A potential link between the appendix and Parkinson's Disease

A new study (literally published today) has found a potential link between the appendix and Parkinson's Disease. Many people (myself included) have long considered the appendix as a useless vestigial appendage, but previous research has already indicated that the appendix plays a role in our immune system. Previous research has also hypothesized that the symptoms of Parkinson's might begin in the gut. 

With this knowledge, researchers analyzed data from approximately 1.7 million Swedish men and women followed up to 52 years to determine if the appendix played any part in this early symptom development. They found that individuals who had their appendix removed had a 19.3% lower incidence of Parkinson's Disease compared to the general population. For individuals who had an appendectomy, the prevalence of Parkinson's was 16.9% lower than the general population. Going even further, Killinger and his team found that individuals who had an appendectomy and still developed Parkinson's Disease developed the symptoms of the disease later than individuals who had not had an appendectomy.

Without trying to get too in depth (which is hard because this research is blowing my mind currently) one major characteristic of Parkinson's Disease is the development of what are known as Lewy bodies, aggregated clumps of a protein called α-synuclein. Researchers found that the appendix of healthy individuals in their study contained these same clumped α-synuclein protein products characteristic of Parkinson's Disease. Based on all of these findings, his team has hypothesized that the appendix actually contains pathogenic forms of α-synuclein and they suspect that the removal of the appendix is what caused the decrease in prevalence and incidence of Parkinson's in their study.

Designer Drugs and Neuron Transplants: Potential Treatments for Pathologic Chronic Pruritus

Writing this post made me itchy, read with caution.

Itches are a curious and strange phenomenon. While conducting observational research on zoo animals, I noticed many of them displaying similar scratching behaviors to what humans have when we feel a sudden, random itch. After thinking for a while, I wondered if perhaps non-pathologic itches maintained some physiological or evolutionary purpose, and thought maybe idiopathic, non-pathologic itches are one way that our nervous systems might perform “maintenance” on our nerve function and our bodies, or bring our attention to parts of our body. But beyond this little idea is the real issue of pathologic itching, or pruritus, in clinical settings.

Pathologic itching is currently a major clinical challenge that severely decreases the quality of life for around 1/5th of patients suffering from various systemic disorders, including ESRD, chronic liver disease, atopic dermatitis, MS, and neuropathy (Garibyan, Rheingold, & Lerner, 2013) (Callahan and Lio, 2012). This is an issue because the presence of co-morbid pruritus is linked to an increase in mortality rates compared to non-itching populations with these disorders (Garibyan, Rheingold, & Lerner, 2013). According to a paper by Callahan and Lio, pathologic itching can be classified as either acute or chronic. Currently, antihistamine treatments are effective in treating acute itching, working to counteract histamine-mediated responses transmitted by C-fibers in the skin. The real issue lies in chronic itching, which anti-histamines (and practically all other treatments) are ineffective in treating long term. There is very little understanding of the physiological mechanisms of chronic pruritus, but a recent study may shine a light in the right direction. Researchers Kanehisa et Al. found that when a population of mice was low in BHLBH5 transcription factor, they displayed increased chronic itch-behavior phenotypes. This suggests that chronic itch may result from a loss of SDH (neuronal circuit) inhibitory interneurons caused by this deficiency. In this study, these mice populations received transplants of embryonic γ-aminobutyric acid (GABA)-ergic precursor neurons that expressed hM3Dq receptors into their SDH. Using DREADD designer drug technology, the researchers used CNO, or clozapine-N-oxide, to activate the hM3Dq receptors in the neuronal cells, enabling a release of GABA that suppressed the itching behaviors in the mice. These is still much unknown about how chronic pruritus works, but this research is a strong step in understanding how pathologic itching works and may lead to potential treatments. Further research is needed before any treatments can be brought into clinical settings.

Cited Sources:

Callahan, S. W., & Lio, P. A. (2012). Current Therapies and Approaches to the Treatment of Chronic Itch. Current Medical Literature: Dermatology, 17(2), 29–40. Retrieved from http://dml.regis.edu/login?url=http://search.ebscohost.com/login.aspx?direct=true&db=aph&AN=77950126&site=ehost-live&scope=site

Garibyan, L., Rheingold, C. G., & Lerner, E. A. (2013). Understanding the pathophysiology of itch. Dermatologic therapy, 26(2), 84-91.

