foundation, 2016).
 </style>
+<style float-left>
+{{:stephen_hawking_2.jpg|Figure 1: Famous physicist Stephen Hawking}}
+   Figure 1: Famous physicist Stephen Hawking
+</style>
+<style justify>
+Drs. Scarmeas, Shih, Stern, Ottoman, and Rowland recently published a scientific article, concluding that subjects with motor neuron diseases were more likely to be slim, or had once been serious athletes. Many famous people in US history have had ALS (Scarmeas, N. et al., 2002). For example:
+  * Lou Gehrig was a very famous Yankee baseball player
+  * Ezzard Charles was a heavyweight-boxing champion
+  * Catfish Hunter- baseball player
+  * Senator Jacob Javits was an avid tennis player
+  * David Niven was a competitive sailor.
+  * Stephen Hawking, the famous physicist
+  * Even some in the musical field were subjected to ALS; Dimitri Shostakovitch and Charles Mingus both vigorously practiced musical instruments
+</style>
+\\
+\\
+\\
+\\
 ====== Epidemiology ======
 <style justify>
-Migraines are more common in males before puberty and in females after puberty with 19% of adult women and 11% of adult males being affected (Vos, 2010). Migraines commonly begin between the ages of 15 and 24 and have an increased incidence in adults aged 35 to 45 (Bartleson, 2010). The incidence of migraines are slightly lower in Asian and African countries, but this may be partially due to lack of diagnostic resources in these areas (Wang, 2003). In the United States, 18% of men and 43% of women will experience migraines at some point in their lives with about 6% of men and 18% of women experiencing migraines in a given year. Europeans have a lifetime risk of migraine between 12 and 28%. Chronic migraines occur in about 1.4 to 2.2% of the population. Worldwide, migraines affect about 15% of the population (Vos, 2010).
+ALS strikes about six to eight people per 100,000 (ALS Society of Canada, 2012).In any given year, about two new cases of ALS per 100,000 people will be diagnosed (ALS Society of Canada, 2012). In the US, approximately 5,000 people are diagnosed yearly with ALS (Kiernan, MC. et al., 2011).. With an estimated Canadian population of 34 million, approximately 2,000 - 3,000 people in Canada currently have ALS (ALS Society of Canada, 2012). The incidence (new cases) of ALS increases with age. Most are between the ages of 40-70, but it can also occur in older and younger adults, and rarely in teenagers.  Presently in the United States, about 30,000 people are victims of ALS; most will die within 3-5 years of contracting the fatal syndrome.  Ten percent of all known cases are hereditary.  Although males are more prone to ALS, the condition has no racial, ethnic or socioeconomic boundaries (Kiernan, MC. et al., 2011).
 </style>
-{{:stats_about_migraines_2.gif| Figure 1: Prevalence of migraines in Canada by age group and sex. The above graph illustrates that females are  significantly more likely to experience migraines compared to males after the age of 12. Individuals between the ages of 30 to 49 have the highest incidence rate for migraine attacks and act as the reference group to establish statistical significance between other age groups. http://www.statcan.gc.ca/pub/82-003-x/2014006/article/14033/c-g/fig1-eng.htm}}
+{{:prevalence_of_als.gif|Figure 2:The figure shows prevalence rates per 100,000 population for cases of amyotrophic lateral sclerosis in the United States, by age group, on the basis of data from the National ALS Registry for October 19, 2010-December 31, 2011. Prevalence rates were highest for persons aged 70-79 years and lowest for those aged 18-39 years.}}
-   Figure 1: Prevalence of migraines in Canada by age group and sex
+   Figure 2: The figure shows prevalence rates per 100,000 population for cases of amyotrophic lateral sclerosis in the United States, by age group, on the basis of data
+   from the National ALS Registry for October 19, 2010-December 31, 2011. Prevalence rates were highest for persons aged 70-79 years and lowest for those aged 18-39 years. Available at:
+   http://www.cdc.gov/als.
@@ Line 72: / Line 90: @@
 {{:als_pathophysiology.jpg|Figure 3: The pathophysiology of ALS}}
-   Figure 3: The Pathophysiology of ALS
+   Figure 3: The Pathophysiology of ALS (Vucic et al, 2014)
 </style>
 <style justify>
-Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. It is characterized by the loss of motor neurons in both the brain and spinal cord (Majoor-krakauer et. al, 2011) There is no single cause of ALS, as the disease is currently characterized by its major symptom: the death of motor neurons. For this reason, it is classified as a Complex Genetic Disorder, with no single genetic or environmental factor causing onset, and a combination of factors uniquely contributing to each case (Gordon, 2011). Due to the variety of underlying causes and mechanisms that result in ALS, there are two accepted “forms” of the disease that result in similar pathophysiology.  In approximately 10% of cases, ALS is a mostly genetic disease and is inherited, this is known as Familial ALS, or FALS. The other 90% is thought to be caused by a unknown mix of environmental factors as well as genetic predisposition, and is known as sporadic ALS or SALS (Kato, 2008). Both forms are poorly understood, and the major differentiator between the two is observable family history.
+Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily involves the motor neuron system. It is characterized by the loss of motor neurons in both the brain and spinal cord (Majoor-krakauer et. al, 2011) There is no single cause of ALS, as the disease is currently characterized by its major symptom: the death of both upper and lower motor neurons. For this reason, it is classified as a Complex Genetic Disorder, with no single genetic or environmental factor causing onset, and a combination of factors uniquely contributing to each case (Gordon, 2011). Due to the variety of underlying causes and mechanisms that result in ALS, there are two accepted “forms” of the disease that result in similar pathophysiology.  In approximately 10% of cases, ALS is a mostly genetic disease and is inherited, this is known as Familial ALS, or FALS. The other 90% is thought to be caused by a unknown mix of environmental factors as well as genetic predisposition, and is known as sporadic ALS or SALS (Kato, 2008). Both forms are poorly understood, and the major differentiator between the two is observable family history.
 </style>
@@ Line 129: / Line 147: @@
 </style>
 <style justify>
-The only FDA approved treatment available to date is the drug Riluzole. It belongs to the class of drugs known as antiglutamates and whose chemical formula is C8H5F3N2OS (Figure 6). It functions to prevent the overactivation of neurons by regulating neurotransmitter activity and inhibiting neuronal firing (Dall’Igna et al, 2013). Dall’Igna et. al (2013) studied the influence of riluzole on glutamate uptake at doses that did not induce damage on the studied cells within a 1 h time frame (0.1–100 M). One hour pre-incubation of riluzole significantly enhanced glutamate uptake in C6 astroglial cell cultures (Figure 8a). In further studies, the researchers chose the lowest effective dose of riluzole to alter glutamate uptake (10 M). Because EAAC1 is the main glutamate transporter in C6 astroglial cells, they analyzed the effect of riluzole on EAAC1 expression (Figure 7). Treatment with 10 M riluzole for 1 h induced an 18% increase in the expression of EAAC1 transporter as detected by Western blotting, indicating a possible mechanism for the increase in glutamate uptake (Figure 7). The increase in glutamate uptake was demonstrated to be dependent on PKC, PI3K and ERK intracellular pathways; riluzole had the opposite effect on glutamate uptake when it was added simultaneously with inhibitors of these enzymes (Figure 8b). Co-incubation of riluzole with the inhibitors of PKC (bisindolylmaleimide II), PI3K (wortmannin) or FGFR (PD173074) not only blocked the stimulatory effect of riluzole on glutamate uptake, but the riluzole plus inhibitor combination also decreased glutamate uptake levels to below the basal controls (Figure 8b). Such effects occurred in doses of bisindolylmaleimide II, wortmannin and PD173074 that alone had no significant effect on basal glutamate uptake (Dall'Igna, 2013).
+The only FDA approved treatment available to date is the drug Riluzole, which is thought to extend life expectancy by 2-3 months (Dall'Igna et. al, 2013). It belongs to the class of drugs known as antiglutamates and whose chemical formula is C8H5F3N2OS (Figure 6). It functions to prevent the overactivation of neurons by regulating neurotransmitter activity and inhibiting neuronal firing (Dall’Igna et al, 2013). Dall’Igna et. al (2013) studied the influence of riluzole on glutamate uptake at doses that did not induce damage on the studied cells within a 1 h time frame (0.1–100 M). One hour pre-incubation of riluzole significantly enhanced glutamate uptake in C6 astroglial cell cultures (Figure 8a). In further studies, the researchers chose the lowest effective dose of riluzole to alter glutamate uptake (10 M). Because EAAC1 is the main glutamate transporter in C6 astroglial cells, they analyzed the effect of riluzole on EAAC1 expression (Figure 7). Treatment with 10 M riluzole for 1 h induced an 18% increase in the expression of EAAC1 transporter as detected by Western blotting, indicating a possible mechanism for the increase in glutamate uptake (Figure 7). The increase in glutamate uptake was demonstrated to be dependent on PKC, PI3K and ERK intracellular pathways; riluzole had the opposite effect on glutamate uptake when it was added simultaneously with inhibitors of these enzymes (Figure 8b). Co-incubation of riluzole with the inhibitors of PKC (bisindolylmaleimide II), PI3K (wortmannin) or FGFR (PD173074) not only blocked the stimulatory effect of riluzole on glutamate uptake, but the riluzole plus inhibitor combination also decreased glutamate uptake levels to below the basal controls (Figure 8b). Such effects occurred in doses of bisindolylmaleimide II, wortmannin and PD173074 that alone had no significant effect on basal glutamate uptake (Dall'Igna, 2013).
