Resveratrol and the Eye

Within the last decade, the discovery of red wine as a proponent for increased cardiovascular health has been prominent in science-related media . The compound in question is called “Resveratrol,” and its ability to lead the consumer to a longer, healthier life has been controversial due to lack of reproducible results of Dr. David Sinclair, molecular biologist at Harvard Medical School and founder of Sirtis (SIRT research).

Upon clarification by more recent research, Resveratrol is thought to boost activity of the enzyme SIRT1, in conjunction with a bulky hydrophobic amino acid residue, to de-acetylate proteins involved in aging and metabolism. Resveratrol acts on a wide variety of proteins, and the full extents of its effects are still to be determined.

More recently, researchers have been exploring the use of resveratrol in other areas of health, namely in the reduction of ocular hypertension (OHTN). Systemic, topical, periocular, or intravitreal use of steroids (as therapy for ailments of the eye) can lead to onset of OHTN, which can then lead to glaucoma. Current therapies are not effective in reducing intra-occular pressure (IOP) and often cause negative effects systemically and locally, so there has been a push to develop better treatment options for patients suffering from OHTN. A recent study has successfully used resveratrol to reduce IOP in rats.

The experiment was two-part: IOP reduction by resveratrol in normotensive rats, and IOP reduction by resveratrol in steroid-induced OHTN rats. Both the normotensive and OHTN groups tested a vehicle (control) solution in one eye. A vehicle solution contains everything that the drug solution contains, except the drug; in this case, the vehicle contained 3% polyvinylpyrrole (PVP), which was used to dissolve the resveratrol in the drug solution. The drug solution contained trans-resveratrol, which is the more biologically active conformation of the compound (as compared to cis-resveratrol).

The study showed that application of trans-resveratrol was effective in reducing IOP in both the normotensive and steroid-induced OHTN rats. In both sets of rats, 0.2% trans-resveratrol achieved peak IOP reduction: 15.1% reduction in the normotensive rats and 25.5% reduction in the OHTN rats. This study lends possibility to new treatments for OHTN, but also to untapped uses of resveratrol in the eye. I will actually be exploring one of these uses in an Opthalmology lab at the Anschutz Medical Campus—I’ll be testing the effect of resveratrol on dry eye in a murine model.

How Getting Fit Can Protect Against Stress-Induced Depression

          The idea that exercise can help reduce stress and mood is widely known. The most common known reason is the fact that endorphins are released during exercise which elevates mood. New research done by the Karolinska Institutet in Sweden has found that exercise can help protect the brain against stress-induced depression through an avenue not previously explored. Exercise is used clinically as part of treatment protocol for depression and this research helps provide reasoning as to why it is so important.   

          With exercise, a protein called PGC-1a1 increases in skeletal muscle causing an increase in enzymes known as KATs, (Karolinska Instiutet 2014). These enzymes break down a substance, kynurenine, that is in high levels of people with mental illness and is also formed during stress, (Karolinska Instiutet 2014). These harmful substances are no longer able to cross the blood brain barrier, creating a protective effect against depression. The research also showed that high levels of PGC-1a1 in mice allowed for a preventative measure against stress, (Karolinska Instiutet 2014).  When mice that had high levels of PGC-1a1 were injected with high levels of the stress related substance, kynurenine, they did not display any depressive behavior, (Karolinska Instiutet 2014).     This is in contrast to mice who did not have high levels of PGC-1a1 who did display depressive behavior when given an injection of kynurenine, (Karolinska Instiutet 2014). This is important in warding off depression during times of high stress.    

          Medications could be made which mimic the effects of exercise on the skeletal muscle, decreasing stress byproducts that are known to damage the brain, (Aguedelo et al. 2014). Most pharmaceutical treatments for depression involve targeting chemicals in the brain where as this new research could facilitate new advancements in medications that target the skeletal muscle. Creating a medication with an alternative pathway in treating depression could open the door to protecting the brain from depression. 

