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Stony Brook Young Investigators Review

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A Conversation with Dr. Anne Moyer

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The Effects of Social Networking on Academic Achievement

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Immunotherapy to Treat Multiple Sclerosis

Volume 8 Spring 2017


Stony Brook Young Investigators Review Staff 2016 - 2017 Editor-in-Chief Amanda Ng ’17

Layout Chief Samuel Lederer ’17

President Aaron Gochman ’17

Managing Editors Jenna Mallon ’18 Sahil Rawal ’19

Assistant Layout Editor Dana Espine ’18

Cabinet Peter Alsaloum ’19 Benjamin Kerner ’18 Kyle Pacia ’19

Associate Editors Christin Abraham ’19 Samara Khan ’19 Rachel Kogan ’19 Julia Newman ’19 Nicole Olakkengil ’19 Anna Tarasova ’19 Copy Editors Taylor Ha ’18 Aaradhana Natarajan ’20 Lillian Pao ’18 Daniel Walocha ’19

Layout Editors Dahae Jun ’19 Sarah Lynch ’17 Arun Nallainathan ’18 Abrar Taseen ’19 Webmasters Ronak Kenia ’18 Arslan Shahid ’17

Photographers Evelyn Kandov ’17 Jerin Thomas ’19 Advisors Dr. Peter Gergen Dr. Giancarlo la Camera Dr. Laura Lindenfeld

Writers Ericka Berman ’17 Meghan Bialt-Decelie ’19 Yasmine Brown-Williams ’18 Alison Chan ’19 Sanket Desai ’19 Christopher Esposito ’18 Andrew Kim ’19 Haarika Korlipara ’19 Alden Liang ’20 Richard Liang ’18 Fatima Maqsood ’19 Rideeta Raquib ’19 Lee Ann Santore ’19 Caleb Sooknanan ’20 Megan Y. Tan ’19 Anna Tarasova ’19 Patrick Yang ’20

Letter From the Staff Dear Reader, Stony Brook Young Investigators Review (SBYIR) was founded in 2008 by a small group of undergraduates intent on promoting and fostering undergraduate research at Stony Brook. Since then, SBYIR has taken every advantage to expand and grow in terms of our staff members, writers, and journal content; what began as an undergraduate biology journal now boasts inclusion of all disciplines of research occurring within our university. Further, SBYIR has had the opportunity and privilege to publish seven issues of our now biannual publication, and host prominent researchers such as the Queen of Carbon Science, Dr. Mildred Dresselhaus, Hero of the Planet, Dr. Sylvia Earle, and Dr. Donald Ingber, the Founding Director of the Wyss Institute for Biologically Inspired Engineering at Harvard University. To celebrate the debut of our eighth issue, we have the pleasure of hosting Dr. Arthur Horwich, a leading voice in the field of ALS research. To continue our upward trend, we now present our eighth issue. Inside, readers will find a diverse range of topics, from the role of mirror neurons in Autism to new treatments for Multiple Sclerosis to an overview of broken-heart syndrome. We are also privileged to feature faculty interviews with Dr. Anne Moyer of the Psychology Department, a beloved Honors College advisor and cancer intervention researcher, and Dr. Sarah Malmquist of the Biology Department, a BIO 203 professor focused on improving education through her research. Readers will also become immersed in the research of Stony Brook’s own Haarika Korlipara, as she studies the determinants of cardiovascular disease. As always, we would like to attribute our success to the hard work and commitment of our staff members and writers, without whom none of this would be possible. Additionally, we would like to thank our partners at the Alda Center for Communicating Science for their constant support, as well as our faculty advisors, Dr. Peter Gergen, Dr. Giancarlo La Camera, and Dr. Laura Lindenfeld for their guidance. This issue could not have been published without the help of our generous donors, so we also thank the Departments of Microbiology and Neurobiology. Welcome to SBYIR. We sincerely hope you enjoy.

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Table of Contents Research Profiles and Interviews

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Research News

The Key to Youth via Senescent Cell Removal

By Patrick Yang ’20

A Step in the Right Direction: Educational Research with Dr. Sarah Malmquist ................................................................................................................................6

Fatima Maqsood ’19

A Conversation with Dr. Anne Moyer...............................................................................8 Lee Ann Santore ’19

Reviews

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The Ketogenic Diet: A Potential Cure-All?....................................................................10 Anna Tarasova ’19

Music Therapy: A Noninvasive Treatment of Psychological and Physiological Illnesses......................................................................................................................................13 Andrew Kim ’19

Takotsubo Cardiomyopathy: An Overview of Broken Heart Syndrome..................15

Alison Chan ’19

Recent Advances in Alzheimer’s Disease......................................................................18

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Yasmine Brown-Williams ’18

The Effects of Social Networking on Academic Achievement..............................21 Alden Liang ’20

Utilizing New Targeted Immunotherapy and Remyelination Techniques to Treat Multiple Sclerosis.......................................................................................................23 Sanket Desai ’19

Mirror Neuron Activity and Its Relationship with Social Deficits in Individuals with Autism.............................................................................................................................25 Christopher Esposito ’18

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Primary Research Article Prognostic Value of Neutrophil to Lymphocyte Ratio in Determining Coronary Artery Disease Severity and Adverse Outcomes..........................................28 Haarika Korlipara ’17, Puja Parikh MD, Allen Jeremias, MD, Javed Butler, MD, Luis Gruberg, MD.

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Climate Change Triggers Local Extinctions

Researchers believe the key to anti-aging may be the removal of senescent cells

By Rideeta Raquib ’19 As individuals age, the ability of tissues to carry out adequate function deteriorates and age-related diseases become more prominent. Senescent cells are found in huge quantities of these diseases, but there is limited research regarding whether these cells caused such degeneration. Senescence occurs when cell division is halted in healthy cells due to exposure to prolonged stress and through the action of p16lnk4a and p21Cip1, molecular alterations that cause cell arrest. Although the idea of eliminating age is still a fantasy, researchers at Erasmus University Medical Center in the Netherlands proposed a means of removing senescent cells in order to retain youth. The research team analyzed senescence in mice models, in which it was found that clearing senescence indeed delayed a decline in health. Next, the prospects for developing therapeutics were undertaken. The two approaches for senescence clearance were treatment with quercetin or dasatinib and panB-cell-lymphoma (pan-BCL) inhibitors ABT-263 or ABT-737. Quercetin, a compound found in fruits and vegetables, has been previously associated with antiaging properties. Dasatinib is an inhibitor of the Src kinase family and can be used against acute myeloid and lymphoid leukemia

because Src kinase proteins are present in certain cancers. Both of these compounds are not specific to senescence and thus were not the best solution. The pan-BCL inhibitors, however, were discovered to be selective against senescent cells and cancers. Negatively, BCL-2 inhibits apoptosis, which could be harmful to other cell types. The ideal compound that could be employed for anti-aging therapy is one that both targets senescence with specificity and stimulate rejuvenation. FOXOs are cell cycle inhibitors present in flies, nematodes, and mammals. These inhibitors can target insulin or insulin-like growth factor pathways, as well as mediate antioxidant response and repair DNA damage. Targeting FOXOs can be a plausible way to eliminate senescence. Overall, targeting senescent cells is a possible way to tackle aging, but there is much more research to be done to narrow down compounds that contain therapeutic properties. Discovering a therapy will not only lead to anti-aging, but reduce many of the health risks associated with age.

Average annual temperatures worldwide have reached an approximate 1°C increase since 1880 – a shift hardly noticeable to humans, but a harbinger of biodiversity loss in plants and animals, especially in warmer regions. Previous models have predicted 0% to >50% species loss due to future climate change. However, the extent of biodiversity loss is much harder to ascertain because of the variety of responses a species may have, including local extinction. Local extinction can be interpreted as simply migration, but it also means that these species cannot adapt to a warmer climate and must migrate in order to survive. In a new study, Dr. John Wiens of the University of Arizona investigated the current extent of local biodiversity loss. He performed a meta-analysis on 27 studies that recorded the migration shift of 976 plant and animal species. These studies spanned an average of approximately 50 years and observed species that lived in the warmest edge of their climate range. Many geographic regions, including North and South America, Asia, and Europe, were represented in the analysis; an equal amount of studies observing tropical and

temperate regions were also included. Warm-edge contraction, or the migration of an entire species to a higher elevation and colder environment, was considered criteria for climate-based local extinction. Warm-edge contraction, or local extinction, occurred in 47.1% of the surveyed species. Local extinction occurred significantly more in tropical animals than temperate animals – 52.4% of surveyed tropical species fell to local extinction, compared to 38.8% of surveyed temperate species. Animals also had more incidents of local extinction than plants – 50% of surveyed animal species fell to local extinction, compared to 39% of surveyed plant species. With climate increase projected to increase from 1 to 4°C by the end of the century, these current local extinctions have grim implications for the extent of future biodiversity loss. As global temperatures continue to rise, there will be less suitable migration destinations and local extinction may escalate to global extinction. References 1. J. Wiens, Climate-related local extinctions are already widespread among plant and animal species. Public Library of Science (2016). doi: 10.1371/journal.pbio.2001104. 2. Image retrieved from: https://www.flickr. com/photos/49399018@N00/4686421824

References 1. Peter L.J. de Keizer, The fountain of youth by targeting senescent cells?. Trends in Molecular Medicine 23, 6-17 (2017). doi: 10.1016/j. molmed.2016.11.006. 2. Image retrieved from: http://www.drsecretstore.com/wp-content/uploads/2011/10/antiaging-skin-care.jpg

Increased global temperatures force animals to migrate, causing local extinction.

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Vanadium Dioxide Conducts Electricity, But Not Heat

Effects of Chikungunya Fever on Pregnancies and Newborns

By Megan Tan ‘19

By Caleb Sooknanan ‘20

Thermal and electrical conductivity need to be proportional in electrical conductive solids. Although several metals can conduct electricity better than they can conduct heat, this phenomenon has only been known to occur at extreme temperatures. However, a recent study led by Professor Junqiao Wu and his team of researchers from the University of California, Berkeley has found that metallic vanadium dioxide can conduct electricity without conducting heat. Vanadium dioxide exhibits certain unconventional properties, such as its ability to switch from an insulator to a metal at 152 degrees Fahrenheit and its transparent appearance below 86 degrees Fahrenheit. Using results from simulations and Xray scattering experiments, Wu calculated the phonon dispersions using the density functional theory for vanadium dioxide in bulk and in a nanobeam. The phonon thermal conductivity was then calculated by subtracting the nanobeam phonon thermal conductivity value from the measured value. The results showed that the thermal conductivity attributed to the electrons is ten times smaller than expected in other metals. This was caused by the electrons moving in unison with each other and not in the random motion that was

Chikungunya is a mosquito-borne virus that incites severe joint pain and fever. The chikungunya fever (CHIKF) epidemic in Latin and South America in 2013 revealed that the virus posed a threat to maternal and child health. However, information surrounding the risks and effects of mother-to-child transmission of the virus is limited. Dr. Jaime R. Torres and his team of researchers at La Universidad Central de Venezuela performed a study to analyze the effects of CHIKF on infants born to infected mothers during the epidemic’s peak. To perform this study, the researchers collected clinical and epidemiological data for 169 infected newborns. The newborns were examined within four regional maternity hospitals in El Salvador, Colombia, and the Dominican Republic. The researchers also evaluated pregnancy outcomes in 191 infected mothers from two of these clinical centers. The newborns and mothers were evaluated as symptomatic cases, or cases that displayed observable symptoms of infection. The most common symptoms in newborns included fever, rash, edema, and heightened sensitivity to pain. When symptoms occurred during the first week of life, but evidence of a mosquito bite was not present,

VO2, vanadium dioxide, is a metal that can conduct electricity without conducting heat.

expected. In this fluid-like motion, there are fewer configurations available for electrons to randomly hop between, causing heat transfer to be less efficient. More significantly, the study also showed that the electric and heat conductivity in vanadium dioxide can be altered by mixing it with other materials. When vanadium dioxide was mixed with tungsten, the samples turned metallic at a lower temperature, and it also caused the electrons to conduct heat more efficiently. This thermal conductivity research could lead to a wide range of applications, such as stabilizing temperature and dissipating heat-- potentially leading to more efficient engines. Researchers can also test vanadium dioxide with other elements in the periodic table to examine the electrical and heat conductivity for future research. References 1. J. Wu, et. al., Anomalously low electronic thermal conductivity in metallic vanadium dioxide. Science 355, 371-374 (2017). doi: 10.1126/science.aag0410. 2. Image retrieved from: http://www.mse. berkeley.edu/~jwu/publications/Lee-Science2017.pdf

it was theorized that the disease had a vertical mother-to-child transmission. Seventy-nine infected newborns with signs of acute CHIKF were studied more closely, as their symptoms appeared 3 to 9 days after birth. Four of the newborns died due to extremely low birth weights and infections, a case fatality rate of 5.1%. The newborns demonstrated clinical effects similar to those reported in previous studies. However, there were fewer cases with neurological problems, a deviation from the current theory that CHIKF may represent a major cause of central nervous system diseases in children. The researchers suggested that neonatal subjects diagnosed with CHIKF should have follow-ups to address any neurological problems resulting from their infections. The researchers also suggested that clinicians, especially within countries affected by CHIKF epidemics, should become more acquainted with the effects of mother-to-child transmission. This may help improve treatments for infected newborns and women in the Americas.

Nineteen participants, with an average age of 40.1 years, meeting the criteria for MDD were recruited to undergo a positron emission tomography scan and a magnetic resonance imaging scan to determine potential differences in norepinephrine transporter availability. Patients had no other history of major medical illness and were free of other psychiatric disorders. Researchers used the Hamilton Depression Rating Scale and the Beck Depression Inventory-II to determine the severity of patients’ MDD. Participants completed the Trail Making Test and Symbol Digit Modalities Test to give data on visual attention and working memory. Individuals with MDD showed significantly higher levels of norepinephrine transport-

Major depressive disorder (MDD) is a debilitating illness characterized by low mood and loss of interest in activities. The

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neurotransmitter norepinephrine is believed to be dysregulated, contributing to the depressive symptoms. In an attempt to identify potential associations with clinical symptoms, patients

with MDD were tested for norepinephrine transporter availability. Previous studies have looked at the norepinephrine transporter in MDD, but not at the correlation between norepi-

By Richard Liang ’18 Autoimmune diseases occur when an individual’s im-

References 1. J. Torres, et. al., Congenital and perinatal complications of chikungunya fever: a Latin American experience. International Journal of Infectious Diseases 51, 85-88 (2016). doi: 10.1016/j.ijid.2016.09.009.

nephrine and MDD symptoms. Dr. Sho Moriguchi and his team of researchers recruited participants from two psychiatric hospitals and two clinics in the Chiba, Japan area.

widespread, comprehensive understanding of the relation between norepinephrine transporter availability and MDD.

References 1. S. Moriguchi, et. al., Norepinephrine transporter in major depressive disorder: a PET study. The American Journal of Psychiatry 174, 36-41 (2016). doi: 10.1176/appi. ajp.2016.15101334. 2. Image retrieved from: https://commons. wikimedia.org/wiki/File:Dr._Nora_Volkow_ with_patient_in_PET_scan.jpg

Uncovering new evidence of biological predictors of psychological disorders helps point researchers in the right direction for creating more effective treatments.

