Tuesday, January 28, 2020

Effects of Paraneoplastic LEMS on Neuromuscular Junction

Effects of Paraneoplastic LEMS on Neuromuscular Junction Qing Zhi Tan Effects of Paraneoplastic  Lambert-Eaton Myasthenic Syndrome on the Neuromuscular Junction IntroductionThe Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease. It is characterised by muscle weakness of the proximal lowerlimbs as a result of auto-antibodies produced against the voltage-gated calcium channels (VGCC) found on the presynaptic membrane of the neuromuscular junction(1). Most of the time, LEMS is classified as a paraneoplastic syndrome as it is often associated with cancer (small cell lung cancer in particular) (2, 3). One of the earliest descriptions of this disease was reported by Anderson and his colleagues in the year 1953, describing a 47-year-old patient with bronchial carcinoma presenting with progressive muscle weakness(4). Upon examining this patient, Anderson wrote: His (the patients) muscle power was generally weaker than his muscle bulk would suggest, especially the muscles of the shoulder girdle, hip girdle, trunk, and anterior compartments of the legs.(4) Since then, much research has been done to find out more about this disease. It is now known that the auto-antibodies are primarily directed against the P/Q-type VGCCs at the neuromuscular junction (1-3, 5, 6). This report will discuss the effects of LEMS on the neuromuscular junction. Voltage-Gated Calcium ChannelsIt would be useful to first understand the structure of the voltage-gated calcium channels (VGCC). In general, VGCCs are made up of 5 subunits (ÃŽÂ ±1, ÃŽÂ ±2, ÃŽÂ ², ÃŽÂ ´, ÃŽÂ ³) and can be divided, according to the electrophysiological and pharmacological properties of their ÃŽÂ ±1 subunit, into 5 different subtypes (L, N, P/Q, R and T-type)(2, 7). The structure of a typical VGCC is shown in Figure 1 below. As mentioned before, the LEMS auto-antibodies are mainly directed against the P/Q-type VGCCs (1-3, 5, 6). The ÃŽÂ ±1 subunit of the P/Q-type VGCCs is known as ÃŽÂ ±1A(8). This ÃŽÂ ±1A subunit forms the channel which allows the movement of Ca2+ ions into the synaptic knob(8), and can be further broken down into 4 identical domains (I, II, III, IV), each possessing 6 transmembrane segments (S1-S6)(2, 8) (see Figure 2). What Happens at The Neuromuscular Junction?Now that we have understood the basic structure of the VGCCs, let us move on to its role and how it is affected by the pathogenesis of LEMS. The neuromuscular junction is made up of the pre-synaptic membrane, the synaptic cleft and the post-synaptic membrane (5, 9, 10). P/Q-type VGCCs present on the surface of the pre-synaptic membrane play a vital role in allowing synaptic transmissions to cross the neuromuscular junction (7, 9). In studies conducted by multiple different researchers, anti-P/Q-type VGCC auto-antibodies were found in more than 85% of LEMS patients (3, 6, 11). Japanese researchers Masaharu Takamori and his colleagues even went a step further to determine the specific immunodominant sites within the P/Q-type VGCC in which the auto-antibodies would bind. In their study, they found that majority of their test subjects had auto-antibodies directed against domains II and IV of the ÃŽÂ ±1A subunit in the P/Q-type VGCC(12)(highlighted in red in Figure 2). Depolarisation of the pre-synaptic membrane occurs when stimulated by an action potential initiated by a nerve impulse(13). This membrane depolarisation causes the VGCCs to open, allowing the local influx of calcium ions (Ca2+)into the synaptic knob(13). The increase in Ca2+ concentration will stimulate the exocytosis of vesicles containing the neurotransmitter Acetylcholine (ACh) into the synaptic cleft(13). ACh then goes on to bind to the nicotinic acetylcholine receptors found on the motor end plate which will trigger an action potential and subsequently causing muscle contraction.(10, 13) In patients with LEMS, the LEMS auto-antibodies would bind to the VGCC present on the pre-synaptic membrane of the neuromuscular junction(5). This causes the VGCC to lose its ability to function as an ion channel, thus inhibiting the influx of Ca2+ into the synaptic knob during membrane depolarisation(5). Since the exocytosis of synaptic vesicles are dependent on Ca2+ (14), it is believed that a decrease in Ca2+ influx would result in a reduction in synaptic vesicle exocytosis(5, 13, 15). A recent study conducted in 2015 confirmed the phenomenon in which the LEMS IgG directly causes a reduction in the exocytosis of synaptic vesicles (16). They did this by using fluorescence imaging techniques to observe the exocytosis of synaptic vesicles in rat neurons incubated with LEMS IgG (16). Pooled IgG from healthy individuals were used in comparison and as a control (16). Hence, it is evident that the muscle weakness seen in LEMS patients is a direct consequence of reduced exocytosis of ACh-containing synaptic vesicles. In summary, the Lambert-Eaton myasthenic syndrome is an autoimmune disease that causes muscle weakness in patients. The reduction in muscle power is due to insufficient ACh release at the neuromuscular junction. In 85% of these patients, this is caused by auto-antibodies inactivating the P/Q-type VGCCs on the presynaptic membrane. Going Beyond VGCCs So, what happens in the remaining 10-15% of LEMS patients that do not have anti-P/Q-type VGCC antibodies? Many