          Furthermore, it is also important to recognize that this research has provided an additional reason as to why exercise is important as a daily habit and as clinical treatment. There are many people who have bad side effects due to medications for treating depression. While depression treatment protocols need to be advised by a medical professional, the new information showing the mechanism behind exercise and mental health illnesses provide further evidence that exercise should be included in treatment. 

Citations:

Karolinska Institutet. 2014 September 25. How physical exercise protects the brain from stress-induced depression. Science Daily. [Internet]. [cited on 2014 September 28]. Available from:

http://www.sciencedaily.com/releases/2014/09/140925131345.htm

Agudelo LZ, et al. 2014 September 25. Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression. PubMed. [Internet].  [cited 2014 September 28]. Available from:  http://www.ncbi.nlm.nih.gov/pubmed/?term=Skeletal+Muscle+PGC-1%CE%B11+Modulates+Kynurenine+Metabolism+and+Mediates+Resilience+to+Stress-Induced+Depression

Traditional Asian diet can reduce risk of Type-2 Diabetes

http://asa100.com/#/far-away-places/more-southeast-asia/southeast_asia038

Diabetes is becoming more prevalent in people of Asian heritage, increasing from approximately 2.5% in 1994 to 9.7% in present day. In 2011, approximately 50% of the diagnosed cases of type-2 diabetes were patients of Asian and Western Pacific heritage (Hsu et al., 2014). One hypothesis for this increase is Westernization, particularly in diet. The traditional Asian diet is high in fiber and low in fat which may lead to a decrease in insulin resistance because the demand to metabolize sugar is not there. Transitioning to a Westernized diet, one that is high in fat and low in fiber, increases the risk for type-2 diabetes and cardiovascular disease more in Asians than any other ethnicity (Hsu et al., 2014). There appears to be a correlation between Westernization and type-2 diabetes in Asia because prevalence of diagnosis increases in urban areas where a Western diet is more common compared to rural areas (Hsu et al., 2014).

A study conducted by the Joslin Diabetes Center at Harvard Medical School in 2014, compared what they established as a traditional Asian diet (55-70% carbohydrates, 33g/day of fiber, 15% fat and 20% animal protein) to a traditional Western diet (50% carbohydrates, 10-12g/day of fiber, 34% fat, and 60% animal protein) and administered it to 24 Asian Americans and 16 Caucasian Americans with a history of diabetes for 16 weeks (8 weeks on each diet). The study found that participants on the Asian diet had reduced their LDL cholesterol levels and increased insulin sensitivity among both Asian and Caucasian Americans (Bright, 2014). In contrast, the Western diet impaired insulin sensitivity in Asian American participants but not in Caucasian American participants. In addition, all participants on the western diet experienced some form of weight gain and increased BMI (Hsu et al., 2014).

This data supports the hypothesis that Westernization of the Asian diet (most likely due to an increase in fast food chains in Asia) may be a leading factor in the increase of type-2 diabetes being seen in patients of Asian heritage. Further studies should be conducted including a similar study with a larger sample size and inclusion of other ethnicities to observe the effects of a western diet.

References:

Bright, J. (2014, September 18). Lower Diabetes Risk on Asian Diet: Asian-Americans reduced their insulin resistance while eating traditional foods. Retrieved September 28, 2014, from http://hms.harvard.edu/news/lower-diabetes-risk-asian-diet?utm_source=twitter&utm_medium=social&utm_campaign=hms-twitter-general

Hsu, W., et al. (2014). Improvement of insulin sensitivity by isoenergy high carbohydrate traditional asian diet: a randomized controlled pilot feasibility study. PLOS ONE, 9(9). Retrieved September 28, 2014. doi: 10.1371/journal.pone.0106851

Are you on your cell phone, using your laptop, and watching television at the same time? Multitasking with media devices may not be great for the brain.