Kanehisa, K., Shiratori-Hayashi, M., Koga, K., Tozaki-Saitoh, H., Kohro, Y., Takamori, K., & Tsuda, M. (2017). Specific activation of inhibitory interneurons in the spinal dorsal horn suppresses repetitive scratching in mouse models of chronic itch. Journal of Dermatological Science, 88(2), 251-254. doi:10.1016/j.jdermsci.2017.05.017

Obesity: Omega 6 vs Omega 3

A lot of what I intend to focus on in my career is obesity especially when it comes to the preventable and complex disorders that arise from obesity. We have heard time and time again about the great benefits of omega 3 supplementation but many people have probably never heard of omega 6.  According to Artemis P. Simopoulos the ratio of omega 6 to omega 3 has grown exponentially in the last few decades from 1:1 to 20:1 today. The only places where a smaller ratio can be found is amongst Alaskan Natives and those with diets that rely on wild caught fish. According to the article (link below) this increased ratio is due to how we have changed from family to industrial farming and the western diet. Due to industrial feeding practices we have decreased the natural amount of omega 3 fatty acids found in products such as meat, eggs, and fish. The western diet has also increased the amount of processed grains we take in which are heavily packed with omega 6 fatty acids. This is important because omega 6 fatty acids are known to increase arachidonic acid (AA) synthesis which leads to prostaglandins. As we have learned in physiology, these prostaglandins are proinflammatory which does not align well with obesity and cardiovascular issues that are strongly associated with inflammation. These prostaglandins form omega 6 have been found to decrease the browning of fat due to their proinflammatory characteristics that lead to fat being much harder to burn. According to the article (link below) our diets are far too low in omega 3 fatty acids compared to our ancestors. Omega 3 fatty acids are great at browning fat and hence the argument for supplementation.

With all this stated how do we go about fixing this inflated ratio and reducing obesity? Unfortunately, it is not as easy as supplementing your diet with omega 3 fatty acids. Although this will help we have to decrease the omega 6 intake in order for us to even have a chance at balancing out this ratio. This is only one aspect of the obesity epidemic and there are many others but, we can all take the first step in reducing obesity by getting active and reducing processed food intake.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808858/

Death Cafes and Death Doulas in Denver

Two years ago, Colorado voters passed the End-of-Life Options Act or Medical Aid in Dying. The "death positive movement" in Colorado has spurred the creation of more than 6,700 "death cafes" where people can gather to talk positively about death and end-of-life wishes. The emergence of "death doulas" has also come around. Who knew?

The law lays out specific requirements for patients, health care providers, and medical facilities who opt-in. However, the public and private discourse on the matter has created a tangle of barriers for those who wish to take advantage of the act. For example, not all hospitals and pharmacies participate in prescribing or stocking these medications and patients may need to travel extensively to find a willing physician to assist them. Furthermore, most insurances including federal aid (Medicaid and Medicare) do not cover these medical-aided death costs. 

In order to opt-in, patients must be Colorado residents who are terminally ill with six months or less to live and who are over the age of eighteen. They must exhibit the mental capacity to make an informed decision, act voluntarily, and physically be able to self-administer and ingest the lethal medications. Every requirement must be documented and confirmed by a physician who must agree to prescribe the medication. The physician must also refer the patient to another physician who must (1) agree with the diagnosis and prognosis and (2) corroborate that the patient is mentally capable, acting voluntarily, and is not being coerced.

As future practicing physicians, it is imperative we keep a pulse on the community around us and the evolving ethics of what defines care. Another difficult skill is learning where we stand and how we can communicate/ defend our positions.

Dr. Rhee, shared with me his commentary on the matter (posted here). He is a great example of how important it is for us to professionally create platforms that can inform the direction of medicine. What do you guys think? Agree or disagree, if people don't voice their platforms, medicine as a whole becomes less diverse. 

Just like voting, if you care, you should share. Don't you think?

*To throw some physiology in here, a common drug used is secobarbital, a barbiturate that acts as a CNS depressant. The drug is an agonist to GABA receptors and at high concentrations, they also inhibit Ca2++ in the neruotransmission pathway. Too much of this? Trouble aka death. 

References:

Rhee, J. Y., Callaghan, K. A., Allen, P., Stahl, A., Brown, M. T., Tsoi, A., ... & Dumitru, A. M. G. (2017). A Medical Student Perspective on Physician-Assisted Suicide. Chest, 152(3), 475-477.

Cordell, K. & Koehler, L., (2018 Oct) “The Art of Dying Well” 5280 Magazine. https://www.5280.com/2018/09/the-art-of-dying-well/

I can see said the blind mouse! (and hopefully person in the future)

Retinitis Pigmentosa is a genetic disorder that causes degeneration of the photoreceptor cells in the retina. Due to this degeneration the symptoms often start out with night blindness because the rods are affected first and then eventually become completely blind when the rods and cones both deteriorate (Busskamp et al., 2012). There is currently no cure for retinitis pigmentosa, but optogenetics shows potential as a cure.