Understanding C5aR as a factor in Autoimmune Induced Arthritis

Norepinephrine Transporter in Major Depressive Disorder: A PET Study By Ericka Berman ’17

er availability in the thalamus (p=0.007) and a sub-region of the prefrontal cortex (p=0.002). Furthermore, the neurotransmitter binding potential values in the thalamus and locus coeruleus were negatively correlated with scores on Trail Making Tests part A for working memory and attention (p<0.003 and p<0.023 respectively). Future studies could group participants by the different symptoms of depression they experience and test norepinephrine transporter levels accordingly. This study included participants experiencing melancholic depression, so the results of the study cannot be applied to all individuals affected by MDD. Additionally, future studies could recruit more participants for a longitudinal study that can provide a more

In arthritis, joint inflammation causes the cartilage to become worn and damaged.

mune system attacks healthy cells. This can lead to conditions including rheumatoid arthritis, the chronic inflammation of joints. However, the mechanism by which this form of inflammation occurs is unknown. A recent study led by Yoshishige Miyabe from the Center for Immunology and Inflammatory Diseases recently researched the C5a receptor (C5aR) as a key initiator in this type of inflammation. The researchers used a serum from arthritic mice to induce mouse models with arthritis. When viewing the mice under intravital multiphoton imaging, researchers noticed that the neutrophil adhesion marked with red and green colors on ankle joint endothelium ,with the connective tissue was labeled as blue, seemed to ignite

inflammation. As the neutrophils accumulated on the connective tissue, the tissue began to swell and expand. Neutrophils are part of antibody-antigen immune complexes (ICs) which are the underlying causes of the pathogenesis of many autoimmune diseases. The synovial fluid of healthy mice and arthritic mice was also analyzed for any significant differences in composition. Researchers noticed C5a deposition in the synovial fluid of the mice with arthritis at a concentration of 76.33 ± 4.33 pM on day 3 and 856.7 ± 72.19 pM on day 7. However, no C5a was detected in the fluid of the healthy control mice. Based on these results, the researchers concluded that C5aR is the initiator of neutrophil adhesion on joint endothelium.

It is becoming increasingly clear that C5a is a main factor in autoimmune inflammation but it might not be the only molecule involved in this cascade of effects. There might be other undiscovered molecules that play a role in autoimmune diseases that went undetected by the multiphoton imaging. Further research on these molecules can lead to more remedies for the symptoms caused by autoimmune diseases, perhaps one day leading to a treatment for the disorders themselves. References 1. M. Previdi, L. Polvani, Anthropogenic impact on Antarctic surface mass balance, currently masked by natural variability, to emerge by mid-century. Environmental Research Letters 11, 1-9 (2016). doi: 10.1088/17489326/11/9/094001. 2. Image retrieved from: https://c1.staticflickr. com/4/3819/8882225136_1ac556c0b7_z.jp.

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Interview

tion of whether or not they wanted to disclose information such as racial/ethnic group, gender, household income, etc.

A Step in the Right Direction: Educational Research with Dr. Sarah Malmquist Fatima Maqsood ‘19

Dr. Sarah Malmquist is one of the three professors who teach BIO203: Cellular and Organ Physiology. Her current research focuses on using scientific teaching methods, disciplinebased education research, and educational technologies to improve the quality and equity of teaching college biology. Her case study focuses on the BIO203 course. In BIO203, the two experimental groups are the lecture section, which meets twice a week and gives in-person lectures, and the hybrid section, which meets once a week for a review of the two recorded lectures students are expected to watch outside the classroom. Aside from the different layouts, both sections are given the same resources, exams, and assignments. Throughout the course, students are required to take a series of surveys assessing the quality of the course, what improvements could be made, and if they feel that the resources given are adequate. The survey answers, homework responses, midterm, and final exam scores of the two sections are then compared to determine which model is most successful in helping students learn the material. Different socioeconomic factors such as the student’s household income, race, and parents’ educational level are also considered during the study. What are your undergraduate and graduate experiences in teaching and research? I completed my undergraduate degrees in Biochemistry and Genetics at the University of Minnesota. I started getting involved in research working in a genetics lab that studied fruit flies and histone proteins that modify genes. Although my work consisted mainly of washing dishes, it helped me land the undergraduate research opportunities program fellowship, which is very similar to the summer URECA grant here at Stony Brook. After [the summer fellowship], I was able to earn the position of lab manager in a lab that studied the neuronal development of C. elegans, a type of roundworm. Afterwards, I completed my Ph.D. in Molecular and Cellular biology at the University of

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Washington, where I did research in the development of sensory neurons in zebra fish. It was in graduate school that I became interested in teaching, so I participated in teaching internships and joined an organization that sought to address problems associated with teaching biology and how to overcome them. How did you come about developing a new course model that revolutionized BIO 203? Dr. William Collins is a neurobiologist and the other BIO 203 professor. He and I jointly decided to revamp the BIO203 course in order to help students succeed in their upper division courses, graduate courses, and future careers– giving students a strong foundation is critical for everything that follows. Additionally, we wanted to take part in the nation-wide effort of reforming and upgrading biology courses in a way that would help out as many students as much as possible. We sought to incorporate evidence-based learning strategies that would be beneficial for students of all types of backgrounds. This change was partly brought about by some problems associated with the original course, which included the large range of scores nonindicative of performance and no grade contribution besides exams. Did you face any difficulties in getting your course changes approved? After proposing the ideas, we went through the approval process very slowly. We started out by incorporating a few changes into the summer 2016 class, which was the first class to complete pre-class assignments, post-class assignments, and student feedback surveys. All the changes that we implemented were for a reason, either in response to students or to employ successful strategies that had been researched and published in papers. Since we were going to be collecting qualitative and quantitative data, we needed to get permission for human subjects research. When collecting data, we gave students the op-

How did you incorporate the socioeconomic aspect into the course changes? We understood that there were different types of students taking this course whose needs had to be addressed; this included women, first generation students, lower income students, and racial/ethnic minorities. We also understood that students are not different in their intelligence or ability to succeed, rather the differences lie within their previous K-12 education, parent’s education, income levels, and family situations. There are some students who need to work to pay their tuition, and there are some who do not. So our end goal was to make the course more equitable and beneficial for all. What role do teaching assistants and assignment graders play in the two models? The undergraduate teaching assistants are previous students who did well in the course, and they play a part in helping students learn. They hold office hours and are available to discuss the course material and study habits with current students. Students learn in lots of different ways, so it is helpful to get guidance from someone who has already completed the course. The graduate teaching assistants have experience in physiology, grade the homework assignments, and grade the exam short answer questions. How is student feedback from surveys used to bring about changes? We receive student feedback from online evaluations about the class setting, textbook, and the assignments, and we try to implement the most useful suggestions. Through feedback, we are able to determine what is the most useful aspect of the class, what is the most challenging, and what needs to be improved. What are your findings from course research, and are there significant differences between the two models? From what we have gathered, the course changes in both the lecture and hybrid have improved student attendance and participation in class. We found that fewer students withdrew or dropped the class, and naturally, positive student opinion in both has increased. Contrary to popular belief, the hybrid students do not seem to be at a disadvantage when compared to the lecture students. In fact, some believe they have an advantage because they have the opportunity to review material and apply it to challenging problems. Overall, both groups display similar trends for homework grades as well as midterm and final exam scores due to repeated practice with online quizzes and assignments with feedback. There are four aspects that are assessed within the two groups: exam scores, passing or failing the course, whether the students stay in science and graduate in a STEM field, and the student’s self-efficacy. The student’s self-efficacy refers to how well the student perceives he/she is able to do, which is a question asked through surveys. This data is in the process of being evaluated but broadly speaking, there are no major differences between the two sections.

Would you encourage future students to pick one section over the other? Both sections have their benefits, but at the end of the day, it comes down to the student’s work ethic. If a student feels that they are able to keep up with attendance, and complete the assignments sooner, then the lecture might be a good fit. If the student has scheduling difficulties or time constraints, and does not wish to sit through in-person lectures, the hybrid may be a better idea because the student can easily access his lectures online on his own schedule. Overall, the hybrid is more flexible and engaging, and helps increase enrollment without waitlists because it is offered every semester whereas the lecture is only offered in the fall. What other classes do you teach, and do you employ similar research model for your other courses? In addition to BIO203, I also teach BIO335: Neurobiology Lab and BIO328: Mammalian Physiology. Although I do not carry out formal research in my other courses, I do try to incorporate teaching success strategies backed by research and make the courses as equitable as possible. I also respond to student feedback in my other courses and identify what is helpful in regards to my teaching and what is not.

References 1. S. Malmquist, Interview with Dr. Sarah Malmquist. Rec February 2017. MP3 2. Images courtesy of Jerin Thomas.


Interview

A Conversation with Dr. Anne Moyer Lee Ann Santore ‘19

Dr. Anne Moyer has her Ph.D. in Social/Health Psychology. She specializes in topics including medical decision making and psychosocial issues surrounding cancer. She earned her B.A.&Sc. in Psychology from McMaster University in Canada, and her Ph.D. from Yale University. She has worn many hats in her time here at Stony Brook including Director of Undergraduate Studies for the Psychology department, Faculty Director of the Undergraduate College of Science and Society, and Faculty Director of the Honors College. She is a favorite of many students who have taken her Introduction to Psychology course and Positive Psychology seminars. She is immensely supportive and informative to her students, and is an integral part of the Stony Brook community. How did you first develop an interest in psychology? I went to school in Canada, and there is less of a tradition of a liberal arts education there. Normally, students are fairly streamlined in terms of their majors, but I was fortunate in that I had an opportunity to be part of something that is very similar to the Honors College, here at Stony Brook, called the Arts and Science Programme. This was an interdisciplinary program within the larger university, which gave me a liberal arts background to my education, similar to how the Honors College students get to do it. I did not have an opportunity to take psychology at the high school level, as some students here get to take AP psychology, and so I didn’t know that I liked psychology until I got to college. That’s when I decided that I was going to major in it. I didn’t anticipate going on to a career in psychology right away. I just took it step by step and by the time I was in my fourth year, I thought

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I would like to go to grad school. I’m not one for long range plans like that, so it was something that grew organically. What did you do after undergrad? I went to school in Canada and I had 13 years of school before graduating high school, then I went straight into a Ph.D. program after undergrad. That meant that I was a little bit older anyway, and then on top of that, I took a year off to travel after high school. By the time I completed my undergraduate degree I was 24, and I felt I had a lot of readiness to go on in this direction. Why did you decide to specialize in health psychology? The field of health psychology is actually fairly new. It’s an applied field that looks at all the ways that psychology and all of its insights can be brought towards encouraging people to lead healthy lives. It focuses on getting people disengaged from behaviors that are health threatening, like smoking, and increasing their engagement in behaviors that are health promoting, like exercise. Health psychology is also directed towards helping people manage and cope with disease when they fall ill by helping them with things like making treatment decisions, adhering to medication regimens, or coping with some of the side effects of existential or psychological issues that sometimes accompany life threatening diagnoses like cancer. I got really interested in health psychology because it was new, and I thought it was completely fascinating to think about the mind-body connection and how the way we think can influence the way we feel.

What was one of the first studies you worked on in graduate school? I was really fortunate to be mentored in graduate school by Dr. Judith Rodin. At the time, I was interested in eating disorders and body image, because, if you think about it, eating isn’t just taking in nutrients, it’s sitting down with family, it’s your culture, and it’s the emotions that you associate with eating. This activity is really relevant to our health and our well-being, but it’s also really relevant in psychology and social relationships in our cultural context. I was also really interested in stress, specifically stress that is caused by a lack of control, and the idea that our psychological stress causes physiological reactions. When I first went to graduate school, we did a study that hypothesized that people who are under stress secrete higher levels of cortisol, which we already know, but also that this may lead to preferential deposit of body fat in areas that are actually harmful. We were trying to consider to what extent stress in humans could be related to them depositing body fat in their abdominal region. What’s wrong with that is that the fat is close to your vital organs and that can be related to your health outcomes. We exposed participants to different stressors to ensure they were being evaluated under a simulated lack of control. I was really excited about that because it looked at the mind-body connection.

which to study psychology. It’s a really ripe area for psychologists to get involved. We’ve done some studies with undergraduates using the subject pool in the psychology department where we give them a scenario and vary the way the information is framed and what the characteristics of the clinical situation are, and then we see what people would decide. Now we are going to bring that to an actual emergency veterinary clinic. Our study will involve dogs coming in with a particular medical condition whereby there are two absolutely reasonable treatments but one involves you extending the life, but not saving the life of the dog, through a lot of intensive treatments and vet visits, while the other choice is euthanasia which is also perfectly reasonable because the dog has a very dire condition. So, there’s two perfectly humane perfectly viable options which gives us the opportunity to look at what psychological and interaction variables from the provider may predict whether people go one way or the other. We think that this kind of stuff hopefully could be very valuable to veterinarians. We are also hoping that this will be clinically useful and that we could tell veterinarians that when someone comes in with these characteristics, this is what you say or this is what you might want to think about if you want to understand what decision they are going to make.

How did you evolve from conducting studies focusing on eating disorders to studies focusing on cancer patients? My mentor was very accomplished and ended up rising through the ranks and becoming the first woman president of an Ivy League university. That happened right in the middle of my graduate career, so I ended up having to move to another lab, directed by Peter Salovey, who is now the President of Yale. The connection I made between my old and my new lab was a focus on body image. Eating disorders are a big component of body image. People often fall into eating disorders because they are thinking about preserving, changing, or improving their look. In cancer, particularly breast cancer, the surgeries that are involved in treating it can be disfiguring and can create disturbances in body image. Some of the procedures that women go through, like reconstruction, are related to preserving body image. That’s where I could see a connection, and once I became part of that lab and started reading more about cancer, I never looked back.

What does your family think of what you do? I have a wonderful husband, Marc, and two wonderful step kids, Mia and Michael. Mia goes to SUNY Oswego and is studying Anthropology. That’s a whole other way of being interested in people. It’s very interesting to learn what she’s learning about people using a different lens. Michael likes animals and has his own landscaping business, but he’s still in high school so he isn’t specializing in anything in particular yet!

What is one of your favorite studies? We do a lot of good work, but I do like to single out one very unusual study. I have a student who is planning to on becoming a veterinarian, but has also been working for several years on decisionmaking. We have put together a program of research that involves decision-making in the veterinary medical context because she works in an emergency vet clinic, and she saw all kinds of ways in which psychology was intersecting with veterinary medicine. We now know that, especially in decision-making, psychologists can play a role in the medical field. The trouble is when you’re a vet, you have your client, who is a human, and you have the animal, which is the patient. The owner is making decisions on behalf of the animal and so there’s this more complex scenario because you can’t really ask the patient what their preference would be. We are studying something called surrogate decision making, which is when a human becomes incapacitated or he arrives unconscious in the emergency room. This means he can no longer make the decision of whether or not he wants to get resuscitated. Then a family member gets put in the position of being a surrogate decision maker because the patient can no longer choose for himself. My student and I had a light bulb moment where we realized that when you bring your pet into the veterinarian, you are always a surrogate decision maker, and so we can say that it’s a very clean model from

Why do you teach and advise? My father worked in a university and he loved it. I think that rubbed off on me. He got to travel, he had a flexible schedule, he got to be an expert in stuff and write a book and so, to me, that looked really cool. He never really pushed me, but he modeled what seemed to be a really cool life. When I got to university I loved it and wanted to just keep doing the same thing. I want to keep learning and discovering things. I think it keeps you young to continue interacting with people who are younger and are more in touch with the current trends in all kinds of ways. Even my graduate students pick up on things that I might not pay attention to and infuse them into our research. It’s a dream job.

What are your current teaching and advising positions? I teach undergraduate and graduate courses in the psychology department and a course in the Honors College. I’m also an advisor in the Honors College to help students think about their career plan once they leave and to try to help students find a good research placement for their senior thesis by seeing how they could best connect with a potential mentor.

What is your favorite thing about Stony Brook? I’m so glad to be part of Stony Brook because it’s a place where people are making themselves and finding their dreams. People are reaching their full potential, but still have a lot of possibility and optimism for what the future will hold, and being part of that is super cool. I feel privileged to be part of everyone’s growth, and participating and cheering for them from the sidelines References 1. A. Moyer, Interview with Dr. Anne Moyer. Rec January 2017. MP3 2. Photos courtesy of Jerin Thomas.