Today’s society is all about technology and innovation.  It is not uncommon to see people consumed by smart phones, tablets, and etc. in many areas of their life.  Often we hear how technology is ruining social interactions because everything seems so impersonal.  What about how technology affects the individual anatomically and physiologically?

Two researchers Kep Kee Loh and Dr. Ryota Kanai from the University of Sussex located in the UK examined the differences in brain anatomy between individuals who use only one media device infrequently and individuals who use multiple media devices simultaneously and often.  Media devices were limited to cell phones, computers, t.v, and printed publications (Paddock 2014).  A total of 75 participated in surveys relating to their media device usage and a functional MRI scan (fMRI).

The fMRI revealed differences in gray matter within the anterior cingulate cortex.  This area of the brain is known to play a role in cognition, emotion, and a wide array of physiological functions.  Users who used multiple media devices often had lower amounts of gray matter in direct comparison to those who use one media device infrequently.  Previous studies looked at the link between extensive media device consumption and the appearance of depression and anxiety concluding that there is a link (Paddock 2014).  This recent study strengthens the previous finding due to the presence of decreased gray matter levels associated with regular media device multi-tasking individuals (Paddock 2014).   

So what is the big deal?  The brain is known to change whether that is in size of an area or re-mapping areas in response to our environment.  Is the over consumption of media devices leading to a decrease in the gray matter of the anterior cingulate cortex? The study mentioned the need to evaluate whether individuals with previously established lower gray matter in the anterior cingulate cortex are more likely to use multiple media devices simultaneously (Paddock 2014). In other words are changes in the brain leading to increased media device usage rather than media device usage leading to changes in the brain?

Technology does have many advantages but as with many things, overconsumption could have several affects.  Suppose overconsumption consistently correlates with drastic negative effects, is it too late to change how technology is incorporated into our daily lives?

Source:

Paddock, Catharine. 2014 Sept 26. "Multitasking with media devices linked to brain changes." Medical News Today [Internet]. MediLexicon, Intl. [cited 28 Sep 2014]. Available from:  <http://www.medicalnewstoday.com/articles/283059.php>    

 

The new toxin: Amino Acids "The Silent Fire"

When you think of a toxin or poison, what do you think of? Anthrax? Ricin? Venom? How about a amino acid? Twenty-one years ago this month, Christopher McCandless died due to being poisoned by an amino acid, beta-N-oxalyl-L-alpha-beta diaminopropionic acid, which is a structural analogue to glutamate.

Who is Christopher McCandless? He was the inspiration for the book "Into the Wild," and for many years was thought to have died from strictly starvation. In one of his last journal entries, Mr McCandles speaks of feeling weak and ill and blames is on the "Pot[ato] seed" he was ingesting. This fact was originally discredited as plant toxins are often come in the forms of an alkaloid. The seeds of the wild potato, Hedysarum alpinum, were tested no toxic alkaloids were found.

So, no alkaloid no toxin right? Wrong. What Hedysarum alpinum does have is .394 percent beta-N-oxalyl-L-alpha-beta diaminopropionic acid, more commonly known as ODAP, by weight. This compound affects each individual differently, however, the group at highest risk is physically active young males with a limited diet. Christopher unknowingly sealed his own fate by being a young male, living meagerly off the land, being physically active (hiking, hunting, etc) and ingesting a plant that was thought to be non- toxic.

However, this compound is not new. Records show that the Nazi Concentration camp Vapniarca experimented with a similar amino acid of the wild grass pea. The seeds were made into bread and fed to the inmates. The prisoners over time developed paralysis from over stimulation of neurons. Sadly, once the condition started, it could not be reversed. This condition is referred to as "neurolathyrism", or more commonly, “lathyrism.”

Although what happened to Mr. McCandless is very sad, it is a good reminder of how much we do not yet understand about the world around us.