Optogenetics is the practice of artificially introducing light sensitive proteins into specific target cells to make them sensitive to light. There are two main light sensitive proteins that are currently used in research: channelrhodopsin-2 found in a type of algae and halorhodopsin found in a haloalkaliphilic archaeon. Channelrhodopsin-2 is a gated channel that depolarizes in response to light, thus activating a cell. Halorhodopsin is a chloride pump that inhibits the cell upon light activation. These two proteins can be isolated and then expressed in target tissues. (Busskamp et al., 2012)

Previous trials for using optogenetics for Retinitis Pigmentosa have used mice that lack functional rods and cones and humans post-mortem. Trials with mice have shown restoration of retinal function by introducing a viral vector containing channelrhodopsin-2 through intravitreal injection. After channelrhodsin-2 was expressed, retinal ganglion cells showed ON responses and the brains of the mice showed visual responses. Furthermore, researchers have found that expressing halorhodopsin in the human retina post mortem resulted in hyper-polarization of the cones when stimulated with light indicating that these proteins could be used in humans. (Busskamp et al., 2012)

While optogenetics shows a promising future for treating some forms of blindness, there is not currently enough human research to advocate for its use in humans yet. However, just this year the first clinical trials for the use of optogenetics for retinitis pigmentosa were approved. In the study, subjects will receive an optogenetic treatment that gives light sensitivity to the ganglion cells and will then be given eyewear that amplifies the light signal to activate these cells (Shaberman, 2018). The future is looking BRIGHT! (pun intended)

Busskamp, V., Picaud, S., Sahel, J.A., and Roska, B. (2012). Optogenetic therapy for retinitis pigmentosa. Gene Therapy 19, 169–175.

Shaberman, Ben. (2018) Clinical Trial to Launch for System Combining Optogenetics and Eyewear - Eye on the Cure.

Beer calories count too!

In Human Physiology, we recently discussed calorie intake and recommended amounts for healthy individuals. A typical 75Kg male was found to need about 2,000 calories daily.

As I thought about my diet, I had to consider the fact that I do work at a brewery and get some of my calories come from beer. Surprise surprise! So do many young people. Based on a data brief of U.S. men and women, on average people aged 20-39 years old consume almost double the amount of calories from alcoholic beverages than those aged 60 years old and older. So what?

Dietary guidelines suggest that these calories need to be taken into consideration when an individual is trying to maintain a healthy caloric intake. A survey of U.S. binge drinkers reports some pretty crazy results. The average of drinking habits for participants was about four drinks on binge nights and about four nights of this per 30 day period. It was found that on these heavy drinking nights, about 1,000 calories are attributed to alcoholic beverages. That is half…half of the amount of calories recommended for a healthy 75kg male!

This becomes a problem quickly if an individual is trying to manage weight. From class, we discussed how important it is to match your intake of calories to your output in energy in order to maintain a healthy body composition. With most people our age not taking into account alcoholic beverages, we continue to progress our national obesity problem, which we know can cause a whole host of physiological issues.

Under the basis of beneficence, I wanted to share this information with my fellow classmates so that we can all keep healthy lifestyles and realize that EVERYTHING we put into our bodies should be taken into account. You all rock, and come have a beer with me at 10 Barrel (and then lets work out together after).

References:

Adam E. Barry, Shawn D. Whiteman & Jennifer Cremeens-Matthews (2016) Alcohol-Attributable Calories Consumed as a Result of Binge Drinking: A National Survey of Drinkers in the United States, Substance Use & Misuse, 51:7, 932-936, DOI: 10.3109/10826084.2016.1155610

Nielsen SJ, Kit BK, Fakhouri T, Ogden CL. Calories consumed from alcoholic beverages by U.S. adults, 2007–2010. NCHS data brief, no 110. Hyattsville, MD: National Center for Health Statistics. 2012.

Mindfulness Meditation counteracts Chronic Stress

Stress is bad for us. How many times have you heard that one? There are numerous studies out there about how your brain changes with stress. The HPA-axis is a driver for our stress levels, and has been shown to be responsible for increasing glucocorticoids such as cortisol. The amygdala is a structure in the brain responsible for sending signals of stress, fear, or other emotions to the hypothalamus and other parts of the brain. Under chronic stress, the amygdala structurally changes to have more connections to the HPA-axis and also increases in size. This study wanted to look at how mindfulness meditation affects stress response. They had two groups, one that was assigned a 3-day mindfulness meditation training, and the other a 3-day relaxation training without a mindfulness component. None of their subjects had any previous experience with mindfulness meditation. They found that the mindfulness meditation group had reduced amygdala sizes compared to the relaxation group, as well as lower glucocorticoid levels in hair follicles, immediately after the experiment, and also at a four month follow-up. Something still being heavily researched is how mindfulness meditation can cause structural changes in the brain, thus far all being the exact opposite of the structural changes caused by chronic stress. It still isn’t understood why or how mindfulness meditation causes these things, but study after study has shown that mindfulness meditation reverses many negative changes in the brain caused my stress.