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Science Review

The Ketogenic Diet: A Potential Cure-All? Anna Tarasova ‘19

Modern media has a constant and pervasive focus on current trends in dieting. The purposes of these diets, such as the alkaline, macrobiotic, and paleo, are typically weight loss and fitness maintenance. But despite the publicity fad diets receive, their purported successes are not always empirically established. In fact, it may even be possible that some fad diets, such as the very-low-carbohydrate (ketogenic) diet, (VLCKD) may have health effects that extend further than physical appearance. While past studies have suggested that VLCKDs are useful for controlling seizures, current research proposes that VLCKDs may have the potential to cause improvements in many other areas, such as diabetes (1). History and Mechanism of Function VLCKDs first came into the public eye in the 1970s for the purpose of weight loss, when Dr. Robert Atkins suggested that consuming fewer carbohydrates would lead the body to turn to other sources of energy, such as fat and protein. However, written records of the use of fasting to alleviate symptoms of epilepsy have existed since the first century BC (2). More recently, in 1921, Dr. Russell Wilder conducted a smallscale study testing the effects of the diet on epileptics. A lack of viable pharmaceutical treatments during this time period led to widespread research on and use of the ketogenic diet as a treatment for epilepsy. But in 1938, with the discovery of the effective anti-seizure medication phenytoin, the diet was mostly abandoned in favor of studies on additional medications of this kind. It was in the 1990s that media focus on intractable epilepsy prompted a return to non-traditional treatment options (2). The main feature of the classic VLCKD is the consumption of less than 50 grams of carbohydrates per day with a higher proportion of fat and protein than a typical American diet. Typically, approximately half of the daily intake of calories comes from carbohydrates, but in a VLCKD, the majority of those calories come from fat. This is because VLCKDs induce a process known as ketosis (1). When carbohydrates are scarce, the body uses alternative metabolic pathways to synthesize energy. The central nervous system (CNS) cannot utilize fat reserves to generate ATP, so it instead turns to the body’s glucose reserves. After 3-4 days, when the glucose reserves have been depleted, the overproduced acetyl coenzyme A (CoA) is used. This in turn leads to ketogenesis, or the over-

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production of substances known as ketone bodies (KBs) in the mitochondrial matrices of the liver. Once the concentration of KBs in the bloodstream increases to about 4 mmol/L, they begin to be used as an energy source by the CNS. Overall, the metabolism of KBs produces significantly more energy than that of glucose (1). The Ketogenic Diet and Weight Loss While empirical evidence has established that VLCKDs cause weight loss, the mechanism that causes this effect remains a point of debate. Weight loss may occur due to an overall reduced caloric intake that results from increased satiety from protein. In fact, there is evidence that ketosis modifies hormone levels, thus suppressing appetite, but the process remains to be examined in detail. Another possibility is that metabolizing proteins for energy is a more calorie-intensive process, but there is less support for this theory (1). Additionally, lipogenesis, the production of fat, has been shown to decrease as a result of VLCKD. Besides playing a role in weight loss, this particular factor may also have a positive effect on the blood lipid profile, which includes triglycerides (TAG) and cholesterol. Heightened levels of these two substances in the bloodstream increase the risk of stroke, heart attack, and heart disease because they can cause blockages in blood vessels (1). This finding is especially interesting considering that despite the higher proportion of fat consumed as part of maintaining a ketogenic diet, cardiovascular risk factors are lowered. High-density lipoprotein (HDL) is widely known as “good cholesterol,” while low-density lipoprotein (LDL) is known as “bad cholesterol” because of its higher atherogenecity, or ability to cause artery blockages. During VLCKDs, HDL levels have been shown to increase while LDL particles reduce in size and volume (1). Previously, media and scientific attention focused on fat as the enemy of health and weight loss. However, a recent meta-analysis by Bueno et al. evaluating 13 studies that compared the long-term effects of low-fat diets (LFD) and VLCKDs found that carbohydrate restriction has more benefits than lowering dietary fat consumption. The meta-analysis focused on weight loss and changes in cardiovascular risk factors, such as blood lipid profiles, as a result of dieting. Only studies with at least a 12-month post-intervention check-up were included in order to evaluate long-term effectiveness of the diet (3).

Dr. Bueno and his team were able to draw several conclusions from their analysis. Firstly, those on VLCKDs typically had greater reduction in weight than those on LFDs, with a weighted mean difference of almost one kilogram. Secondly, levels of TAG in the blood and diastolic blood pressure showed greater decreases in those on VLCKDs. Lastly, greater increases were found in the HDL and LDL levels of VLCKD subjects, although only the increase in HDL was statistically significant over time. Thus, reductions in both weight and cardiovascular risk factors were greater in the VLCKD group than the LFD group consistently across all studies. The researchers’ main concern was the difficulties patients had in adjusting to the major life changes that come with a VLCKD. They suggested that clinicians compare its benefits against these difficulties before prescribing the diet (3). Furthermore, an analysis by Alessandro et al. compared the effects of a VLCKD to those of the Mediterranean diet (MD). The key features of the MD include a high proportion of fruits, vegetables, nuts, and legumes, a healthy fat content, and a low sodium content. Thirty-two healthy adult subjects were randomly separated into two groups. The first group began with 20 days on the ketogenic diet, continued to 20 days of a low-carbohydrate non-ketogenic diet, and ended with 2 months on the MD. The second group followed the MD for 20 days, a calorie-restricted MD for 20 days, and went back on the MD for 2 months. Significant weight loss occurred in both groups; however, whereas average weight loss in the second group was 5.1 kg, average weight loss in the ketogenic diet group was 8.4 kg. The latter also showed a greater fat loss percentage (4). The Ketogenic Diet and Epilepsy: Mechanisms In recent years, VLCKDs have been used as a treatment for otherwise untreatable epilepsy, and it has been found to be especially effective in children. This is thought to be due to age-dependent alterations in monocarboxylate transporters (MCTs) across the blood-brain barrier. MCTs transport ketone bodies from the body’s circulatory system to that of the brain and may be more efficient in children (5). There are several main hypotheses about the mechanism of the ketogenic diet’s influence on epilepsy. The first is that KBs act directly as anti-seizure agents. In the 1930s, acetoacetate specifically was found to protect against seizures, and this was further corroborated in the 1950s by studies on the modulatory effects of KBs on neurotransmitters (5). The second hypothesis involves the effects of VLCKDs on neurotransmitter systems and ion channel regulation. This is evinced by altered neurotransmitter synthesis and clearance from the synaptic cleft, the space between neurons. More specifically, the GABAergic hypothesis suggests that GABA, which is the main neurotransmitter that inhibits the action of neurons, is upregulated as a result of VLCKDs. Glutamate, the neurotransmitter that “excites” neurons into action, is converted to GABA in a chain of molecular events involving astrocytes, a type of nervous system support cell. Suppressed glutamate release is also associated with suppressed neuronal excitability. Seizures are brought on by highly excited neurons, so this change in neurotransmitter levels means that the probability of a seizure decreases dramatically (5). The third hypothesis proposes that VLCKDs act by

counteracting the effects of the disturbed mitochondrial energy metabolism observed in epilepsy. As described earlier, VLCKDs boost ATP reserves by producing more energy overall than the metabolism of glucose. Mitochondrial production in the hippocampus is also increased. Free radical effects on mitochondria, which are known to be associated with seizures, are also neutralized through antioxidant biochemical mechanisms incited by VLCKDs. Free radicals are involved in inflammation processes. Thus, further research into this hypothesis may reveal more about inflammation of brain areas as part of the symptomatic landscape of epilepsy (4). The fourth hypothesis focuses on fatty acid oxidation and the action of polyunsaturated fatty acids (PUFAs). PUFAs are produced in the liver and exported into the circulatory system as a result of VLCKDs. This type of fatty acid has been shown to possess neuroprotective properties and is therefore thought to be involved in lowering the rate of seizures. However, studies comparing consuming PUFA supplements to a placebo have shown that dietary PUFAs may not have the same benefits as those produced endogenously. The metabolism of PUFAs merits further research since it may be this process and not the levels of PUFAs themselves that produce the anti-seizure effect (4). Many more potential seizure-related mechanisms remain to be studied, considering the many biochemical changes incited by VLCKDs. Furthermore, it is likely that several mechanisms work in tandem to alleviate the symptoms of epilepsy. Knowledge of these mechanisms has the potential to give scientists a new outlook onto other epilepsy treatments. Since VLCKDs require major lifestyle changes and thus have the drawback of low adherence, it will be worth exploring what other treatment options are available based on how VLCKDs operate. The Ketogenic Diet and Epilepsy: Quality of Life A diagnosis of epilepsy, especially in children, is further complicated by an increased risk of developing persistent psychological and other neurodevelopmental disorders such as anxiety and depression. Patients also typically have considerable feelings of helplessness and hopelessness. It is important for practitioners to attempt to maintain an epilepsy patient’s quality of life (QoL) to the best of their ability in order to minimize the chance of additional health problems. Studies on this topic are few, and those that exist use different definitions and measurements for QoL, making meta-analyses difficult (6). A 2017 study by Bruce et al. examined changes in QoL in families with children diagnosed with epilepsy undertaking a VLCKD. QoL with respect to seizures was self-evaluated by family members using a simple 0-10 scale and was meant to reflect condition improvement and changes in family expectations. The researchers worked with a sample of 12 children with a median age of 3.5 who had severe epilepsy and had not been responsive to other treatments. The main trend was gradual improvement in QoL among the families. Bruce and colleagues acknowledge that the improvement is in part due to the decrease in number of seizures caused by the VLCKD. Another contributing factor may be psychological, in terms of the families being given the ability to re-evaluate condition improvement. Considering that self-reports of QoL are prob-

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ably influenced by feelings of satisfaction with treatment, this study shows how important it is for practitioners to combine epilepsy treatment with psychological support for the patients and their families, since a supportive environment could ward off complications associated with epilepsy (6). The Ketogenic Diet and Other Disorders The ketogenic diet has also been shown to have a therapeutic effect on patients presenting with Type 2 Diabetes (T2D). The main symptom of T2D is insulin resistance, which means that muscle cells cannot take up circulating glucose very efficiently. Thus, dietary carbohydrates, when consumed by a diabetic, will be converted to fat in the liver instead of being used for energy. However, when the intake of carbohydrates is limited, the few carbohydrates consumed become an efficient energy source, and so insulin resistance and its accompanying symptoms diminish significantly. Furthermore, studies have suggested that higher KB levels are also associated with better glycemic control, or blood sugar levels, in diabetics, but this effect has yet to be tested on non-diabetic persons (1). Several other areas of research related to the ketogenic diet are emerging, including its influence on acne, cancer, PCOS, and neurological diseases such as Alzheimer’s and Parkinson’s. With regard to acne, two major causes are thought to be a high-glycemic-load diet and the effect of insulin on hormone levels. There is also emerging evidence that heightened blood levels of insulin may play a role in cancer mechanisms such as proliferation, metastasis, and protection from cell death. Thus, the ketogenic diet might incite improvement in acne and slow the progression of certain types of cancers. Lower blood sugar levels brought on by VLCKDs may also reduce tumor growth by inciting glucose “starvation” of tumors. However, studies on this topic are still in the preliminary stages (1). Negative Effects of the Ketogenic Diet As described above, VLCKDs have extensive therapeutic potential and can be applied to a variety of populations. However, preliminary research suggests that there may be medical drawbacks to using VLCKDs for treatment. Lauritzen et al. evaluated the effects of VLCKDs on mice with damaged forebrain mitochondria. Due to the high energy demand of neurons, mitochondrial dysfunction can lead to neurodegeneration and is a major part of neurological disorders like Alzheimer’s and Parkinson’s. Unhealthy mitochondria generate high levels of reactive oxygen species free radicals, which can cause further neurological damage. Prior research has shown that VLCKDs increase the number and performance of neuronal mitochondria. Lauritzen’s team used a sample of transgenic mice with damaged mitochondrial DNA in the forebrain. Specifically, the mice used were expressing a mutated version of the human mitochondrial DNA enzyme (mutUNG-1). The goal of the study was to examine whether a VLCKD would slow down or alleviate neurodegeneration in the mutated tissue. Lauritzen hypothesized that generating new mitochondria is too energetically costly and cannot be supported by the damaged mitochondria; therefore, the process is an energy drain and not a solution to the deficit in energy (7). Whereas VLCKDs increased mitochondrial mass in the normal mice of the control group, in the transgenic mice, a VLCKD accelerated negative processes such as neuronal atro-

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phy. Shrinkage was noted in some brain regions, both in terms of volume and neuron count. There was no overall degeneration of condition in the mice, as indicated by their ability to maintain a steady weight while on the diet. However, a comparison with the normal mice, which gained weight throughout the duration of the study, shows that the transgenic mice were unable to produce enough energy to gain weight. The researchers propose that both the neuronal and physical effects of the VLCKD could be mediated by its high fat content. In the transgenic mice, it is possible that mitochondrial damage impeded lipid metabolism more than carbohydrate metabolism. Therefore, it would have been more difficult for these mice to use lipids as an energy source rather than carbohydrates (7). It remains to be seen whether these findings are generalizable to humans. Furthermore, the study used an 84-16-0% ratio of fats-proteins-carbs, which may not be representative of a diet that would be prescribed to humans. For example, the study conducted by Alessandro et al., which worked with human subjects, used a 43-43-14% ratio during the VLCKD phase. A diet with at least a minimal proportion of carbs would then be more realistic. The overall implication of the results of this study is that VLCKDs should be administered with caution rather than regarded as a cure-all, especially in the case of neurodegenerative disorders. The effectiveness of the treatment depends on disease conditions, and all factors must be considered by practitioners in order to achieve the best possible outcome. As the population ages, finding plausible treatments for neurodegenerative diseases of aging is vital. Obesity and diabetes, which also have the potential to be treated with VLCKDs, are major public health problems, and can lead to other disorders. However, before prescribing new treatments, practitioners must consider all aspects of the patient’s health issue and lifestyle, as well as examine the latest research on the topic, to make sure that there are no undesirable side effects. One of the main benefits of using VLCKDs instead of medication to treat disorders such as epilepsy appears to be the relative lack of drawbacks; the issue may be that this topic has not yet been examined in enough detail to know for certain.

References 1. A. Paoli et al., Beyond weight loss: a review of the therapeutic uses of verylow-carbohydrate (ketogenic) diets. European Journal of Clinical Nutrition 67, 789-796 (2013). doi: 10.1038/ejcn.2013.116. 2. J. Wheless, History of the ketogenic diet. Epilepsia (suppl. 8) 49 , 3-5 (2008). doi: 10.1111/j.1528-1167.2008.01821.x. 3. N. Bueno et al., Very-low-carbohydrate ketogenic diet v. low-fat diet for longterm weight loss: a meta-analysis of randomised controlled trials. British Journal of Nutrition 110, 1178-1187 (2013). doi:10.1017/S0007114513000548. 4. R. Alessandro et al., Effects of twenty days of the ketogenic diet on metabolic and respiratory parameters in healthy subjects. Lung 193, 939-945 (2015). doi: 10.1007/s00408-015-9806-7. 5. J. Rho, How does the ketogenic diet induce anti-seizure effects? Neuroscience Letters 637, 4-10 (2017). doi: 10.1016/j.neulet.2015.07.034. 6. S. Bruce et al., Changes in quality of life as a result of ketogenic diet therapy: A new approach to assessment with the potential for positive therapeutic effects. Epilepsy & Behavior 66, 100-104 (2017). doi: 10.1016/j. yebeh.2016.10.001. 7. K. Luritzen et al., A ketogenic diet accelerates neurodegeneration in mice with induced mitochondrial DNA toxicity in the forebrain. Neurobiology of Aging 48, 34-47 (2016). doi: 10.1016/j.neurobiolaging.2016.08.005. Images retrieved from: https://commons.wikimedia.org/wiki/File:Fresh_cut_fruits_and_vegetables.jpg

Music Therapy: A noninvasive treatment of psychological and physiological illnesses

Science Review

Andrew Kim ‘19

When trying to treat patients with anxiety and pain issues, physicians commonly prescribe narcotics and anti-anxiety medications. These prescriptions are often accompanied by negative side effects, such as nausea, insomnia, depression, and muscle pain. However, within the last few years, some therapists have proposed an alternative solution to treating these diseases in a way that prevents side effects: music therapy. Music therapy is a method of incorporating music to treat not only psychological illnesses, but also physiological disorders. Some methods include the patient playing instruments, singing, listening to music, or even controlling their breathing to match the music’s rhythm. The large variety of therapeutic techniques highlights its flexibility when tending to patients with a plethora of issues; however, the effect of each method has yet to be explored. Many individuals with psychological illnesses have found music therapy helpful in relieving depressive symptoms, improving social skills, and increasing their self-esteem (1). One possible approach involves having the clinician perform music during therapy sessions. Maria Gavrielidou of Anglia Ruskin University conducted a case study on the effects of music therapy on a schizophrenic patient’s expression following a pivotal moment, or a point when a person experiences a change in his or her outlook on life (2). During the study, Gavrielidou discussed the patient’s communication issues, particularly with his family, and then played music on the

piano. In the first few weeks, the patient was reluctant to share details about himself and only listened to the therapist perform improvisations on the instrument. During the seventh week, the patient experienced a pivotal moment and became emotionally vulnerable with the therapist by sharing his internal conflicts. This was shown through his willingness to sing and suggest songs related to his issues, something he was unable to do previously. According to Gavrielidou, music therapy enabled the patient to gain motivation and work to improve his problems. Often times, it is only by recognizing the necessity to change that one can direct his or her life toward a more beneficial path. Music therapy provides a gateway for people to be more comfortable in expressing their emotions and communicating more effectively. A separate study conducted by Teresa Fernández Juan from the College of the Northern Border observed the positive effects of music therapy on Mexican and Cuban women who had previously been in abusive relationships (3). The therapist observed how music therapy helped the women overcome their traumatic experiences by improving their self-image and self-esteem. Throughout the study, the women sang and listened to songs related to their conflicts. In one of the activities, the individuals were instructed to alter the lyrics of alreadyknown songs and sing them to each other. Singing acted as a medium for the women to channel their emotions into a form other than a simple discussion. This eased their burden and stress, allowing them to become more open with the therapist.