References/Further readings:
http://www.christophermccandless.info/Ronald-Hamilton/ronald-hamilton-intothewild1.html
http://www.scribd.com/doc/166341536/The-Silent-Fire
http://www.newyorker.com/books/page-turner/how-chris-mccandless-died

Looking for a Cure: HIV and Timothy Ray Brown

Image from Davidson College

            With an unclear origin, the human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) is a complex mystery that science has been unable to solve.  Of the millions affected with AIDS in the United States, approximately 1 in 6 is unaware of their infection and is consequently not seeking any treatment for it.  This is particularly relevant because 1 out of every 4 infections is amongst those ages 13 to 24.  Since its discovery in the 1980s, AIDS has claimed approximately 636,000 lives in the US alone. 

            A new piece of the puzzle may have been discovered.  Timothy Ray Brown, otherwise known as the Berlin patient, has rid himself of the HIV.  After living for 11 years on antiretroviral drugs (ARD), Brown was diagnosed with acute myeloid leukemia.  When the chemotherapy did not work, Brown received a bone marrow transplant.  His immune system was irradiated and his doctor sought out a bone marrow donor who had a rare mutation that led to a mutated receptor on white blood cells that would normally lead to infection.  After 7 years, Brown has only trace amounts of viral DNA that is unable to replicate in its host.

            Because of Brown, three possible factors have emerged in the scientific HIV community that could lead to a HIV cure.  The first is due to the irradiation of his immune system, the second is the mutated WBC receptor, and the third is the possibility that Brown’s new immune system destroyed his original HIV-infected immune system.  

            A study conducted by Mavigner et. al, was focused on the bone marrow transplant aspect of Brown’s cure.  This research group took three rhesus monkeys and extracted stem cells.  They then infected the monkeys with Simian/Human Immunodeficiency Virus (SHIV).  The monkeys were given ARDs for a several weeks.  They were then given myeloablative total body radiation, which reduced their CD4+ helper T-Cells by 94-99%.  The monkeys were then given stem cell engraftment.  Unlike Brown, these monkeys were tested to have rapid rebound of the SHIV.  Although this study was unable to cure the monkeys of SHIV, it does lead to a new idea about Brown’s cure.  That the role of the graft versus host plays a key role in finding a cure HIV and AIDS.

When is the Male Birth Control Revolution Coming?

Image: Spermatozoa

Source: WebMD

About fifty or so years ago, oral contraception became a ground breaking tool for facilitating a generational women’s rights movement while effectively turning the social landscape of the 1960s upside-down. With fifty years or so behind us, female reproductive technologies have been produced and tweaked to near perfection. With a plethora of female contraception options available (i.e. pills, injections, hormonal patches, IUDs), it appears befitting to use the English metaphorical idiom of there being a pink elephant in the room in regards to male contraceptive technologies. Currently, options for male contraception include condoms and invasive vasectomies, which are more often difficult to reverse. So, with all the reproductive technologies in existence for female contraception, why does the viability of various forms of male contraception remain so elusive?  

The invention of male contraceptive technologies is complicated when it comes to the male reproductive system since the testes possess dual functionality. The testes are involved in maintaining appropriate body homeostasis while serving as the primary site for spermatogenesis.  A recent article from the Bioorganic and Chemistry Letters journal has shown promising insight into this particular social issue which may result in a lateral shift effectively leading to more male reproductive responsibility in the contraception arena.

One such study includes investigating the capabilities of vitamin A metabolism. The process of meiosis, in both males and females, requires retinoic acid (a byproduct of vitamin A) in order to take place. A study conducted in mice with a retinoic acid inhibitory drug effectively rendered mice unable to produce viable, functioning sperm. Essentially, this inhibitory drug blocks the enzyme from turning vitamin A into retinoic acid, thus, interfering with sperm formation. Another such study, demonstrated hormonal control of spermatogenesis through testosterone and progestin. This involves the down regulation of pituitary gland releasing of FSH and LH resulting in the impairment of spermatogenesis. Yet, another clinical study focuses on the Na+/K+ ATPase pumps on the α4 polypeptide flagella subunits of the spermatid. Drug specificity makes these pumps an ideal target for reversible male contraception. 