References
Taren, A. A., et al. (2014). Mindfulness meditation training alters stress-related amygdala resting
state functional connectivity: A randomized controlled trial. Social Cognitive and Affective Neuroscience, 10(12), 1758–1768.

Were you destined to be an alcoholic?

            My brothers best friend from elementary school went through a traumatic accident when he was young. He was the oldest of his siblings, he was 10 when his parents had passed away leaving behind him, his 8-year-old brother and their 3 year old sister. When the accident occurred, there was an outpour of support to their family although their extended family themselves had started to fall apart. Growing up with him, my oldest brother notice he had to stand up and take a large role in parenting his younger siblings at such a young age. My brother said he was never calm and or happy, constantly in a state of worry and stress thinking of his siblings rather than himself. As they continued to get older, my brother noticed changes in him physiologically from when he was a young and happy kid. He started turning to drinking and drugs. This story peaked my interest in the effects of child stress into young adult or adulthood. 

            According to Early childhood stress exposure, reward pathways, and adult decision making, there is a large correlation between chronic stress in early childhood and a higher risk for behavioral problems in adulthood (Birn, et al., 2017). They used Monetary Incentive Delay (MID) task which activates the brains reward circuit along with Cambirdge Gambling Task (CGT) another risk taking decision making test. Both of these allowed for the understanding that the higher exposure to stress at a young age, the higher risk in decision making people are to make as they get into adulthood. This study allowed for me to see insight into why my brothers friend could’ve been exposed to poor risky behavior as he grew up compared to those with low stress exposure as a child. Along with this, a study on childhood stress and mother-rearing, (similar to growing up without parental guidance and relationship), in monkeys made the correlation to alcohol consumption as well. The higher ethanol drinking was greater in monkeys that were nursery reared. This was shown through their cerebrospinal fluid (CSF), which is related to behavioral changes, increasing. The levels of 5-hydroxyindoleacetic acid (5-HIAA) in the CSF are directly related as well allowing us to examine these measurements in the brain to predict behavioral outcomes, the larger activity in the CSF and 5-HIAA tissues, the more likely to have alcohol consumption. 

References:

Birn, R. M., Roeber, B. J., & Pollak, S. D. (2017). Early childhood stress exposure, reward pathways, and adult decision making. Proceedings of the National Academy of Sciences, 114(51), 13549-13554. doi:10.1073/pnas.1708791114

Huggins, K. N., Mathews, T. A., Locke, J. L., Szeliga, K. T., Friedman, D. P., Bennett, A. J., & Jones, S. R. (2012). Effects of early life stress on drinking and serotonin system activity in rhesus macaques: 5-hydroxyindoleacetic acid in cerebrospinal fluid predicts brain tissue levels. Alcohol, 46(4), 371–376. https://doi-org.dml.regis.edu/10.1016/j.alcohol.2011.11.003

Does that nap make a difference?

This past year I have been considering much more about the importance of early development and napping after becoming an aunt, and about the circumstances of circadian misalignment because I work a nightshift job. My night job’s shifts are from midnight to eight in the morning the following day, so my circadian cycle is probably enduring the consequences of misalignment. I am curious as to whether naps can possibly make up for this circadian misalignment. It also interests me to analyze the differences in toddlers who nap compared to toddlers who do not nap.

Individuals with later dim light melatonin onsets are more likely to have later bedtimes, midsleep times, and morning wake times. Sleep/wakefulness occurring at inappropriate circadian phases results in a circadian misalignment. This factor contributes to the increased risk of disease, work-related accidents, and poor school performance. Very little is known about the processes of DLMO and the consequences of circadian misalignment in early childhood. Previous findings provide evidence of maturational circadian shifts which likely occur as a result of biological processes changing (pubertal development) and relevant social and environmental time cues. Sleep disturbances is early-childhood persists into school-age years and is associated with attentional problems and predicts the onset of emotional/cognitive problems in adolescence.

Akacem (2015) hypothesized that napping toddlers would have later sleep timing, longer sleep onset latencies, and shorter nighttime sleep durations than those who did not nap, that napping in comparison to non-napping toddlers would have later circadian phases, and that nap frequency, duration, and timing would be positively correlated with melatonin onset. The researchers also explored the associations between napping and phase differences.  