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Following each session, the women met with the therapist to discuss their troubles. According to the music therapist, the women reported experiencing less anxiety and gaining confidence and self-esteem. In general, clinicians may spark deeper discussions because music therapy can enable patients to be more open about sharing their emotional scars. With the new information gained from the therapy sessions, physicians can explore more options when trying to determine the optimal treatment for a patient. Because of these effects, music therapy may seem like a more inviting and safer platform for some individuals. In addition to treating mental illnesses, music therapy can also be used to remedy physical ailments. Over the course of six weeks, Bernardo Canga from the Louis Armstrong Center for Music and Medicine investigated how music therapy can aid in treating chronic pulmonary disease and its negative

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“Many individuals with psychological illness-

es have found music therapy helpful in relieving depressive symptoms, improving social skills, and increasing their self-esteem.”

psychological effects (4). Individuals with chronic pulmonary disease typically find breathing burdensome, making it difficult for them to maintain a normal lifestyle. As a result, these patients are at a higher risk for depression. Both before and after the six week trial, patients filled out the Beck Depression Inventory 2nd Edition-Fast Screen, a questionnaire asking them on a scale from 0-3 how much sadness, pessimism, or self-dislike they felt. Individuals in the experimental group were subject to 45-minute long sessions in which they controlled their breathing to match the rhythms of music, played wind instruments, and sang. The control group was exempt from the 45-minute long sessions. Before and after each session, the patients informed the therapist of how easy or difficult it was to breathe. Throughout the trial’s duration, both groups engaged in pulmonary rehabilitation, which consisted of eating healthily and exercising. After six weeks, the group with music therapy exhibited lower levels of dyspnea, or difficulty breathing. Additionally, these individuals scored lower on the Beck Depression Inventory 2nd Edition-Fast Screen, showing they had a decrease in their levels of depression. This ability to breathe more easily, coupled with lower depression levels, illustrates how people could benefit from music therapy. Patients with respiratory difficulties often found it easier to breathe during music therapy because the activities served as distractions that potentially helped alleviate their symptoms. As a result, correlations between music therapy and its effects on patients may be useful when treating individuals with mental and physical disabilities. Eylem Toker from Kahramanmaras Sutcu İmam University in Turkey studied the effect of music therapy on pregnant women with preeclampsia (5). Preeclampsia is a condition in pregnant women characterized by swelling in the body, high blood pressure, and high protein concentration in urine. Many hypertension medications are prohibited for pregnant woman because they may cause damage to the fetus. In Toker’s experiment, 70 women with preeclampsia were separated

into two groups: one group that listened to music, and one that did not. Each day, the experimental group was instructed to listen to classical music for 30 minutes, whereas the control was directed to rest in bed for 30 minutes. The anxiety levels of both groups were measured five days prior to delivery and two days after delivery. Even though the researchers did not find significant changes in patients’ anxiety, they discovered that the average systolic and diastolic blood pressures were significantly lower in groups receiving the music therapy, compared to the control. The decrease in the patients’ blood pressure may indicate a remedial effect of music therapy. A person’s increased comfort level and lower blood pressure might be a consequence of the dynamic of the music listened to, such as its rhythm, loudness, and even its style. Thus, physicians may be able to prescribe music therapy in order to bypass the negative side effects of certain medications, while at the same time treating the condition’s symptoms. Although music therapy has shown great promise, it is not perfect. Because its methods are so diverse, it can be difficult to determine the most suitable treatment for each individual. Different variables, such as the type and duration of music individuals listen to, can also provide different results. A person who sings or plays an instrument can have a different response to the therapy versus if he or she were the one listening to the music being played. Despite the ongoing debates regarding its procedure, music therapy remains as a potentially beneficial form of therapy. Its lack of side effects and non-invasive procedure can make it more accessible and appealing to individuals suffering from physiological and psychological illnesses alike. Music therapy is not yet widely explored, and consequently, its potential has not been fully fleshed out. However, the wide array of options available with this type of treatment makes it possible to be administered to a large number of patients experiencing varying issues. In the future, music therapy may become a more common form of therapy as it becomes increasingly tailored to individuals’ needs. Its potential lies in the fact that it is not restricted to any age and has no harmful repercussions. By stressing the lack of side effects and flexibility associated with this treatment, health professionals can potentially incorporate music therapy into their medical practices, establishing music therapy as a more common practice.

Science Review

Takotsubo Cardiomyopathy: An Overview of Broken Heart Syndrome Alison Chan ‘19

References 1. S. Hanser, L. Thompson. Effects of music therapy strategy on depressed older adults. Journal of Gerontology 46, 265-269 (1994) doi: 10.1093/geronj/49.6.P265. 2. M. Gavrielidou, H. Odell-Miller. An investigation of pivotal moments in music therapy in adult mental health. The Arts in Psychotherapy 52, 50-62 (2017). doi: 10.1016/j.aip.2016.09.006. 3. T. F. de Juan. Music therapy for women survivors of intimate partner violence: an intercultural experience from a feminist perspective. The Arts in Psychotherapy 48, 19-27 (2016). doi: 10.1016/j.aip.2015.12.007. 4. B. Canga, et al., AIR: advances in respiration – music therapy in the treatment of chronic pulmonary disease. Respiratory Medicine 109, 1532-1539 (2015). doi: 10.1016/j.rmed.2015.10.001. 5. E. Toker, N. Kömürcü. Effect of turkish classical music on prenatal anxiety and satisfaction: a randomized controlled trial in pregnant women with preeclampsia. Complementary Therapies in Medicine 30, 1-9 (2017). doi: 10.1016/j. ctim.2016.11.005. 6. G. V. Espí-López et al., Effect of low-impact aerobic exercise combined with music therapy on patients with fibromyalgia: a pilot study. Complementary Therapies in Medicine 28, 1-7 (2016). doi: 10.1016/j.ctim.2016.07.003.

Introduction The heart is a profound symbol in fairy tales, mythology, and literature. A broken heart is seen as one of the most powerful metaphors for anguish, despair, humiliation, shock, and melancholy. When someone experiences a tragic event, the resulting emotions may be overwhelming. This stress can intensify to the point where it induces physical harm and even a fatal outcome. The affected person may begin to experience chest pains, lightheadedness, and shortness of breath: symptoms common in those undergoing a heart attack. When examined by a doctor, their electrocardiogram (ECG) and blood work is usually found to be abnormal, even though their arteries have no blockages. This condition is called takotsubo

cardiomyopathy (TCM), otherwise known as “broken heart syndrome.” Overview of Heart Function The heart is separated into four chambers: the right atrium, the right ventricle, the left atrium, and the left ventricle. The right atrium of the heart receives blood from the superior and inferior vena cava, while the left atrium collects blood from the pulmonary vein. The blood that flows into the atria is then pumped into the ventricles through the semilunar valve. As this happens, the atria begin to fill with blood again (1). The ventricles stop contracting, causing a decrease in pressure that leads the pulmonary valve to close and prevent

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after a traumatic event, such as the death of a loved one, an intense argument, or severe fear, weakens and triggers changes in the heart muscle. Chest pain, sweating, and heavy breathing are the most common symptoms. Other symptoms include loss of consciousness, palpitations, shock, vomiting, and hypotension, or low blood pressure (2). More life-threatening complications can include cardiogenic shock (when the heart isn’t able to pump enough blood to meet the body’s needs), ventricular arrhythmias (the ventricles beat rapidly), pulmonary edema (excess fluid in the lungs), obstruction of the left ventricle, and cardiac arrest (3).

Figure 1 A diagram of blood circulation in the human heart.

the backflow of blood from the arteries. As the pressure from the ventricles drops, the atrioventricular valve opens and the process repeats. Causes and Symptoms The Japanese word “takotsubo” refers to a ceramic trap that fishermen use to catch octopuses. During systole, the contraction of the heart chamber, the ballooning of the left ventricle resembles the shape of that trap. TCM is an uncommon, recently recognized clinical illness. It’s a cardiac syndrome characterized by an abrupt onset of chest discomfort and breathing difficulties that mimic a heart attack in clinical and electrocardiographic findings. The primary difference between the two is that heart attacks include a blockage of the arteries, while TCM does not. Aside from the lack of obstruction in the arteries, TCM differs from a myocardial infarction, or a heart attack, in that those with TCM have left ventricular blood ejection rates that are only 40% the rate of those with a myocardial infarction (1). Medical experts believe that the adrenaline produced

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Risk Factors TCM occurs predominantly in elderly women, with 90% of reported cases in women ages 58 to 75. In a British study involving 908 relatives of patients who had died, it was found that 4.8% of bereaved close relatives died within a year of bereavement compared with 0.68% of a non-bereaved control group. In addition, among widows and widowers the mortality rate was 10 times greater than that of the matched controls. After the first year of bereavement, however, mortality rates of relatives of a deceased person did not differ significantly from the control group (2). Although women are at a greater risk of developing TCM, men develop more severe heart complications, such as severe pump failure and cardiovascular death, during their hospitalization than women. As a result, fatality rates among men are higher than that of women (4). Treatment The mortality rate of this syndrome ranges from 0 to 10%, depending on factors like timely diagnosis and appropriate management. There are no proper scientific guidelines for treating broken heart syndrome, but most practitioners agree that the aim of treatment should be supportive, meaning they work to maintain cardiac function and prevent life-threatening complications in their patients (3). In treating TCM, clinicians usually prescribe standard heart-failure medications, such as beta-blockers, ACE inhibitors, and diuretics, since as many as 20% of sufferers may develop heart failure. Beta-blockers prevent the production of epinephrine, the hormone that increases a person’s heart rate, as well as decrease blood pressure and increase blood flow throughout the body. In addition to beta-blockers, a person with TCM may also be prescribed alpha-blockers. Alpha-blockers prevent norepinephrine from tightening muscles in small arteries and veins, improve blood

Medical experts believe that the adrenaline produced after a traumatic event, such as the death of a loved one, an intense argument, or severe fear, weakens and triggers changes in the heart muscle.

flow, and decrease blood pressure. ACE inhibitors prevent the production of angiotensin II, an enzyme that narrows blood vessels and signals the release of angiotensin II, a hormone that narrows blood vessels and increases blood pressure. Diuretics incite the kidney to release more sodium and water into a person’s urine. This decreases the amount of water in a person’s blood and lowers his blood pressure. Over the course of one to four weeks of treatment with medications, the ballooning in the left ventricle begins to fade, and the chamber returns to its original pumping power. Most patients recover fully within two months with no long-lasting effects on the heart muscle. Less than 10% of patients will encounter a relapse following the completion of treatment. Although stress is a factor known to be correlated with the development of TCM, attacks are still unpredictable (5).

An unrecognized clinical problem? The idea of a “broken heart” has been seen across cultures as a figure of speech that represents a person’s reaction to trauma. For years, medical practitioners were reluctant to explore the possibility of it being a physical condition (3). When researchers in Japan first detected and coined the term for the illness, they simultaneously discovered the effects of stress on the heart (7). Broken Heart Syndrome has received more attention and research in recent years and has since been regarded as a serious and potentially tragic medical condition. Despite this, the number of reported and studied cases still remains small and there are still questions concerning the causes, effect of treatment, and genetic risks (8).

The Case of “Anna” In 2005, a 71-year-old woman, who will be referred to as “Anna,” was brought into the emergency room of Albert Einstein College of Medicine with complaints of chest pain. Her husband had died four months prior to her admittance into the hospital and she had been experiencing severe emotional distress. While being transferred to a different care center she began to experience tachycardia, a resting heart rate that was over 100 beats per minute. Anna’s heart had a left ventricular ejection fraction of 35%. A diagnosis of Takotsubo cardiomyopathy was considered. In the coronary care unit, she received beta-blockers in order to reduce her blood pressure. An echocardiography performed 3 days after Anna’s admittance revealed improved left ventricular function and a left ventricular ejection fraction of 45%. 6 weeks after her hospitalization, an echocardiogram reading revealed normal left ventricular function and an ejection fraction of 55% (6). Anna’s case illustrates the typical progression and treatment of TCM.

1. Y. Jenab, M. Taher & S. Shirzad. Broken heart syndrome: a case report. Journal Of Tehran University Heart Center 7, 136-139 (2012). 2. T. Efferth, M. Banerjee & N.W. Paul, Review: broken heart, tako-tsubo or stress cardiomyopathy? metaphors, meanings and their medical impact. International Journal Of Cardiology, (2016), doi:10.1016/j.ijcard.2016.12.129. 3. M. Vakamudi, ‘Broken-heart syndrome’… be aware. Indian Journal Of Anesthesia 60, 155 (2016). 4. T. Murakami, et al., Gender differences in patients with takotsubo cardiomyopathy: multi-center registry from Tokyo CCU network. PLoS ONE 10 (2015), http://doi.org/10.1371/journal.pone.0136655. 5. Mending broken heart syndrome: sudden stressful events can trigger heart attack-like symptoms. Healthy Years 12. (2015). 6. M.D. Metzl et al., A case of takotsubo cardiomyopathy mimicking an acute coronary syndrome. Nature Clinical Practice Cardiovascular Medicine 3, 53-56. (2006). doi:10.1038/ncpcardio0414. 7. L. S. Marshall, Broken heart syndrome. Journal of Radiology Nursing 35, 133 (2016). doi:10.1016/j.jradnu.2016.04.002. 8. S. Nóbrega, D. Brito, Review article: the “broken heart syndrome”: state of the art. Revista Portuguesa De Cardiologia (English Edition) 31, 589-596 (2012). doi:10.1016/j.repce.2012.07.006.

References

Images retrieved from https://commons.wikimedia.org/wiki/File:A_pain_stabbed_my_heart.jpg https://commons.wikimedia.org/wiki/File:Diagram_of_the_human_heart_ (cropped).svg https://commons.wikimedia.org/wiki/File:US_Navy_110718-N-QD416-015_ Medical_personnel_perform_an_echocardiogram_on_a_patient.jpg

Figure 2 An echocardiograph being performed on a US Navy member

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Science Review

Recent Advances in Alzheimer’s Disease Yasmine Brown-Williams ’18

Figure 1 Differences between non-diseased Neuron and dieased neurons.

Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder and a common form of dementia, which is characterized by cognitive decline that disrupts daily activities. AD is progressive, and currently affects over 5.1 million Americans (1). It is generally believed that dementia disorders only occur in the elderly, or that the development of AD is a normal stage in aging. However, these are misconceptions because 500,000 Americans under the age of 65 suffer from some form of dementia, meaning this disorder is not explicitly correlated to age (1,2). The most

common symptoms include memory deficits, social disengagement, and apathy. Another symptom that occurs early on is gradual loss of executive functioning, which includes cognitive processes such as problem solving, attention control, and reasoning. History Alzheimer’s disease was first characterized in 1906 by Dr. Alois Alzheimer (3). He described a 50-year-old patient suffering from this disease as experiencing memory loss, paranoia, and psychological changes, such as increased aggression and confusion. After her death, five years after admission to the hospital, Dr. Alzheimer conducted a histology on the patient’s brain. He discovered there was noticeable shrinkage of the nerve cells, large atypical deposits between neurons, and tangles within the neurons. Today, these are still the cardinal signs associated with AD, and the deposits are called “plaques.” In 1906, Dr. Alzheimer presented his findings at a German psychiatric conference. The study, however, was not given much attention, and the disease was not formally named until 1910, when the German psychiatrist Emil Kraepelin included Alzheimer’s disease in his book, Psychiatrie. The invention of the electron microscope in the 20th century enabled researchers to further study the signs of AD within the brain because they were able to look at cells more closely (6). In 1968, the first cognitive measurement scale was introduced to detect and standardize cognitive and functional decline in elderly adults. This allowed physiological abnormalities, such as brain lesions and damaged tissue, to affect cognitive ability, leading to a better understanding of Alzheimer’s disease. In 1984, the polypeptide amyloid beta was identified as the primary constituent of plaques and a key player in the stimulation of nerve cell damage (3). In the years following, experimenters concluded that the tau protein is a major component of the tangles that exist in the brains of AD patients. Since then, researchers have been further exploring the connection between these proteins and Alzheimer’s disease. Signs and Symptoms Individuals with Alzheimer’s disease undergo a preclinical stage, a period when the disease progresses but there are no clinical symptoms (8). Although it is not specific how long the preclinical stage lasts, researchers have declared that Pittsburg compound B positron emission tomography (PET) and hippocampal volume testing can be used to detect the preclinical stage. Noticeable cognitive decline often begins seven to ten years after clinical diagnosis, but the preclinical stage may persist for up to five years prior to diagnosis (4). Typical cognitive symptoms of AD generally include

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episodic memory loss/impairment, dysfunction of executive bodily functions, and visuospatial impairment (5). Latter-stage symptoms include deficits in language and behavior. Semantic memory, which encodes generalized information and facts, is also affected. From a neurobiological standpoint, the AD brains have been characterized as having plaques and tangles present (6). Beta-amyloid plaques are capable of blocking cell-to-cell signaling and may incite the immune system to attack cells. The presence of accumulated beta-amyloid peptide in the brain is a main indicator of AD because it is the result of unbalanced negative feedback mechanism. As amyloid (a normal protein found throughout the body) is produced, the protein is supposed to be cleared. However, in an AD brain this procedure is dysfunctional. Neurofibrillary tangles, another clinical symptom noticed by Dr. Alzheimer, are abnormal twisted fibers of the tau protein that form inside of cells in the AD brain (7). The primary component of the tangles is a hyperphosphorylated form of tau protein, phosphotau, which aids in vesicle transport and promotes the stability of microtubules. However, the entanglement of tau fibers prevents the transport system from working and thereby stops nutrients from passing through cells, leading to ultimate death of those cells (7). There is a positive correlation between the number of neurofibrillary tangles and the severity of AD present in the brain (4). One biomarker test for Alzheimer’s disease requires the measurement of two types of phosphotau amino acids and total tau in the brain. Additional evidence in the literature points to beta-amyloid accumulation as a stimulant that prompts tau aggregation (4). However, in a recent study published by Dr. Hassenstab, researchers noted that signs of AD could be detected in vivo using cerebrospinal assays (CSF), PET, and both structural and functional magnetic resonance imaging (fMRI) (8). Customarily, as outlined in the Diagnostic and Statistical Manual of Mental Disorder: 5th Edition (DSM-5), the existence of amyloid plaques and tau neurofibrillary tangles could only be confirmed postmortem (9). However, early plaque deposition of an isomer of amyloid beta, amyloid beta-42, can be detected with the aforementioned PET, CSF, and MRI tests. But although these measures can successfully detect neuronal damage, they are not specific enough to precisely identify Alzheimer’s disease as the underlying illness. Causes Alzheimer’s disease may be the result of oxidative stress, a disruption of the blood-brain barrier, hypometabolism which is abnormally slow metabolism, neuroinflammation which is inflammation of nervous tissue, and/or mitochondrial impairment (10). When unfolded proteins (beta-amyloid plaques) accumulate in the brain, there is oxidative and inflammatory damage (4). Oxidative stress is the inability of the body to counteract the harmful effects of free radicals through antioxidant neutralization. The blood-brain barrier, a semipermeable membrane, is a distinct division between the capillaries in the brain that transport blood and the structures of the central nervous system or CNS, ensuring no harmful chemicals are exchanged between the CNS and the circulatory system. Alzheimer’s disease, as with all dementia, is idiopathic, meaning it has an uncertain cause. Currently, there is no cure

for AD but symptom treatments do exist, and current research is focused on how to delay the onset of this disorder, slow its course, or prevent it entirely. Psychological Diagnoses and the 10/66 Algorithm Some diagnostic features include decline in memory and learning, cognition without the presence of long-lasting plateaus, and a lack of comorbidities with other neurodegenerative or cerebrovascular diseases (9). Probable diagnosis of AD requires genetic testing to detect an Alzheimer’s disease gene that may be the result of a mutation of family history. Behavioral diagnostic identifiers include depression, apathy, psychotic features, irritability, agitation, combativeness, and wandering. While later in the disease progression, symptoms can become so disruptive that the patient experiences incontinence and seizures (9). On a global scale, there are over 35 million cases of AD worldwide (4). In fact, roughly 66% of dementia cases occur in underdeveloped countries. Unfortunately, only 10% of the research on this disease is conducted in these countries. Diagnostic guidelines for Alzheimer’s disease were primarily developed in western countries. Therefore, cultural differences between the western world and underdeveloped countries can serve as a barrier that leads AD to be underdiagnosed (11). The scientific community is currently working towards fixing this under-diagnosis. A group of researchers who formed the 10/66 Dementia Research Group, a coalition of scientists who conduct population-based research on dementia, aging, and non-communicable disease in underdeveloped and lowincome countries, formulated their own algorithm to correct for the under-detection of dementia that can result from cultural differences (11,12). The 10/66 Algorithm was the result of a claim made by the researchers that declared the DSM-IV criteria too restrictive to be applicable and accurately diagnose all dementia cases. Their method is said to detect dementia with 94% sensitivity, which is a statistical measure that describes how susceptible a value is to change based on alterations in the variables. Therefore, the 10/66 Algorithm is very sensitive to changes in the variables (cultural differences) that lead to their AD diagnoses.

Figure 2 There are several neurologic indicators of Alzheimer ’s disease, such as the buildup of amyloid plaques, cleavage of beta-amyloid, neurofibrillary tangles, disintegrating microtubules, and the loss of neuron communication.

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Treatment The two subgroups of AD treatments are symptomatic and etiology-based (10). Symptomatic treatments are methods of therapy that focus primarily on the symptoms associated with the disease. An example, with respect to Alzheimer’s disease treatment, is an acetylcholinesterase inhibitor. Etiologybased treatments place emphasis on the causal relationship. Examples include secretase inhibitors and amyloid binders. Acetylcholine (ACh) is a neurotransmitter that mediates learning and memory activities in the brain (10). The relationship between ACh and beta-amyloid is a negative feedback system that prevents overproduction of beta-amyloid. When this feedback loop is disrupted, aggregates of beta-amyloid are able to form in the brain—one of the primary neurological indicators of Alzheimer’s disease. Therefore, this type of symptomatic treatment relies on the use of acetylcholinesterase inhibitors, which block the enzymes that degrade ACh, which allows for the continuation of the functional negative feedback loop. ACh inhibitors have been determined to be safe, side effects are generally related to dosing discrepancies. Additionally, ladostigil— an ACh inhibitor that is still being clinically tested—has been reported to also be an effective antidepressant (10). Secretase is a protein enzyme that produces a soluble version of beta-amyloid peptides. A secretase inhibitor would thereby prevent the production of beta-amyloid and avoid the development of plaques and tangles. Amyloid binders are protein binders that attach to amyloid to prevent aggregation. Novel Approaches A recent study conducted at Stony Brook University in the lab of Dr. John Robinson hypothesized that measuring only the levels of beta-amyloid protein accumulation is not a reliable predictor of cognitive decline. Robinson instead posited that factors such as the location of the plaques and protein deposits are better indicators. The study utilized transgenic mouse strains (Tg-5xFAD and Tg-SwDI) that displayed beta-amyloid accumulation to observe changes over time. Spatial distance between the brain deposits of beta-amyloid was significantly more indicative of cognitive decline in mouse models than merely its level (13). Behavioral tests were conducted to detect for changes in spatial learning and memory. This included observing the ability of the mice to revisit a box they had previously chosen (Barnes Maze) under various conditions, such as light/dark, on a rotating rod, and other conditions. Tissue analysis of the insoluble and soluble brain fractions was performed postmortem to measure the levels of beta-amyloid-42 and beta-amyloid-40. Beta-amyloid-42 is considered the more harmful of the two because it is more likely to aggregate into a toxic structure. At three months, the Tg-SwDI mice accumulated more beta-amyloid-40 and the Tg-5xFAD mice experienced greater accumulation of beta-amyloid-42. However, at six months Tg-5xFAD mice showed significantly elevated levels of both beta-amyloid variants as compared to the Tg-SwDI strain (13). Additionally, after three months the Tg-SwDI strain displayed signs of behavioral deficits while the Tg-5xFAD strain did not. However, the latter mice did have significantly higher levels of beta-amyloid deposits in the nervous tissue. By the sixth month, both groups showed observable behavioral deficits, although the Tg-5xFAD mice still retained the largest amounts of

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beta-amyloid plaques. Interestingly, although the Tg-5xFAD mouse strain sustained the highest levels of beta-amyloid deposits throughout the study, the Tg-SwDI mice were the first to display observable signs of cognitive and behavioral deficits. This data prompted the researchers to posit that these measures were not appropriately correlated with cognitive impairment. Therefore, they looked to observe the location of the deposits within the brain. This analysis showed that Tg-5xFAD mice had more plaque aggregates in the cortex and thalamus. The Tg-SwDI mice presented with deposits in the subicular region, the area between the hippocampus and other subcortical structures in the brain. Furthermore, it was found that the amyloid accumulation in the Tg-SwDI mice are small, spotty deposits in the microvascular system of the cerebral structures. The Tg-5xFAD mice show much larger plaque deposits, and the cerebral microvascular deposits characteristic of the Tg-SwDI mice are absent in the Tg5xFAD strain. Therefore, researchers concluded that the early trigger of cognitive impairment is the early-onset accumulation of beta-amyloid in the small vessels of the cerebral structures as opposed to a wider distribution throughout the brain (13). Conclusion Alzheimer’s disease is the most common form of dementia, which affects primarily individuals over the age of 65. The key behavioral and cognitive signs of the disease’s onset are memory loss and impairment, disorientation, and inability to complete visuospatial tasks. The primary neurological indicators are the presence of beta-amyloid deposits in the brain and neurofibrillary tangles. Alzheimer’s disease is idiopathic and there is no current cure, although several types of treatments exist. Diagnostic criteria, as well as the way the indicators are correlated to the diagnosis of AD, are changing. The mechanisms of the disease are also developing. New indicators, such as synaptic failure, mitochondrial dysfunction, and even the effects of the absence calcium regulation are being discussed in relation to Alzheimer’s disease. The field of dementia research is constantly changing, and as the most prevalent form of this condition among the elderly, so is Alzheimer’s disease. References 1. About alzheimer’s disease. Alzheimer’s Foundation of America, (2016). 2. What is alzheimer’s?. Alzheimer’s Association, (2017). 3. Major milestones in alzheimer’s and brain research. Alzheimer’s Association, (2017). 4. H. W. Querfurth, F. M. LaFerla, Alzheimer’s disease. The New England Journal of Medicine 362, 329-344 (2010). Doi: 10.1056/NEJMra0909142. 5. D.A. Wolk, B. C. Dickerson, Clinical features and diagnosis of Alzheimer disease. UpToDate, (2017). 6. A.A. Davis, J.J. Lah, A.I. Levy, The american psychiatric publishing textbook of psychopharmacology. American Psychiatric Publishing (2009). 7. Alzheimer basics: plaques and tangles. Alzheimer’s Association, (2017). 8. J. Hassenstab et al., Certified normal: alzheimer’s disease biomarkers and normative estimates of cognitive functioning. Neurobiology of Aging 46, 23-33 (2016). 9. Major or mild neurocognitive disorder due to alzheimer’s disease. American Psychiatric Association (2013). 10. J.Mendiola-Precoma et al., Therapies for prevention and treatment of alzheimer’s disease. Biomed Research International, (2016). 11. The 10/66 dementia research group. 1066 Dementia Research Group (2015). 12. Alzheimer’s disease. Nature Education, (2014). 13. Fig. 1 Image Retreived from: https://zh.wikipedia.org/wiki/%E9%98%BF%E5 %85%B9%E6%B5%B7%E9%BB%98%E7%97%85 14. Fig 2 Image Retrieved from: https://commons.wikimedia.org/wiki/ File:Characteristics_of_AD.jpg

Science Review

The Effects of Social Networking on Academic Achievement Alden Liang ’20

Social media is a collection of websites and applications that allows users to easily connect to one another. Nowadays thousands of games and entertainment platforms such as Facebook, Snapchat, and YouTube can be easily accessed. In 2016 alone, there were over 1.86 billion monthly active Facebook users worldwide, a 17% increase from 2015 (1). According to Pew Research Center, 71% of teens use more than one social network site (2). Students often utilize these sites both at home and during classes to keep up with current events and fill free time (3). This widespread usage of social media has raised questions regarding if it negatively affects students. Currently, many studies have found that daily social media usage negatively affects students’ psychology in a way that often decreases their academic performances. The analysis of student GPAs and amount of time spent browsing the Internet in public and private schools has revealed that students’ academics can be significantly affected by persistent social media usage. A recent study by a team in Ghana found that private school students used Whatsapp and Facebook more often and spent more hours online when compared to public school students. 46% of the respondents reported using social networks primarily for pictures and videos and 32% reported using them for posting updates. The study also found that private school students were more addicted to social media than public school students, with 55.6% of private school students and 44.4% of public school students admitting to social

media addiction. These results may provide an explanation for the private students’ greater time online. Additionally, 56.8% of the private school students admitted to decreased spelling proficiency during exams in comparison to 43.2% of public students. Increased social media usage was found to negatively influence students’ academics not only in respect to spelling, but also in respect to their GPA. A higher proportion (57.3%) of students from the private schools experienced a greater decrease in their grades compared to their counterparts (42.8%) in the public schools. Therefore, increased social media usage, particularly in an addictive manner, can generally lead to a lower GPA (4). Although it has been found that social media usage lowers academic performance in high school students, this trend has not been identified in medical students. In a study led by Dr. Ahmed Tawfeeq Alahmar of the College of Medicine at University of Babylon, researchers used an online questionnaire to evaluate the impact of social media on the academic performance of second year medical students. According to the study, 42% of the students stated that social media had a positive influence on their grades, while 33% and 25% of the students stated that it had a negative and neutral influence respectively. Those who reported a positive effect used social media primarily for visiting medical pages and groups, while those who reported negative effects admitted to spending excessive time on Facebook and other social media apps for non-academic purposes. Despite what the students stated regarding the amount of time

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they spent on social media and whether they observed any or no affect on their academic performance, their grades did not differ. Additionally, despite the perceived differences in their time spent on social media, the individuals spent roughly an equal amount of time browsing the Internet (5). Although these results do not follow the same negative trend as that of high school students, they demonstrate that medical students spend less time on social media. Teens spend roughly nine hours on social media as opposed to the average five hours the medical students in this study spent (6). It is possible that no correlation was found between social media usage and the medical students’ GPAs because medical students on average spend a smaller amount of time on social media than high school students. Studies have also shown that daily social media usage inflicts negative psychological effects that interfere with one’s self-esteem. For instance, a recent study led by Dr. Ruoxu Wang and her team at Penn State University found that those who viewed others’ selfies, or self-portrait photographs, repeatedly on social media had lower opinions of themselves (7). This occurred partly because individuals’ self-esteem decreased while viewing a smiling photo of someone else. This effect, likely associated with jealousy, may be a factor for increasing loneliness. However, group pictures with the person included in the photo were revealed to boost self-esteem because people felt a sense of popularity. Similarly, in a project led by Dr. Kagan Kircaburun of Duzce University, correlation analysis and structural equation modeling revealed that daily social media usage was negatively associated with self-esteem (8). Many individuals who had low self-esteem avoid real-life interactions and use social media as an escape to a virtual world. Although social media is perceived as a safe place, some individuals are unaware that social media can lower self-esteem. Many individuals on social media project false images of their daily lives, making them appear more ideal than their reality. Thus, many individuals become jealous of others’ supposed perfection, and their self-esteem lowers. The study also found that as students’ self-esteem levels declined, depressive symptoms were more likely to appear. The constant desire to be someone else may cause one to lack confidence and thus increase his or her likelihood of depression. Overall, these studies demonstrate that daily social media usage can negatively affect one’s self-esteem and can lead to depression. Loneliness has been demonstrated to increase daily social media intake in adolescents and negatively affect their GPA. A recent study utilized personal information sheets to explore whether social media usage was related to academic performance and loneliness among university students. The researchers found that students who felt isolated in real life went on social media more often because they believed they could express themselves more easily on the internet. In turn, this increased social media usage prompted them to continuously interact in virtual reality rather than in real life. This suggests that social media is a platform that many students turn to when they feel a need to compensate for their loneliness. However, the study also found that as social media usage increased, the students became less focused in school and their grades decreased more than those who spent less time on social media. This study implies that academic and social aspects of loneliness correspond to increased social media usage (9).