scientists have asked the same question and investigations have been carried out to find alternative mechanisms in the pathogenesis of LEMS in seronegative patients. (The term seronegative is used to describe patients with undetectable anti-P/Q-type antibodies.) In the absence of anti-P/Q-type VGCC antibodies, it is almost impossible that LEMS would have the same pathogenesis in seronegative patients. Yet, it is found that there are no significant differences in the electrophysiological and clinical characteristics between the seronegative and seropositive patients(17, 18). One possible explanation for this phenomenon is that there might be auto-antibodies directed against a different molecule involved in the synaptic transmission; hence causing seronegative patients to have the same clinical and electrophysical features albeit having no anti-P/Q-type VGCC antibodies. To date, many auto-antibodies with different target molecules have been found in LEMS patients. One of the earliest to be discovered is an auto-antibody to synaptotagmin, which is a protein involved in synaptic vesicle exocytosis (2, 5, 13, 15, 19). Furthermore, antibodies to the M1-type presynaptic muscarinic ACh receptor (M1-mAChR) have also been discovered(20). The M1-mAChR is a G-protein coupled receptor that regulates ACh release at the neuromuscular junction(5, 20). We will not be going into the specifics of these antibodies in this report as the mechanisms involved are largely complicated. ConclusionEven though LEMS is a rare autoimmune disease, the prevalence of LEMS as a paraneoplastic syndrome in patients with small cell lung cancer (SCLC) is extremely high. More than half of LEMS patients have SCLC and more often than not, the diagnosis of LEMS precedes the diagnosis of SCLC(21). Therefore, LEMS could potentially play a crucial role in allowing certain cancers to be detected at an earlier stage. Hence, understanding the pathophysiology of this disease would not only prove useful in discovering better treatments for LEMS patients but also aid the early detection of cancer. References: 1.Weiss N, Koschak A. Pathologies of Calcium Channels. Weiss N, Koschak A, editors: Berlin, Heidelberg : Springer Berlin Heidelberg : Imprint: Springer; 2014. 2.Takamori M. An autoimmune channelopathy associated with cancer: Lambert-Eaton myasthenic syndrome. Intern Med. 1999;38(2):86-96. 3.Lennon VA, Kryzer TJ, Griesmann GE, OSuilleabhain PE, Windebank AJ, Woppmann A, et al. Calcium-Channel Antibodies in the Lambert-Eaton Syndrome and Other Paraneoplastic Syndromes. New England Journal of Medicine. 1995;332(22):1467-75. 4.Anderson HJ, Churchill-Davidson HC, Richardson AT. BRONCHIAL NEOPLASM WITH MYASTHENIA. The Lancet. 1953;262(6799):1291-3. 5.Hulsbrink R, Hashemolhosseini S. Lambert-Eaton myasthenic syndrome diagnosis, pathogenesis and therapy. Clin Neurophysiol. 2014;125(12):2328-36. 6.Motomura M, Lang B, Johnston I, Palace J, Vincent A, Newsom-Davis J. Incidence of serum anti-P/Q-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Journal of the Neurological Sciences. 1997;147(1):35-42. 7.Catterall WA. Voltage-gated calcium channels. Cold Spring Harbor perspectives in biology. 2011;3(8):a003947. 8.Structure and Regulation of Voltage-Gated Ca2+ Channels. Annual Review of Cell and Developmental Biology. 2000;16(1):521-55. 9.Hughes BW, Kusner LL, Kaminski HJ. Molecular architecture of the neuromuscular junction. Muscle Nerve. 2006;33(4):445-61. 10.Martini F, Nath JL, Bartholomew EF. Fundamentals of anatomy physiology. San Francisco: Benjamin Cummings; 2012. 11.Motomura M, Johnston I, Lang B, Vincent A, Newsom-Davis J. An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. Journal of Neurology, Neurosurgery Psychiatry. 1995;58(1):85-7. 12.Takamori M, Iwasa K, Komai K. Antigenic Sites of the Voltage-gated Calcium Channel in Lambert-Eaton Myasthenic Syndromea. Annals of the New York Academy of Sciences. 1998;841(1):625-35. 13.Lang B, Newsom-Davis J. Immunopathology of the Lambert-Eaton myasthenic syndrome. Springer seminars in immunopathology. 1995;17(1):3-15. 14.Mechanisms of Synaptic Vesicle Exocytosis. Annual Review of Cell and Developmental Biology. 2000;16(1):19-49. 15.Takamori M. Lambert-Eaton myasthenic syndrome as an autoimmune calcium channelopathy. Biochem Biophys Res Commun. 2004;322(4):1347-51. 16.Spillane J, Ermolyuk Y, Cano-Jaimez M, Lang B, Vincent A, Volynski KE, et al. Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca2+ channels. Neurology. 2015;84(6):575-9. 17.Oh SJ, Hatanaka Y, Claussen GC, Sher E. Electrophysiological differences in seropositive and seronegative Lambert-Eaton myasthenic syndrome. Muscle Nerve. 2007;35(2):178-83. 18.Nakao YK, Motomura M, Fukudome T, Fukuda T, Shiraishi H, Yoshimura T, et al. Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients. Neurology. 2002;59(11):1773. 19.Takamori M, Hamada T, Komai K, Takahashi M, Yoshida A. Synaptotagmin can cause an immune-mediated model of Lambert-Eaton myasthenic syndrome in rats. Annals of neurology. 1994;35(1):74-80. 20.Takamori M. Lambert-Eaton myasthenic syndrome: Search for alternative autoimmune targets and possible compensatory mechanisms based on presynaptic calcium homeostasis. Journal of Neuroimmunology. 2008;201-202:145-52. 21.Titulaer MJ, Verschuuren JJGM. Lambert-Eaton Myasthenic Syndrome. Annals of the New York Academy of Sciences. 2008;1132(1):129-34.