Children required to stop napping may not be able to adapt to associated increases in homeostatic load and may suffer from daytime sleepiness, poor daytime functioning, or parasomnias like night terrors. The time of life at which children stop napping varies across cultures. Napping ending occurs on average at a later age in the United States and varies across ethnicities. The results indicate that napping in toddlerhood is not only associated with evening sleep timing, shorter nighttime sleep duration, and longer sleep onset latencies, but also later timing of the circadian clock.

The limitations of this study were that the sample size was small (20 toddlers) and the researchers only used healthy good sleeping toddlers, so the findings may not be reflective of the general population.

Reference: Akacem, Lameese D., et al. “The Timing of the Circadian Clock and Sleep Differ between Napping and Non-Napping Toddlers.” Plos One, vol. 10, no. 4, 2015, doi:10.1371/journal.pone.0125181.

Monsters Inside Mice: Malaria Parasites Rely on Host's Circadian Rhythms

Humans rely on their circadian rhythms for numerous processes and functions, but so do the organisms living within humans. Parasites depend on daily (circadian) rhythms to maximize fitness within their hosts. A host’s circadian rhythms are responsible for the timing of rhythms in parasite development and are a crucial component in parasite replication. A better understanding of the regulation of parasites’ rhythms and their effect on fitness could dramatically influence the severity and circulation of numerous parasitic diseases. 

In this study, the researchers analyzed how hosts’ circadian rhythms affected the replication of malaria parasites in mice. They disturbed the normal feeding patterns of mice by 12 hours to “desynchronize the host’s peripheral oscillators from the central, light-entrained oscillator in the brain and their rhythmic outputs” (Prior et. al, 2018). This caused the malaria parasites to have an inverted circadian rhythm within mice fed during the day compared to mice fed at night. 

Their results found that the mice’s feeding times and metabolisms determined the parasites’ rhythms more significantly than the time of day. The parasite rhythms were also found to depend on the hosts’ blood glucose levels. Their research asserts that the malaria parasites actively control their own developmental rhythms based on the hosts’ feeding time and dynamic circadian rhythm. 

This research in host-parasite-vector coevolution has various implications in areas of bioscience, pathology, microbiology, and more. This research is particularly revealing of many parasites’ abilities to employ effective strategies within hosts, even adapting to their host’s circadian rhythm, to enhance their survival and reproductive efficacy. Perhaps, future studies and medical treatments could find a way to exploit this unique relationship between hosts and parasites to effectively reduce the severity and transmission of parasitic diseases, including malaria, which is a leading cause of death and disease in many countries.

Prior, K. F., Veen, D. R., O’Donnell, A. J., Cumnock, K., Schneider, D., Pain, A., . . . Reece, S. E. (2018, February). Retrieved from 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843352/

Acute physical exercise in humans enhances reconsolidation of emotional memories.

There has been an increasing amount of evidence that suggest that memory can be manipulated due to environmental and pharmacological means. We know that memory recall is activated through retrieval. However, because your memory can be altered you may strengthening a memory of something that didn't actually happen. Physical exercise has been proven to act as an important contributor to memory reactivation. This study focused primarily on the effect of exercise when trying to retrieve traumatic memories. 

The study entailed 54 undergraduate students watching a traumatic film depicting the aftermath of a highway car crash (Keyan, 2017). Two days later participants were asked to do one of the following which included: a) 20-25 min of increment cycling with a memory reactivation induction (reactivation/exercise), b) 20-25 min of mild cycling (reactivation/no exercise), c) 20-25 min of incremental cycling but with no memory reactivation ( no reactivation /exercise). Saliva samples were then taken from each individual, both before and after the activity and memory recall occurred . A questionnaire related to declarative and intrusive memory was completed, two days after the memory reactivation. 

The results showed that the participants that participated in the reactivation/exercise demonstrated that they could recall much more details in comparison to the other participants. These same participants also proved to show and increase amount of cortisol, which was expected in terms of memory recall. Which proved that exercise does help with memory recall and reactivation in terms of traumatic events. 

This could potentially help with other types of memory retrieval, which could potentially lead to understanding if exercise does in fact help with memory recall. Or if it's the idea of doing an activity such as a cross word puzzle, in order to help with memory retrieval?

The

Keyan, Dharani, and Richard A. Bryant. “Acute Physical Exercise in Humans Enhances Reconsolidation of Emotional Memories.” Psychoneuroendocrinology, vol. 86, Dec. 2017, pp. 144–151. EBSCOhost, doi:10.1016/j.psyneuen.2017.09.019.