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Examination of loneliness and the academic performances among first-year college students has further demonstrated that loneliness can be a predictor for decreased academic performances. Regression analyses in a recent study led by Dr. Eyal Rosenstreich at Peres Academic Center in Israel found that loneliness was negatively associated with recognition memory performance and with grades. Loneliness is characterized by high levels of cortisol, a hormone which can increase stress and anxiety. The negative effects of stress and anxiety biologically distract students and make it more difficult for them to concentrate on school material. It has been demonstrated that mindfulness practices reduce these negative effects. Mindfulness practices such as meditation lowers blood pressure and dismisses worrying and stress. This can explain why the students who participated in the mindfulness workshops improved their memory and received higher grades. Increased loneliness levels were correlated with low memory performance and test grades, whereas, mindfulness workshops increased one’s GPA. This study suggests that academic performance may be sensitive to a student’s emotional state, and mindfulness practices can subside the effects of loneliness on students’ academic achievements (10). Social media usage will likely persist on its upward path for years to come. As social media applications and the number of students using them continue to increase, students may experience a drop in their GPA. In turn, it is possible that grade inflation may rise in schools to counteract the declining GPAs. Although social networks offer many positive features, students should also be aware that their time spent on social media can negatively impact their mental health drastically. This lack of motivation and self-esteem may also decrease their GPA. For future research, researchers should investigate new methods to reduce the negative effect social media has on user’s selfesteem. These methods may aid students in maintaining their mental health and academic strength despite the stressors associated with social media.

References 1. Top 20 facebook statistics. Zephoria Inc., (2017). 2. A. Lenhart, Teens, social media & technology overview 2015. Pew Research Center: Internet, Science & Tech, (2015). 3. Social media use among college students and teens: what’s in, what’s out, and why. Modo Labs, (2016). 4. J. Mingle et al., A comparative analysis of social media usage and academic performance in public and private senior high schools. Journal of Education and Practice 7, 13-22 (2016). 5. A.T. Alahmar, The impact of social media on the academic performance of second year medical students at college of medicine, university of babylon, iraq. Journal of Medical & Allied Sciences, 77-83 (2016). doi: 10.5455/jmas.236927. 6. H. Tsukayama, Teens spend nearly nine hours every day consuming media. The Washington Post, (2015). 7. R. Wang et al., Let me take a selfie: exploring the psychological effects of posting and viewing selfies and groupies on social media. Telematics and Informatics, (2015). doi: 10.1016/j.tele.2016.07.004. 8. K. Kircaburun, Self-esteem, daily internet use and social media addiction as predictors of depression among turkish adolescents. Journal of Education and Practice 7, 64-72 (2016). 9. G. Stankovska et al., Social networks use, loneliness and academic performance among university students. Higher Education, Lifelong Learning & Social Inclusion, 255-261 (2016). 10. E. Rosenstreich, M. Margalit., Loneliness, mindfulness, and academic achievements: amoderation effect among first-year college students. The Open Psychology Journal 8, 138-145 (2015). 11. Image retrieved from: https://pixabay.com/en/media-social-media-apps-998990

Utilizing New Targeted Immunotherapy and Remyelination Techniques to Treat Multiple Sclerosis

Science Review

Sanket Desai ‘19 Introduction Multiple sclerosis (MS) is a debilitating neurological disorder that damages the myelin sheath, which is a protective covering for axons (1). The resulting demyelination disrupts communication between neurons, causing physiological and psychological problems. Some of the symptoms of Multiple Sclerosis include the loss of sensation in the extremities, difficulty with vision and balance, and slurred speech (2). The body has a method of repairing the myelin sheath through oligodendrocytes, which are a type of glial cells found in the human body that can remyelinate the myelin sheath. However in MS, neurons demyelinate so quickly that the oligodendrocytes are unable to repair them all (1). Researchers are currently working on ways to induce the oligodendrocytes to myelinate the neurons and treat MS.

tosis (5). Although immunotherapy has been very effective, it still exposes the body to additional diseases. Therefore, researchers have begun to utilize a method to induce myelination that does not require immunotherapy. Currently, several drugs have been created that aid in correcting nerve damage and promoting remyelination. Fluorosamine is an established drug that induces the remyelination of neurons by indirectly promoting the growth of precursor cells (6). NDC-1308 is a relatively new drug that aids in remyelination, but unlike fluorosamine, it induces the precursor cells to mature into oligodendrocytes (7). Despite the use of these treatments, there are still many who suffer from the effects of MS.

Background Multiple sclerosis is classified as an autoimmune disorder, meaning that the immune system attacks itself, incurring damage in different parts of the body. In MS specifically, B and T cells of the immune system identify the myelin sheath as an antigen and then attack it. Unmyelinated neurons lack the nodes of Ranvier, components of the myelin sheath, which aid in the transmission of action potentials. Thus, when an unmyelinated axon sends an action potential, it is sent at a significantly lower speed. This delay in communication renders neurons unable to coordinate an action and causes a person to lose motor control (3). For example, when an unmyelinated neuron instructs the finger to contract, its signal takes longer to reach the muscle, causing a disconnection between the brain and the muscle as well as a loss of fine motor control (4). Current Methods of Treatment One of the leading methods to test MS is immunotherapy. Immunotherapy is a process that entails the use of drugs to repair the immune system. So far, drugs have been developed that can attack and neutralize the T and B cells that destroy the myelin sheath. One type of drug blocks the immune cells from crossing the blood brain barrier, thus preventing the immune cells from attacking the myelin sheath. Another therapeutic drug induces the apoptosis of immune cells by acting as a ligand to a protein on the cell membrane. Additionally, immunotherapy can restrain the proliferation of T and B cells by acting as a ligand that signals the cell cycle to stop. Finally, there is another type of drug that destroys immune cells by entering the cell and becoming incorporated into the DNA, which is then translated into a protein that signals for apop-

Figure 1 Anatomical depiction of the components of the myelin sheath.

Future Methods of Treatment Gene therapy is a promising technique that stops multiple sclerosis at the source, thus preventing side effects. In gene therapy, genes in immune cells can be altered so that they no longer treat myelin sheath as an antigen. For example, gene therapy could possibly deactivate the angiotensin receptor, involved in increasing immune activity, so the appropriate peptides cannot bind to the receptor (8). This hinders the T cells, thereby preventing damage to the myelin sheath (8).

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Image retrieved from: http://www.publicdomainpictures.net/view-image.php?image=131274&picture=brain-signals Gene therapy also entails the use of foreign genes to alter immune cell activity. Researchers at the University of Florida used a method of viral transfection to treat hemophilia (9). This method could also apply to MS (9). They hope to be able to insert a gene into the liver to induce the production

Figure 2 Functional parts of T-cell that play a role in its immune cell properties

of regulatory T cells (9). Through a combination of immunotherapy and gene therapy, T cells can be regulated so that they no longer attack the myelin sheath (9). Although gene therapy in the immune system can be useful, it cannot directly help the body. However, a group of researchers at the University of British Columbia has found a promising gene that could be used as a new approach to treat MS. When NR1H3 is mutated pre-natal, axons lose the myelin sheath which could lead to multiple sclerosis (10). By turning off this gene, it can no longer be mutated and could prevent the onset of MS. Additionally, it has been discovered that EphrinB3, a protein found on the surface of the oligodendrocyte membrane, inhibits the formation of oligodendrocytes. Researchers hope to knock out the gene that is responsible for the creation of the Ephrin B3 protein, so that the oligodendrocyte will mature and remyelinate. Researchers are developing new ways to stimulate oligodendrocyte activity by expressing the corresponding genes (11). Finding genes responsible for MS is difficult. As a result, there are not many treatments being developed using gene therapy. New drugs are being developed that act as antigenspecific treatment by deactivating T-cells (12). For example, a drug can be manufactured such that a T cell identifies the drug as an antigen and binds to it (12). This drug will then inhibit the T cells from damaging the myelin sheath (12). Researchers also hope to use natural means to suppress the immune system (12). For example, estriol, a hormone involved in pregnancy, plays a role in the suppression of the immune system, which has been shown to limit the inflammation seen in patients of MS (12). Finally, new drugs are being developed that act on the T cells, even as they are destroying the myelin sheath (12). In this type of treatment, the drug binds to the T cell and activates various internal processes to degrade it (12). Researchers intend to improve upon existing immunotherapy methods by utilizing nanotechnology to aid in drug delivery (12). Nanotechnology involves the injection of small devices carrying a small dose of a drug into the bloodstream, where

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it will be directed to the brain. Upon reaching the brain, the drug will act on the immune cells to suppress their activity. This is superior to existing treatments, since the drug is able to directly act on its target and will not travel around the body, causing unwanted side effects (13). The existing class of drugs needs to be refined to better aid in remyelination. One such improvement is to utilize small molecules that can induce a change in the pathways of cellular processes, which will then activate the oligodendrocytes to repair the myelin sheath (1). This method has not been properly developed, due to the lack of research surrounding the cellular pathways inside oligodendrocytes (1). Additionally, researchers think enzymes could be used to clean up the myelin sheath debris found around the axon so that the oligodendrocytes can more easily arrive to it (1). This method proves difficult because axons with no myelin sheath can have scattered debris that prevent the proper delivery of these enzymes (1). Finally, it is noted that problems with cell signaling contribute to the lack of coordination among oligodendrocytes to myelinate the axon (1). Drugs can act as ligands to differens to restart the process of cell signaling (1). These new developments will allow for a more effective approach in treating MS.

Mirror Neuron Activity and its Relationship with Social Deficits in Individuals with Autism Christopher Esposito â&#x20AC;&#x2DC;18

Conclusion Many treatments have been developed that can treat multiple sclerosis. However, these treatments have side effects and are inefficient. These issues can be resolved in the upcoming years through advancements in the fields of gene therapy and drug delivery. New genes will be discovered that contribute to oligodendrocyte promotion and inhibition. Additionally, new drugs will be developed that have better efficacy for oligodendrocytes promotion and immune cell suppression. Also, new technologies will aid in the delivery of these drugs. Although it is unknown when a cure will be discovered, new

References 1. D. E. Harlow, J. M. Honce, A. A. Miravelle. Remyelination therapy in multiple sclerosis. Frontiers in Neurology 6, 257 (2015). doi: 10.3389/fneur.2015.00257. 2. Symptoms & diagnosis. National Multiple Sclerosis Society, (2017). 3. A.N. BoÄ­ko, O.O. Favorova, Multiple sclerosis: molecular and cellular mechanisms. Molekuliarnaia biologija 29, 729-749 (1995). 4. A. Pietrangelo, Multiple sclerosis from top to bottom getting the complete picture. Healthline, (2013). 5. K. Bashir, J.N. Whitaker, Current immunotherapy in multiple sclerosis. Immunology and Cell Biology 76, 55-64 (1998). doi: 10.1046/j.1440-1711.1998.00714.x. 6. MS society-funded research team develops and tests a new compound to promote myelin repair in mice. Multiple Sclerosis Society of Canada, (2016). 7. NDC-1308, a potential multiple sclerosis treatment. Multiple Sclerosis News Today, (n.d.). 8. D. G. Harrison, T.J. Guzik, Studies of the t-cell angiotensin receptor using cre-lox technology. Circulation Research 110, 1543-1545 (2012). doi: 10.1161/ CIRCRESAHA.112.271411. 9. A. Frawley, Researchers testing gene therapy to thwart effects of multiple sclerosis. UF News: University of Florida, (2014). 10. UBC-Vancouver coastal health scientists find genetic cause of multiple sclerosis. The University of British Columbia, (2016). 11. I. Franks, Remyelination studies abound, but how about a workable therapy? Multiple Sclerosis News Today, (2016). 12. G. Blevins, R. Martin, Future immunotherapies in multiple sclerosis. Medscape, (n.d.). 13. I. Tabansky, et al., Advancing drug delivery systems for the treatment of multiple sclerosis. Immunologic Research 63, 58-59 (2015). doi: 10.1007/s12026015-8719-0. Images retreived from: https://commons.wikimedia.org/wiki/File:Neuron_with_oligodendrocyte_and_ myelin_sheath.svg https://commons.wikimedia.org/wiki/File:T-cell_dependent_b-cell_act.svg https://upload.wikimedia.org/wikipedia/commons/5/56/Oligodendrocyte_HE_ stain_high_mag.jpg

Introduction The discovery of mirror neurons in 1992 captivated researchersâ&#x20AC;&#x2122; interests because they display unique neural response patterns to performed and observed motor actions (1, 2). Neurophysiological examination via positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and electroencephalography (EEG) studies have concluded that the mirror neuron system (MNS) likely consists of pathways located in the frontal, parietal, and cerebellar brain regions, including the premotor and sensorimotor cortices (3, 4, 5, 6). A study conducted by Ferrari et al. investigated the MNS in monkeys. They concluded that neurons fired in the monkeys when the monkey performed specific motor actions and when it observed another monkey performing a similar action (7). Similar mirror neuron activity (MNA) was ob-

served in human populations (8, 9). Hand tasks have been the common method used to evaluate MNA by having an individual perform a task and then having that same individual watch the same action being performed by another person. Research has shown that during observation, similar brain regions are activated as when the individual performs the action (10). Even more interestingly, the mirror neuron system may also play a role in the foundation of social skills (11). Autism Spectrum Disorder (ASD) is a widely recognized social disorder characterized by deficits in higher order social cognitive processes, such as predicting and understanding the mental states of peers, language, and imitating peers (2, 11, 12, 13, 14). The MNS has been thought to underlie stimulation processes to the social deficits in individuals with ASD (15).

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close to touching a person’s hand, or a cotton swab touching a stranger’s hand. The participants were told to imagine how the strangers felt in the images. The results of the study showed that the participants’ mu suppression to the painful stimuli were greater than the suppression to the non-painful stimuli.

view four videos, including a bouncing ball, a stranger’s hand performing an action, a family member’s hand performing the same action, and the participant’s own hand performing the same action. It was seen that both the participants with and without ASD showed greater mu suppression to hand actions performed by more familiar individuals, compared to unfamiliar individuals. When the participants with ASD viewed stranger’s actions, their MNA was significantly less than that of the typically developing participant. Additionally, a study by Fan et al. recruited 24 participants with ASD and 21 TD participants to evaluate their mu suppression to empathy-provoking images of injured people, including a person alone in an accident-caused painful situation, a person alone in a non-painful situation, a person in an intentionally painful situation caused by another individual, and two individuals walking in a non-painful situation (7). The images were observed while an EEG recorded the participants’ resting brain activity. The results of this study oddly revealed that the TD and ASD evinced no significant differences in mu suppression, suggesting that the ASD participants had preserved MNA, including empathy, which has been a hallmark symptom of the social cognition deficits of ASD (23).