Sunday, January 19, 2020

Decubitis Ulcers :: essays research papers fc

1.  Ã‚  Ã‚  Ã‚  Ã‚  Decubitis Ulcers are also known as bed sores.(Marsh 1) They are mostly seen in Geriatrics patients. They occur in people who are put on bed rest, or long periods of wheelchair use. â€Å"A traumatic decubitis ulcer is precipitated by continuous pressure on the skin and deep tissue with ischemic necrosis† (Plewig 369). These particular ulcers are mainly found on bony parts of the body. They develop when the cells die because there is a tremendous amount of pressure put on the skin and it is trapped between a mattress or chair and tiny blood vessels collapse. The parts of the body that are affected by these ulcers are the back of the head, ear, shoulders, elbows, hips, sacrum, knees, ankles, and heels. Decubitis ulcers can be classified into three grades. (1) Area is more reddened, skin is dry. (2) Area is more reddened, epidermal layer of the skin is broken, and blisters form. (3) Deeper layers of the skin are affected, blisters are broken open, and bone m ay be visible. (Hegner, Caldwell 421) 2. Before treating decubitis ulcers, viewing of the nurse or caregivers feelings about the care is important. Heshe should determine whether or not they agree with the patients wishes and is capable of completing that care. â€Å"When making these decisions, consider the stage of the ulcer and the treatment needed, the benefits and the burdens of the treatment, and the anticipated treatment outcome† (Darkovich 47). After these views are looked at, there are many treatments available. If the area is reddened, all that is needed is a gentle massage. If the skin is open, bacteriostatic agents, antiseptic sprays, and antibiotic ointments are used to reduce or prevent bacteria. The surgical process called grafting is practiced to treat these ulcers. This is when a patch of skin is removed from one part of the body, and is placed onto the infected area. Sheepskin pads, alternating air pressure mattresses, heel protectors, and egg crate mattresses are also used. (Hegner, Caldwell 427 ) 3. The first lab test that I found is a urinalysis. This is a test of the urine to detect alcohol, drugs, sugar, and other abnormal substences. This tells us if there is any bacteria in the body, and if it is located in the decubitis ulcer, so we can know if it is infected or not. The second lab test that is done on these ulcers is CD, this determines the antigens on the white blood cells.