Additionally, there are numerous clinical studies involving transdermal patches, hormonal/non-hormonal pathways, and injections. It’s crucial that the development of these pharmaceutical contraceptives be reversible and safe in order to appeal to the marketable male population. The progress of such technologies would allow for men to have more control over their reproductive responsibilities while simultaneously minimizing the polar gap that exists between men and women regarding contraceptive options.

Is cannabis a performance enhancing substance?

Michael Phelps was caught on camera smoking marijuana in 2009 (nytimes):

http://sports.espn.go.com/oly/swimming/news/story?id=3876804

As a result of Michael Phelps's unfortunately public transgression he lost a lucrative contract with Kellogg and USA Swimming banned him from competition for 3 months (nytimes). The United States Anti Doping Agency (USADA) did not move to ban Phelps from competition or punish him in any manner.

Penalties for marijuana as issued by USADA range from 3 months – 1 year dependent upon the severity of the infraction. (usatoday)

USADA policy regarding marijuana are as follows:

“Currently USADA will only consider TUE applications for legal, FDA-approved uses of THC, such as Dronabinol to manage some of the symptoms of AIDS, or to treat nausea and vomiting caused by cancer chemotherapy.”  -USADA

Penalties for performance enhancing substances such as blood doping agent erythropoietin (EPO) are lengthy to permanent bans from competition with associated fines. EPO is an agent that signals for the increased production of erythrocytes, increasing the oxygen carrying capacity of an athlete’s blood.  The reasoning behind the banning of a pharmacological agent that alter the architecture of the blood is self-evident.

Lance Armstrong was stripped of his seven Tour de France titles and issued a lifetime ban from the sport of cycling for knowingly blood doping using EPO (nytimes).

If an agent existed that could pharmacologically enhance pulmonary function would USADA treat it as a performance enhancing substance? One could imagine that if an athlete had the ability to enhance their pulmonary function they would gain an unfair advantage.

Recent research into the pulmonary function has described just such a substance. Spirometry measurements taken from 5115 adults found that vital capacity and forced expiratory volume in 1 second (FEV1) were higher for marijuana smokers than controls (Pletcher). FEV1, which is a measure of the speed at which one can expel air thus measuring resistance through the airway, was elevated in marijuana smokers as compared to controls until individuals were undertaking more than 23 uses/month or had exceeded 32 joint years of lifetime use. The greatest positive effect marijuana consumption had on FEV-1 was a 60ml enhancement at 10 joint years and a 40ml increase at 18 uses/month.

Consider that! The maximum enhancement of marijuana use of FEV1 was found in those using 18 times/month. The people who were smoking more days than not had the best FEV1s.

Even more compelling evidence to marijuana’s pulmonary enhancing qualities is the dose dependent effect on vital capacity. Vital capacity was found to be positively correlated to increased exposure in a linear fashion.

There was no dosage found at which consumption reflected a decline in vital capacity. The more people consumed the higher their vital capacity.

This study and many others quantified the dose dependent, precipitous, and linear decline in vital capacity and FEV-1 of tobacco smokers. The smoking of marijuana clearly has very different effects on pulmonary function than tobacco.

Pletcher et al. presents concrete evidence for marijuana’s sustained performance enhancing effects. USADA would be well advised to reassess its stance on the use of marijuana. Cyclists, Olympic runners, and swimmers could potentially use marijuana with the intention of enhancing their pulmonary function.

If an athlete were intending to use marijuana for the purpose of pulmonary enhancement they would be heartened to learn that not only have the long term pulmonary enhancements of cannabis consumption been elucidated by Pletcher et al., the transient, short-term effects of smoking marijuana have been quantified as well (Tertault et al.). Eleven out of twelve studies found short-term bronchodilation as measured by transient increases in FEV1 (Tertault et al.). These increases were found to be anywhere from 150ml-250ml (Tertault et al.). These values represent roughly a 5% enhancement of FEV1.