Mirror Neurons and Social Skills and Autism The mirror neuron system helps establish a foundation for social skills (11). Specifically, it provides researchers with an understanding of human and primate visual observation and processing. Specific aspects of social cognition, such as imitation, predicting the mental state of an observed individual (commonly referred to as theory of mind), and empathy are aspects of the social network that are foundationally critical to the development of gestural communication (2, 11, 12, 14). Since these social systems are impaired in ASD, it is thought that the mirror neuron system underlies some of the processes related to the social deficits in ASD (15, 19, 20). Therefore, there is reason to believe that impairments in the mirror neuron system may contribute to some of the core social deficits seen in individuals with ASD (16). In an EEG study by Oberman et al. of 10 high functioning participants with ASD and 10 typically-developing (TD) participants, MNA was observed by having the participants perform a hand movement, watch a virtual hand performing the same movement, watch visual noise, and watch a bouncing ball, while an EEG recorded their brain activity (16). It was observed that during hand actions, the MNS was seen to be the only network activated in the premotor and sensorimotor cortices, indicating that mu suppression to observed actions could be used as a selective measure of MNA. The results of this study also showed that the participants with ASD showed significant MNA in response to their self-performed hand movements, but none to the observed hand movements, which suggests a possible dysfunction of MNA in individuals with ASD. However, it has been recommended by the anecdotal reports of Gastaut and Bert, which show that MNA occurs when one identifies with an observed active person (21). In line with these findings, a recent study of 13 participants with ASD and 13 TD participants by Oberman, Ramachandran, and Pineda observed the modulation of MNA by the participant’s ability to relate to observed stimuli (22). Participants were required to

Conclusions and Clinical Implications Since the mirror neuron system plays a critical role in imitation (2), social cognition, empathy (12), and theory of mind (11), all of which are social deficits in ASD (24), MNA could play a pivotal role in helping unveil the neurological basis of the social deficits in individuals with ASD. Additionally, if the study by Oberman et al. is replicated, that may expand to include the social development and friendship-making in individuals with ASD (16). Furthermore, its replication could provide reason to believe that longitudinal research in mu suppression may aid in the advancement of measuring the effectiveness of social interventions for individuals with ASD on a neurophysiological level. Although mu suppression is a popular field in ASD research, it has its limitations as a measure of MNA. Since EEGs are noninvasive, they have poor spatial resolution, and therefore may not be a reliable measure in locating MNA. In fact, a study of 16 TD participants by Braadbaart et al. was designed to evaluate the reliability of the measure by using EEG and sequential fMRI, which is used to capture Blood Oxygen Level Dependent signals; these signals are complemented with computer analyses and are strongly believed to accurately locate MNA (25, 26, 27). The participant’s mu suppression was observed while viewing a video of a stranger performing hand actions and imitating the hand actions in the video. The results of this study reveal that mu suppression is not specific to the activation of the MNS because it involves an array of motor preparation and attention brain regions. Additionally, there is some contradictory literature on mu suppression and ASD. One study suggested that mu suppression is impaired in ASD, while two other studies failed to replicate its findings (14, 16, 28). These contradicting findings could explain why the study by Fan et al. failed to observe mu suppression impairments in its participants (8). Also, their findings suggest the preserved MNA in its ASD participants could have been impacted by the additional brain regions influencing the mu suppression of its participants (7).

Image retrived from: (https://commons.wikimedia. org/wiki/File:Culture_of_rat_brain_cells_stained_with_antibody_to_MAP2_(green),_Neurofilament_(red)_and_DNA_(blue).jpg

Figure 1 This image is a cultural stain of a rat’s neuron. The green indicates the neuron’s dendrites and the red indicates its axons.

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How Mirror Neurons Are Studied The PET and fMRI are both highly complicated and expensive, so a proportionate amount of the present studies evaluating the neurophysiological underpinnings of the MNS utilize EEG, a practical and noninvasive communication channel (10). The EEG has been used to examine brain waves and analyze mu frequency band oscillations (8). The electroencephalographic mu rhythm is generated by the sensorimotor cortex at rest (9). At rest, a person’s mu frequency bands are at baseline, but when a person performs an action or imagines performing an action, there is a decrease in neuronal firing, and therefore, the power of the mu band decreases (5, 6). Similar neuronal activity is seen when a person observes the same action that was just performed (16). Mu frequency has also been seen to attenuate when exposed to sensitive stimuli (18). Research studies using observed hand actions have shown that this process of mu suppression could conceivably be used as a selective measure of mirror neuron system functioning (16). A study by Muthukumaraswamy and Johnson observed 5 right-handed participants perform self-paced hand movements, watch a video of a hand squeezing a ball, perform selfpaced thumb movements, and stare at a crosshair on a computer screen (9). Throughout the study, an EEG recorded their baseline brain activities. The study found that mu suppression occurred both during self-performed hand movements as well as observed hand movements towards objects, which revealed that mu frequency is modulated by object-directed actions as well. Additionally, a study by Pfurtscheller and Neuper used an EEG recording to evaluate the mu frequency of three participants who were told to relax and stare at a fixation crosshair, and then to imagine performing a hand action (5). Compared to the crosshair baseline, their imagined actions showed attenuation of their mu frequencies. Similar results were seen in a study by Pfurtscheller et al. (17), which requited 10 participants to perform similar imagined hand actions, while an EEG simultaneously recorded their brain activity. These findings revealed similar results of mu suppression when imagining hand movements. Empathic neural responses were seen in 30 participants in a study by Perry et al. (18). The study observed the brain activity with an EEG, while the participants were shown images of a baseline crosshair, a needle close to pricking a stranger’s hand, a needle pricking a stranger’s hand, a cotton swab

There is reason to believe that mirror neurons do have the potential to be used as measures of social functioning in individuals with and without ASD. However, mu suppression may not be specific to MNA. Future research should focus on evaluating new measures of MNA in TD and ASD individuals. . References

1. G. di Pellegrino et al., Understanding motor events: a neurophysiological study. Experimental Brain Research 91, 176-180 (1992). doi: 10.1007/BF00230027. 2. G. Rizzolatti, L. Fogassi, V. Gallese, Neurophysiological mechanisms underlying the understanding and imitation of action. Nature Reviews Neuroscience 2, 661670 (2001). doi: 10.1038/35090060. 3. L. Fadiga et al., Motor facilitation during action observation: a magnetic stimulation study. Journal of Neurophysiology 73, 2608-2611 (1995). 4. L.M. Parsons et al., Use of implicit motor imagery for visual shape discrimination as revealed by pet. Nature 375, 54-58 (1995). doi: 10.1038/375054a0. 5. G. Pfurtscheller, C. Neuper, Motor imagery activates primary sensorimotor area in humans. Neuroscience Letters 239, 65-68 (1998). doi: 10.1016/S03043940(97)00889-6. 6. R. Salmelin, R. Hari, Spatiotemporal characteristics of sensorimotor neuromagnetic rhythms related to thumb movement. Neuroscience 60, 537-550 (1994). doi: 10.1016/0306-4522(94)90263-1. 7. Y. Fan et al., Empathic arousal and social understanding in individuals with autism: evidence from fmrI and erp measurements. Social Cognitive and Affective Neuroscience 9, 1203-1213 (2013). doi: 10.1093/scan/nst101. 8. E.l. Altschuler et al., Person see, person do: human cortical electrophysiological correlates of monkey see monkey do cells. Poster Session Presented at the 27th Annual Meeting of the Society for Neuroscience, New Orleans, LA, (1997). 9. S.D. Muthukumaraswamy, B.W. Johnson, Primary motor cortex activation during action observation revealed by wavelet analysis of the eeg. Clinical Neurophysiology 115, 1760-1766 (2004). doi: 10.1016/j.clinph.2004.03.004. 10. J.A. Pineda, B.Z. Allison, A. Vankov, The effects of self-movement, observation, and imagination on/spl mu/rhythms and readiness potentials (rp’s): toward a brain-computer interface (bci). IEEE Transactions on Rehabilitation Engineering 8, 219-222 (2000). doi: 10.1109/86.847822. 11. V. Gallese, A. Goldman, Mirror neurons and the simulation theory of mindreading. Trends in Cognitive Sciences 2, 493-501 (1998). doi: 10.1016/S13646613(98)01262-5. 12. L. Carr, et al., Neural mechanisms of empathy in humans: a relay from neural systems for imitation to limbic areas. Proceedings of the National Academy of Sciences of the United States of America 100, 5497-5502 (2003). doi: 10.1073/ pnas.0935845100. 13. E. Fombonne, The epidemiology of autism: a review. Psychological Medicine 29, 769-786 (1999). 14. V.S. Ramachandran, Mirror neurons and imitation learning as the driving force behind “the great leap forward” in human evolution. Edge, (2000). 15. L.M. Oberman, V.S. Ramachandran, The simulating social mind: the role of the mirror neuron system and simulation in the social and communicative deficits of autism spectrum disorders. Psychological Bulletin 133, 310-327 (2007). doi: 10.1037/0033-2909.133.2.310. 16. L.M. Oberman et al., EEG evidence for mirror neuron dysfunction in autism spectrum disorders. Cognitive Brain Research 24, 190-198 (2005). doi: 10.1016/j. cogbrainres.2005.01.014. 17. G. Pfurtscheller et al., Short lived brain state after cued motor imagery in naive subjects. European Journal of Neuroscience 28, 1419-1426 (2008). doi: 10.1111/j.1460-9568.2008.06441.x. 18. A. Perry et al., “Feeling” the pain of those who are different from us: modulation of eeg in the mu/alpha range. Cognitive, Affective, & Behavioral Neuroscience 10, 493-504 (2008). doi: 10.3758/CABN.10.4.493. 19. A.N. Walker, T.D. Barry, S.H. Bader, Therapist and parent ratings of changes in adaptive social skills following a summer treatment camp for children with autism spectrum disorders: a preliminary study. Child Youth Care Forum 39, 305-322 (2010). 20. G. Rizzolatti, M. Fabbri-Destro, Mirror neurons: from discovery to autism. Experimental Brain Research 200, 223-237 (2010). doi: 10.1007/s00221-0092002-3. 21. H.J. Gastaut, J. Bert, EEG changes during cinematographic presentation; moving picture activation of the eeg. Electroencephalography and Clinical Neurophysiology 6, 433-444 (1954). 22. L.M. Oberman, V.S. Ramachandran, J.A. Pineda, Modulation of mu suppression in children with autism spectrum disorders in response to familiar or unfamiliar stimuli: the mirror neuron hypothesis. Neuropsychologia 46, 1558-1565 (2008). doi: 10.1016/j.neuropsychologia.2008.01.010. 23. S. Baron-Cohen et al., Talent in autism: hyper-systemizing, hyper-attention to detail and sensory hypersensitivity. Philosophical Transactions of the Royal Society B: Biological Sciences 364, 1377-1383 (2009). doi: 10.1098/rstb.2008.0337. 24. R. Raymaekers, R. Wiersema, H. Roeyers, EEG study of the mirror neuron system in children with high functioning autism. Brain Research 1304, 113-121 (2009). doi: 10.1016/j.brainres.2009.09.068. 25. L. Braadbaart, J.H. Williams, G.D. Waiter, Do mirror neuron areas mediate mu rhythm suppression during imitation and action observation? International Journal of Psychophysiology 89, 99-105 (2013). doi: 10.1016/j.ijpsycho.2013.05.019. 26. J.M. Kilner et al., Evidence of mirror neurons in human inferior frontal gyrus. Journal of Neuroscience 29, 10153-10159 (2009). doi: 10.1523/JNEUROSCI.2668-09.2009. 27. N.N. Oosterhof et al., Surface-based information mapping reveals crossmodal vision–action representations in human parietal and occipitotemporal cortex. Journal of Neurophysiology 104, 1077-1089 (2010). doi: 10.1152/jn.00326.2010. 28. Y.T. Fan et al., Unbroken mirror neurons in autism spectrum disorders. Journal of Child Psychology and Psychiatry 51, 981-988 (2010). doi: 10.1111/j.14697610.2010.02269.x.

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Prognostic Value of Neutrophil to Lymphocyte Ratio in Determining Coronary Artery Disease Severity and Adverse Outcomes Haarika Korlipara ’191, Puja Parikh, MD1, Allen Jeremias, MD2, Javed Butler, MD1, Luis Gruberg, MD1 1 Stony Brook University Heart Institute 2 St. Francis Hospital Heart Center

Abstract Atherosclerosis is an inflammatory process that directly causes coronary artery disease (CAD). In this study, inflammatory cells such as neutrophils and lymphocytes were assessed as potential predictors of clinical outcomes, specifically cardiovascular death. The prognostic value of white blood cell profiles in determining in-hospital and long-term mortality and coronary artery disease severity in ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) patients undergoing percutaneous coronary intervention (PCI) was evaluated. This is a retrospective review of 808 patients with a diagnostic of STEMI and NSTEMI. Baseline white blood cell counts , including neutrophils, lymphocytes, and monocyte absolute counts, were analyzed using an automated blood cell counter upon admission. White blood cell counts among 408 patients (50.5%) who had STEMI were compared to 400 patients (49.5%) who had NSTEMI. Furthermore, each group was subdivided into living and deceased. It was observed that patients who had died in hospital and at five years had significantly higher neutrophil to lymphocyte ratio (NLR) values on admission, regardless of the type of myocardial infarction. Using univariate analyses, age, lymphocytes, and NLR on admission appeared to be strongly associated with long-term mortality, but after controlling for other risk factors through multivariate analysis, NLR on admission did not remain an independent predictor of mortality. This study demonstrates that patients with an increased NLR have increased in-hospital and five-year mortality rates. Although NLR was not an independent predictor of mortality after controlling for other risk factors, it appeared additive to conventional risk factors when evaluating the patient’s risk for mortality and cardiac events.

Introduction Cardiovascular disease (CVD) is the leading cause of mortality in men and women of every major ethnic group in the United States and in the western society (1). Conventional risk factors for CVD include diabetes mellitus, hypertension, hyperlipidemia, chronic kidney disease, and smoking status (2). Recent data has shown that inflammation may play a key role in the pathogenesis of atherosclerotic cardiovascular disease. The role and source of inflammation in CVD is not completely understood, but it is thought to have an important part in the initiation and progression of atherosclerosis (3). Since atherosclerosis is a direct cause of CVD and an inflammatory process, inflammatory biomarkers and inflammatory cells such as neutrophils and lymphocytes are being assessed as potential predictors of clinical outcomes and cardiovascular death. The neutrophil to lymphocyte ratio (NLR) is a combination of two independent markers of inflammation: lymphocytes as a marker of the regulatory pathway and neutrophils as a marker of the ongoing non-specific inflammation. Previous studies have shown that NLR may be a better predictor of cardiovascular events in patients with coronary artery disease compared to the white blood cell count or neutrophil count alone (2, 3, 4). The objective of this study was to evaluate whether NLR is an independent predictor of outcomes in patients diagnosed with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). AMI is the clinical term used to define a heart attack while PCI is a nonsurgical procedure that aims to improve overall blood flow to the heart by opening up narrowed or blocked coronary arteries. Methods Patient population The data of 1,102 consecutive adult patients who were admitted to the institution with a diagnosis of an AMI and underwent revascularization by PCI between January 1, 2007 and December 31, 2008 was reviewed. Data

28

with complete white blood cell counts on admission and prior to discharge were available for 808 patients that comprised the sample. The patients’ baseline clinical and angiographic characteristics were analyzed in conjunction with laboratory data. Death or alive status was ascertained from social security numbers after five years to identify whether these patients had died during this time period. For death records with only death of year recorded, and if their admission date was earlier than July 1st of that year, July 1st of the corresponding year was used as their dates of death. Otherwise, if an admission date was later than July 1st, then their discharge dates were used as their dates of death. July 1st, 2014 was used as the last follow-up date for all patients that were still alive. Overall survival was defined as the time from date of admission to last follow-up or death, whichever occurred first. Separate analysis was done according to the type of myocardial infarction: ST-segment elevation myocardial infarction (STEMI) and non ST-segment elevation myocardial infarction (NSTEMI). The primary endpoint of the study was all-cause mortality. Mortality rates were assessed in-hospital, at one and five years. These data were collected by the Division of Cardiology as mandated by law by the New York State Department of Health for quality assurance purposes; therefore, informed consent was not obtained. Waiver of consent for the conduction of the study was obtained from the Institutional Review Board. Laboratory Tests The patient population’s medical history, physical examination and coronary intervention were performed at a tertiary care facility. All patients had complete baseline white blood cell count and subtype including neutrophils, lymphocytes, and monocytes. Absolute counts were analyzed using an automated blood cell counter (Colter LH) upon admission and prior to discharge as per routine clinical practice. The neutrophil to lymphocyte ratio (NLR) was calculated by dividing the neutrophil count by the lymphocyte count.