Saturday, January 11, 2020

Race & Ethnicity: Effects on Life Essay

Ethnicity and race has had a big influence on peoples’ every day life choices. In some way or another, most people will be judged according to their color of their skin or their ethnic background. We live in a society full of different races and cultures affecting the way we interact with each other, as well as influencing our views on equality and differences among the many different races in our society. Often influential media groups and social standards shape our beliefs, also affecting how we interact with cultures different from our own, and how various groups interact with each other. Race and ethnicity may be defined as a type of grouping or classification based on a persons origin of birth and includes their racial appearance, language, religion and culture. Ethnicity can be defined as a social construction that indicates identification with a particular group who share common cultural traits, such as language, religion and traditions. Terms like ethnocentrism, racism, stereotyping, and ethnicity can affect our health status, our economical status, and just basically our status in society. Race defines who we are, and in some cases it is the root of discrimination problems. Individuals dislike other people because they do not like how they are; whether it is physically or the way they think and act. We look at people and experiences through race and culture. I was raised with family that had introverted personalities. This is one of the reasons why my personality is also like that. I grew up recognizing differences in races and ethnicity and it never affected my way of being, I simply saw everyone the same, with the same potential and equal opportunity. I have been taught by the spoken and unspoken ways of my parents, teachers, friends; I have simply grown up recognizing what is wrong and what is right among society. I was born in California but both my parents are Mexican, which makes me Hispanic. My experiences of racial profiling or prejudice due to my ethnic background or my Hispanic look have not been too common or extremely racist. My high school was about 99.99 percent Hispanic student body, so there was very little if any racial tension among students. It was when we would go out of that part of town that I would actually see racial comments made and shown by others. I was involved in the baseball team and tennis team at my  high school, and I would see some sort of labeling or stereotyping aimed at me and my teammates when we would play in other schools with Anglos or Blacks. Since we were one of the poorest schools in the city they would automatically assume we weren’t adequately prepared to be playing a team like them. Their stereotypes of us would make them think that we didn’t speak English and our playing abilities would be very novice since we didn’t have the tools or money to afford good equipment or a coach at a young age. However, I will admit that we would also judge them as being too cocky, and with the conventional ‘white people’ stereotypes. Though most of the time we were right because these were rich kids with almost everything handed to them. Being in the minority has its disadvantages, but people, specifically students can be smart and use those stereotypes to their advantage. I honestly never paid attention to my lack of resources, instead I knew that if I wanted something I was going to try and get it. A big misconception that surrounded our school or the part of town that I lived in was that we were not going to make it to college, in fact, we would be lucky if we actually graduated from high school. The name of our high school was very much and icon or a symbol. I knew some friends that wouldn’t give out the name of our school because they were afraid of being labeled a â€Å"loser† in some way. Basically, going to my school meant that we were low IQ destined to work at low paying jobs, simply because many were Mexican immigrants or first generation American born. For our advantage, now a day being in the minority can actually help you enroll into colleges of your choice and get scholarships to help pay for college. Perceptions play a great roll on judging others; many times it is influenced by race and ethnicity. It is clear to me that if lived in a more diverse part of the city; my experiences would be the very different. As society grows more with different cultures, races and ethnics, tension grows and people start disliking others ways of being that are not like theirs. But it is important to understand that it is not healthy to have prejudice feelings towards others, it only makes one bitter.

Friday, January 3, 2020

Comparing Different Media Matrix, TS Eliots A Journey...

Compare the Matrix with Self Reliance and the Journey of Magi Introduction A common challenge that most people will go through is carefully examining their lives in contrast to the world they live in. This is because they will see conformity as a poison that will harm their ability to think and have greater control over themselves. The Matrix, Self Reliance and the Journey of the Magi are a critical reflection of these ideas over the course of time. To fully understand how all three works are discussing the larger social meaning requires comparing them with each other. Together, these different elements will highlight the way they are criticizing society and technological innovations that are occurring. The Matrix, Self Reliance and the Journey of the Magi In all three works, there is a focus on showing how technological advancements are making society worse off. This is because these kinds of changes are designed to take away any kind of individual creativity and have everyone conform to different social standards. Where, each one is highlighting these transformations throughout the course of human history. In Self Reliance, Emerson is discussing how everyone needs to avoid having a sense of conformity and false consistency that exists in society. This occurs through technological changes, which are used to transform daily life and the way that people view their role in it. It is during this time, that ideas of conformity will be imposed upon the people. This is