These short-term transient effects could provide athletes with an unfair advantage during training. If an athlete were to consume marijuana immediately prior to an aerobic threshold workout they may be able to go harder, and faster during that workout due to significant bronchodilation and increased oxygen delivery. If an athlete were to regularly smoke marijuana prior to strenuous aerobic training they may be able to train at an intensity that would otherwise unattainable for them. Consistent, abnormally intense aerobic training has the potential to provide athletes with an unfair pharmacologically induced advantage. USADA needs to evaluate the research that is available on cannabis consumption and pulmonary function in order to bring their marijuana policy in line with the regulations they have surrounding other performance enhancing substances.

Pletcher MJ, Vittinghoff E, Kalhan R, Richman J, Safford M, Sidney S, Lin F, Kertesz S. Association Between Marijuana Exposure and Pulmonary Function over 20 years The Coronary Artery Risk Development in Young Adults (CARDIA) Study. Journal of the American Medical Association 307(2): 173-181, Jan 2012

http://www.nytimes.com/2009/02/06/sports/othersports/06phelps.html

http://www.usatoday.com/story/sports/olympics/2013/07/17/ross-rebagliati-olympics-marijuana-drug-testing/2528283/

http://www.nytimes.com/2014/04/23/sports/cycling/a-double-standard-in-doping-punishments.html

Tashkin DP. Effects of marijuana smoking on the lung. Annals of the American Thoracic Society 10(3): 239-247, Jun 2013

Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA.  Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Archives of Internal Medicine 167(3): 221-228, Feb 2007

Why use fluoride?

            Fluoride is found in water as well as in many foods. Throughout the day minerals are added to and lost from our tooth’s enamel layer. When the tooth enamel is demineralized, bacteria and sugars in the mouth are usually the causes of the break down. A layer of plaque builds up on the teeth potentially leading to cavities. The reason we brush and floss our teeth is to get the plaque off of the surfaces of our teeth. Fluoride is a mineral that helps with remineralzation to the enamel layer. Other minerals such as calcium and phosphate also help in the remineralization process. When there is more breaking down of the minerals than building up, the enamel can become infected and lead to tooth decay.

            A recent study published in the 2012 Environment Health Perspectives found out that children’s IQs were lowering due to fluoride. Harvard researches suggest that the fluoride is affecting children’s neurodevelopment. They found that those who lived in high fluorinated areas had lower IQs then those living in low fluorinated areas. Researchers considered fluoride to be a toxin but they also noted that most of the elements we experience each day could also be considered toxins.

            In the 1950’s water fluorination was discovered by a significant decrease in dental infections. The Center for Disease Control said that fluoride was ranked in the “10 Greatest Achievements in Public Health of the 20^th Century.”Around 90 other health organizations regarded fluoride a very important mineral to prevent dental decay.

            Other studies conducted about fluoride stated that the exposure of fluoride in large amounts could cause fluorosis. Fluorosis is a discoloration and defect on the surface of the teeth. Teeth exposed to an excessive amount of fluoride are said to increase in the porosity of the enamel, potentially leading to erosion or the crumbling of teeth. Dental journals suggest that kids should not begin fluoride treatment until they are 8 years old. Kids are the main targets for fluorosis because they are growing and their permanent teeth are coming in.

            Due to these studies U.S. Public Health Services are decreasing the amount of fluoride in the water. Water bottle companies are also not putting fluoride in their water. The ADA suggests that infants should be fed formula with non-fluorinated water.

            There are many opinions out there discussing the pros and cons of using fluoride. Further evidence on the matter hasn’t been proven in determining if fluoride is a harmful mineral. Dental professions still believe in the continuation of fluoridation due to the number of people who have prevented dental decay as well as had less cavities and pain.