Statistical Analysis Data were summarized using descriptive statistics. Continuous variables were presented as mean ( standard deviation) and categorical variables by frequency (%). Univariate analyses were performed to compare characteristics between the living patients and deceased patients. Two sample t-tests were conducted between frequencies of categorical variables, as well as independent groups t-tests between means of the continuous variables. The chronological trend of outcomes was compared between the various NLR’s. A Univariate Cox proportional hazard regression model was built to study relationship between confounding factors and overall survival, with estimated hazard ratios and their 95% confidence intervals reported. For categorical variables, a HR (hazard ratio) >1 means that category has more death risk than the reference category. For a continuous variable, a HR>1 means for every unit of increase in the variable, the death risk also increases. Any risk factors with a p-value < 0.1 in the univariate regression models, such as MI type, gender, diabetes mellitus, and NLR on admission, were further considered in the multivariable Cox proportional hazard regression model. The P-value was based on Wald test. Statistical significance was set at 0.05 and analysis was done using SAS 9.3 (SAS Institute, Inc., Cary, NC).   Alive n=642

Deceased n=166

P-value

Age

61.1±13

66.0±14

<0.0001

Male gender (%)

468 (72.9%)

106 (63.9%)

0.03

Female gender (%)

174 (27.1%)

60 (36.1%)

0.03

Active smoker (%)

149 (23.2%)

36 (21.7%)

0.51

Hypertension (%)

138 (21.5%)

48 (28.9%)

0.05

Diabetes (%)

172 (26.8%)

56 (33.9%)

0.08

Atrial fibrillation (%) Chronic kidney disease (%) Normal body mass index (%) Positive family history (%)

30 (4.7%)

1 4 (8.4%)

0.08

37 (5.8%)

15 (9.1%)

0.16

114 (17.8%)

45 (27.1%)

<0.0001

78 (12.2%)

15 (9.0%)

0.26

Myocardial infarction type

acteristics of the patients, according to their five-year survival status. There were significant differences between the two groups; patients that survived were usually younger, with a higher rate of male patients and lower rate of conventional risk factors. As expected, in-hospital mortality rates were higher in STEMI patients compared to NSTEMI patients (p=0.004), whereas NSTEMI patients seemed to have increased one- year mortality (p=0.5) and five-year mortality rates (p=0.001) (Figure 1).

Figure 1: Mortality STEMI vs. NSTEMI

The average NLR on admission in patients that survived was 5.24 with an IQR of 5.5, whereas the average NLR was 6.31 with an IQR of 5.8 in deceased patients (Table 2). The difference in NLR between dead and alive patients was statistically significant (p=0.033).

Alive

Deceased P-value

n=642

n=166

White blood cells

10.5±3.4

10.5±3.8

0.87

Neutrophils

7.48±3.1

7.78±3.4

0.31

Lymphocytes

1.95±1.02

1.65±0.81

<0.0001

Monocytes

0.74±0.46

0.80±0.45

0.13

ST-elevation (%)

334 (52.0%)

74 (44.9%)

0.12

Non ST-elevation (%)

Platelets

230±75

233±91

0.70

308 (48.0%)

92 (55.2%)

0.12

NLR

5.24±5.5

6.31±5.8

0.03

S/P Myocardial infarction (%)

21 (3.3%)

10 (6.0%)

0.11

S/P Percutaneous coronary intervention (%)

135 (21.0%)

36 (21.8%)

0.84

S/P Coronary bypass graft surgery (%)

81 (12.6%)

26 (15.8%)

0.30

Left ventricular ejection fraction (%)

49.7±12.9

48.8±13.2

0.51

Table 2: Laboratory values on admission

Table 1: Baseline clinical characteristics.

Results Between January 1, 2007 and December 31, 2008, a total of 1,102 consecutive patients were admitted to the institution with a diagnosis of an AMI (STEMI and NSTEMI) and underwent PCI. Data with complete white blood cell counts on admission and prior to discharge was available for 808 patients that comprised the study sample. Table 1 shows the clinical char-

Similarly, when the NLR in 408 STEMI patients (50.4%) were compared to the 400 NSTEMI patients (49.5%), a higher NLR was observed in patients who died compared to those who survived (Table 3). However, when comparing the NLR between deceased patients with STEMI and NSTEMI, no significant difference was seen in the NLR on admission (p = 0.99) or on discharge (p = 0.98). Based on a univariate proportional hazard regression model, categorical variables including MI type, gender, body mass index category, hypertension, diabetes mellitus, and chronic kidney disease were found to be predictors of mortality (Table 4). Furthermore, age, lymphocyte count, and NLR on admission are continuous variables that were also found to be predictors of mortality, as shown in Table 5. However, when conducting multivariate analysis, NLR on admission was not an independent predictor of mortality (p = 0.20), whereas body mass index, MI category, and age were independent predictors (Table 6) (Figure 2).

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STEMI

Variable

pvalue

NSTEMI

All (n=408)

Alive (n=334)

Deceased (n=74)

p-value

All (n=400)

Alive (n=308)

Deceased (n=92)

p-value

Admission NLR

5.76±5.03

5.44±4.87

7.21±5.53

0.003

4.8±6.0

4.1±3.7

7.22±9.8

<0.001

0.993

Discharge NLR

4.04±3.75

3.49±2.00

6.31±7.03

<0.0001

4.51±4.6

3.91±1.97

6.33±7.84

<0.0001

0.984

Table 3: Neutrophil to lymphocyte ratio: STEMI vs. NSTEMI

Variable Myocardial infarction Gender Smoking status Alcohol status BMI category Family History Hypertension Diabetes mellitus Chronic kidney disease Previous PCI Previous MI Previous CABG Atrial Fibrillation

Category STEMI vs NSTEMI Female vs Male Yes vs No Unknown vs No Yes vs No Unknown vs No Underweight vs Normal Overweight vs Normal Obese vs Normal Yes vs No Unknown vs No Yes vs No Yes vs No Yes vs No Yes vs No Yes vs No Yes vs No Yes vs No

Hazard Ratio 0.664 1.389 0.861 0.939 0.987 0.995 2.92 0.694 0.651 0.536 0.863 1.385 1.387 1.859 1.17 1.648 1.255 1.581

95% CI 0.51-0.87 1.06-1.82 0.53-1.39 0.61-1.45 0.63-1.55 0.71-1.39 1.63-5.24 0.49-0.98 0.47-0.91 0.32-0.91 0.64-1.16 1.05-1.84 1.05-1.83 1.24-2.80 0.86-1.60 0.98-2.78 0.88-1.80 1.00-2.50

p-value 0.003 0.02

4

0.79 0.99

Discussion The role of inflammatory markers in cardiovascular diseases has been studied extensively in the past, as inflammatory markers have been shown to correlate with CVD and outcomes (5). There are limited data on the value of NLR to predict outcomes/mortality of patients admitted with an acute myocardial infarction.   Patients with an acute myocardial infarction NLR were significantly higher on admission and at discharge in those patients that died during their in-hospital stay and also during their five-year follow up. However, NLR was not an independent predictor of mortality after controlling for other risk factors, but instead appeared additive to conventional risk factors when evaluating the patient’s risk for mortality and cardiac events. Neutrophils and lymphocytes are two types of white blood cells in-

Variable Myocardial infarction type Gender BMI category

<0.0001 0.07 0.02 0.02 0.003 0.32 0.06 0.22 0.05

Table 4: Estimates of hazard ratios and corresponding 95% confidence intervals for categorical variables based on univariate proportional hazard regression model 4, p-value is based on Wald Test from

Family History Hypertension Diabetes Mellitus Chronic Kidney Disease Previous MI Atrial Fibrillation Age NLR at admission

Category STEMI vs NSTEMI Female vs Male Underweight vs Normal Obese vs Normal Overweight vs Normal Yes vs No Unknown vs No Yes vs No Yes vs No Yes vs No Yes vs No Yes vs No -

volved in defending the body from infectious diseases. More specifically, neutrophils are the body’s primary defense against bacterial infection and physiological stress, and lymphocytes are a part of immunological reactions as they are the source of serum immunoglobulins and cellular immune response. Both play a significant role in acute coronary events, such as myocardial infarction and in stable coronary artery disease. (4). Low lymphocyte counts correlate with CAD complications in patients with atherosclerosis (3). Also, low lymphocyte count has been associated with mechanical complications such as left ventricular free wall rupture or the development of acute mitral regurgitation following an acute myocardial infarction (6). Similarly, there have been studies showing a positive correlation between elevated neutrophil levels and increased incidence of heart failure and long-term mortality (2). A variety of proteolytic enzymes, such

Hazard Ratio 0.922 1.122 2.545 0.693 0.689 0.669 1.119 1.398 1.233 1.043 1.324 1.317 1.018 1.014

95% CI 0.67-1.27 0.80-1.58 1.21-5.35 0.46-1.04 0.46-1.04 0.36-1.23 0.71-1.76 0.90-2.17 0.88-1.73 0.60-1.80 0.66-2.66 0.75-2.32 1.01-1.03 0.99-1.04

p-value 0.62 0.51

6

0.0023 0.26 0.14 0.23 0.88 0.43 0.34 0.008 0.20

Table 6: Estimated hazard ratios and corresponding 95% confidence intervals for variables based on multivariable cox proportional hazard ratio model 6,p-value is based on Wald-test from multivariate Cox proportional hazard regression model.

univariate proportional hazard rgression model

Label

Hazard Ratio

95% CI

p-value

Age

1.031

1.021-1.041

<0.0001

Ejection fraction

0.996

0.984-1.009

0.55

White blood cells

0.998

0.979-1.016

0.80

Neutrophils

1.027

0.979-1.077

0.27

0.7

0.576-0.852

0.0004

Monocytes

1.197

0.957-1.496

0.12

Platelet count

1.001

0.999-1.002

0.39

Total count

0.998

0.995-1.001

0.25

Vessels intervened

1.106

0.85-1.439

0.45

NLR at admission

1.021

1.003-1.041

0.02

Drop in NLR

1.003

0.968-1.038

0.89

Lymphocytes

5

Hazard Ratio Smaller

Hazard Ratio Bigger

Table 5: Estimates of hazard ratio and its 95% confidence interval for continuous variables based on univariate proportional hazard regression model 5,p-value is based on Wald-test from univariate proportional hazard regression model.

Figure 2: Forest plot of hazard ratios for variables

30

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as myeloperoxidase, are released by activated neutrophils in response to tissue injury and they may have a critical role in the healing and remodeling of the left ventricle after an acute myocardial infarction (7). Elevated neutrophil levels usually coincide with low lymphocyte counts. Hence, the differential white blood cell count (ratio of neutrophils to lymphocytes) may be a predictor of individuals at risk for future events. The NLR is a combination of two independent markers of inflammation, where neutrophils are a marker of the ongoing non-specific inflammation and lymphocytes are a marker of the regulatory pathway (8). Specifically, high neutrophil count has been associated with increased cardiac events, whereas low lymphocyte count has been associated with worse clinical outcomes (9, 10). The association between the NLR and clinical outcomes has been observed in patients with ischemic heart disease without acute myocardial infarctions, in patients with acute coronary syndromes, and in patients undergoing PCI (3). Previous studies have shown that a NLR >4.7 as a cut-off value was associated with increased all-cause mortality in NSTEMI patients and a similar value was reported by Horne and colleagues in patients with stable coronary artery disease (10, 11). However, in STEMI patients a value >5.44 has been associated with a fourfold risk of death (3). A phenomenon known as coronary no-reflow is also associated with an increased mortality in patients undergoing PCI (12). No-reflow is the failure to normalize coronary flow and myocardial perfusion in patients presenting with STEMI. Studies have previously suggested a correlation between NLR and no-reflow in patients undergoing primary PCI. Another recent study reported that an NLR ratio above 7.5 is an independent predictor of mortality within one year and severe no-reflow development (12). They also determined age, serum creatinine, and glucose levels to be independent predictors for in-hospital and 1-year mortality (12). Other studies, which examined the relationship between NLR and no-reflow reported lower cutoff values due to differences in patient populations and methodology (13). In conjunction however, most previous literature agrees that elevated NLR in STEMI patients treated with PCI correlated with increased no-reflow development and mortality within one year. There were several limitations in this retrospective study because it was conducted in a single tertiary hospital with a limited number of patients. Patients that died prior to a second blood draw were excluded from the analysis and their inclusion may have changed the results. The generalizability of these results is still a matter of debate. Follow-up was per-

31

formed using social security records and may not accurately account for all deaths. Furthermore, the cause of death was not ascertained and therefore, causality cannot be proven. The population sample was also predominantly Caucasian, therefore, these conclusions may not be generalized for other ethnic groups. Conclusion In conclusion, acute myocardial infarction (NSTEMI and STEMI) patients undergoing PCI, patients with an increased NLR on admission will have increased in-hospital and 5-year mortality rates. NLR is not an independent predictor of mortality, after controlling for other risk factors. However, because it is an easily available blood test and seems additive to conventional risk factors and commonly used biomarkers in predicting mortality, differential WBC count (NLR) at admission may still be useful for cardiac risk stratification in patients undergoing PCI. Nevertheless, its value must be confirmed in future analyses and studies. References 1. A.S. Go, et al., Heart disease and stroke statistics—2013 update: a report from the american heart association. Circulation (2013). doi: 10.1161/CIR.0b013e31828124ad. 2. Y. Arbel, et al., Neutrophil/lymphocyte ratio is related to the severity of coronary artery disease and clinical outcome in patients undergoing angiography. Atherosclerosis (2012). doi: 10.1016/j. atherosclerosis.2012.09.009. 3. J.J. Park, et al., Prognostic value of neutrophil to lymphocyte ratio in patients presenting with st-elevation myocardial infarction undergoing primary percutaneous coronary intervention. The American Journal of Cardiology (2013). doi: 10.1016/j.amjcard.2012.11.012. 4. Y. Solak, et al., Neutrophil to lymphocyte ratio independently predicts cardiovascular events in patients with chronic kidney disease. PubMed (2013). doi: 10.1016/j.amjcard.2012.11.012 5. T. Bhat, et al., Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. National Center for Biotechnology Information (2013). doi: 10.1586/erc.12.159. 6. A. Widmer, et al., Mechanical complications after myocardial infarction reliably predicted using C-reactive protein levels and lymphocytopenia. Cardiology (2003). 7. S. Baldus, et al., Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation (2003). 8. J. Nuñez, et al., Usefulness of the neutrophil to lymphocyte ratio in predicting long-term mortality in st segment elevation myocardial infarction. Am J Cardiol (2008). doi: 10.1016/j. amjcard.2007.11.004 9. S. Chia, et al., Association of leukocyte and neutrophil counts with infarct size, left ventricular function and outcomes after percutaneous coronary intervention for st-elevation myocardial infarction. Am J Cardiol (2009). doi: 10.1016/j.amjcard.2008.09.085. 10. B.D. Horne, et al., Which white blood cell subtypes predict increased cardiovascular risk?. J Am Coll Cardiol (2005). 11. B. Azab, et al., Usefulness of neutrophil to lymphocyte ratio in predicting short- and long-term mortality after non-ST- elevation myocardial infarction. Am J. Cardio (2010). doi: 10.1016/j. amjcard.2010.03.062. 12. K. Soylu, et al., The relationship of coronary flow to neutrophil/ lymphocyte ratio in patients undergoing primary percutaneous coronary intervention. J Thorac Dis (2013). doi: 10.3978/j. issn.2072-1439.2013.05.13. 13. M. Akpek, et al., Relation of neutrophil/lymphocyte ratio to coronary flow to in-hospital major adverse cardiac events in patients with st-elevated myocardial infarction undergoing primary coronary intervention. Am J Cardiol (2012). doi: 10.1016/j.amjcard.2012.04.041.


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