 </style>
@@ Line 170: / Line 188: @@
 ====== Conclusion ======
-Overall, ALS is a rapidly, progressing disease that greatly impacts the everyday functioning of the individual who has it. glutamate excitotoxicity in ALS patients can be linked to mutant astrocytes that malfunction and this can be the target of potential therapies. Drug therapy has shown promising temporary effects and although more research needs to be done, there is the potential to use innovative stem cell therapeutics to introduce healthy astrocytes into neuronal regions for longer-term effects.
+Overall, ALS is a rapidly, progressing disease that greatly impacts the everyday functioning of the individual who has it. ALS destroys motor neurons which are an important link in the nervous system. It is through motor neurons that the brain sends messages to the voluntary muscles throughout the body which leads to the individual losing the ability to walk, talk and breath. ALS is now recognized to have multiple interacting causes, all sharing a common pathway leading to the destruction of the motor neurons. Glutamate excitotoxicity in ALS patients can be linked to mutant astrocytes that malfunction and this can be the target of potential therapies. Drug therapy has shown promising temporary effects and although more research needs to be done, there is the potential to use innovative stem cell therapeutics to introduce healthy astrocytes into neuronal regions for longer-term effects.
+====== References ======
+Als society of canada. (2012). A Manual for People Living with ALS. (7th ed.). Retrieved 27 March, 2016, from https://www.als.ca/sites/default/files/files/ALS%20Manual/2012%20Manual%20People%20Living%20With%20ALS%20-%20ENGLISH%20Final.pdf
+Cifra, A., Nani, F., & Nistri, A. (2011). Riluzole is a potent drug to protect neonatal rat hypoglossal motoneurons in vitro from excitotoxicity due to glutamate uptake block. European Journal of Neuroscience, 33, 899-913.
+Dall'Igna, O., Bobermin, L., Souza, D., & Santos, A. (2013). Riluzole increases glutamate uptake by cultured C6 astroglial cells. International Journal of Developmental Neuroscience, 31, 482-486.
+Gijn, J. (2011). Charles Bell (1774–1842). Journal of Neurology J Neurol 258, 1189–1190.
+Gordon PH. Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management. CNS Drugs. 2011;25(1):1-15.
+Guo W, Chen Y, Zhou X, et al. An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol. 2011;18(7):822-30.
+Foran, E., & Trotti, D. (2009). Glutamate transporters and the excitotoxic path to motor neuron degeneration in amyotrophic lateral sclerosis. Antioxidants & Redox Signaling, 11(7)
+Hillel, A. D., Miller, R. M., Yorkston, K., McDonald, E., Norris, F. H., & Konikow, N. (1989). Amyotrophic lateral sclerosis severity scale. Neuroepidemiology, 8(3), 142-150.
+Kato S. Amyotrophic lateral sclerosis models and human neuropathology: similarities and differences. Acta Neuropathol. 2008;115(1):97-114.
+Kiernan, MC; Vucic, S; Cheah, BC; Turner, MR; Eisen, A; Hardiman, O; Burrell, JR; Zoing, MC (12 March 2011). "Amyotrophic lateral sclerosis.". Lancet 377 (9769): 942–55. doi:10.1016/s0140-
+(10)61156-7. PMID 21296405.
+Kondo, T. et al. (2014). Focal transplantation of human iPSC-derived glial-rich neural progenitors improves lifespan of ALS mice. Stem Cell Reports, 3(2), 242-249.
+Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010;9(10):995-1007.
+Majoor-krakauer D, Willems PJ, Hofman A. Genetic epidemiology of amyotrophic lateral sclerosis. Clin Genet. 2003;63(2):83-101.
+Mioshi, E., Hsieh, S., Caga, J., Ramsey, E., Chen, K., Lillo, P., ... & Kiernan, M. C. (2014). A novel tool to detect behavioural symptoms in ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15(3-4), 298-304.
+Rowland LP (March 2001). "How amyotrophic lateral sclerosis got its name: the clinical-pathologic genius of Jean-Martin Charcot". Arch. Neurol. 58 (3): 512–5. doi:10.1001/archneur.58.3.512. PMID 11255459
+Saberi S, Stauffer JE, Schulte DJ, Ravits J. Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants. Neurol Clin. 2015;33(4):855-76.
+Saccon RA, Bunton-stasyshyn RK, Fisher EM, Fratta P. Is SOD1 loss of function involved in amyotrophic lateral sclerosis?. Brain. 2013;136(Pt 8):2342-58.
+Scarmeas, N., Shih, T., Stern, Y., Ottman, R., & Rowland, L. P. (2002). Premorbid weight, body mass, and varsity athletics in ALS. Neurology, 59(5), 773-775.
+Turner, M. R., Parton, M. J., Shaw, C. E., Leigh, P. N., & Al-Chalabi, A. (2003). Prolonged survival in motor neuron disease: a descriptive study of the King’s database 1990–2002. Journal of Neurology, Neurosurgery & Psychiatry, 74(7), 995-997
+Wijesekera, L., & Leigh, P. (2009). Amyotrophic lateral sclerosis. Orphanet Journal of Rare Diseases, 4(3)

Differences

Search

Navigation

Print/export

Tools

QR Code