Limits of the Placebo Effect

I was going through some of our older posts ... figured our blog is a more educational way to procrastinate than Facebook ... and reread the posts about placebos. Recently, I read this absolutely outrageous article that took the placebo effect a step further. A few scientist wanted to see if patients' conditions improved, i.e. had the placebo effect, even if they were told they were taking pills with no active ingredient. Basically, the scientist gave one group of patients placebos and told them they were taking fake pills. The other group received no treatment.

Surprisingly enough, some patients showed improvements even when told about the fake pills, and did much better than the no treatment patients. A caveat: The study is quite small. That said it still provides a great "proof-of-concept" and is definitely worth further investigation.

The article that gives new meaning to mind over matter:

http://www.guardian.co.uk/science/2010/dec/22/placebo-effect-patients-sham-drug

-Vinoo

Study Break

I figured we could all use a little study break from finals so I thought I would share this with everyone. I thought this was so awesome when I came across this the other day and immediately shared it with some of my other PSIO friends. After that I realized how much of a nerd I was. Anyways, enjoy this little break and check out the site below. Good luck with finals everyone and congratulations to all the graduates!

http://learn.genetics.utah.edu/content/begin/cells/scale/

More about resveratrol!

After reading the article about resveratrol and learning about its possible roles in the prevention of numerous pathologic processes from its cardio protective, anti-cancer, anti-oxidant, and anti-inflammatory properties, I was interested in looking more into the background of resveratrol and its content in foods.

In addition to the potential benefits mentioned above, recent studies on administration of resveratrol have also found it to extended lifespan in a number of species by altering gene expression in the heart, brain, and skeletal muscle, comparable to that induced by caloric restriction.

As for the resveratrol content in foods, below is a list of some foods with resveratrol:

Relating back to the article in class, for the daily resveratrol intake of the mice in the study to be equivalent to that to that of a human, which was 1,944mg/60kg person, one would have to consume approximately between 273-1,013L of red wine (global) or 7,477-19,4400cups of raw peanuts or 1,556-8,100cups of red grapes! This of course seems like a ridiculous amount because if anything, you’ll probably get alcohol poisoning from drinking too much wine before reaping any of the potential benefits of resveratrol. But as the paper mentioned there are commercial daily supplements that range from 50-2000mg of trans-resveratrol.

However, since resveratrol has only been mainly studied in animals, presently little is known about the effects of resveratrol in humans or the effective dose of resveratrol for chronic disease prevention in humans.

So I’m still not entirely convinced, and I definitely think the translatable effectiveness of resveratrol as potential therapeutic approach in humans is still questionable, how about you?

http://lpi.oregonstate.edu/infocenter/phytochemicals/resveratrol/#sources

http://www.createbalance.net/support/science/resveratrol_cancer_prevention.pdf

Potential personalized treatment to target inflammation?

This article talks about a new potential form of personalized therapy to target inflammation by mimicking the body’s natural mechanism of fighting inflammation. Microparticles are very small particles released by cells during inflammation. However, researchers at Barts and The London School of Medicine and Dentistry and Harvard Medical School have discovered certain microparticles that contain anti-inflammatory lipids that are beneficial to our health. These microparticles are precursors for compounds that stimulate the termination of inflammation and return the body to its normal balance.

Researchers are mimicking this natural communication process to produce new personalized delivery system for anti-inflammatory therapeutics based on natural human microparticles. Since these microparticles do not rely on synthetic biomaterials, they reduce potential toxicity. In this study, researchers used human neutrophil-derived MPs to construct novel nanoparticles containing anti-inflammatories asprin-triggered resolvin D1 and lipoxin A4 analog, and found dramatically reduced polymorphonuclear cell influx, enhanced wound healing, and protection against inflammation. These humanized nanoparticles termed nano-proresolving medicines may offer a new therapeutic approach that could have implications in a number of inflammatory diseases including cardiovascular diseases, arthritis and temporomandibular disorders.

L. V. Norling, M. Spite, R. Yang, R. J. Flower, M. Perretti, C. N. Serhan. Cutting Edge: Humanized Nano-Proresolving Medicines Mimic Inflammation-Resolution and Enhance Wound Healing. The Journal of Immunology, 2011

http://www.sciencedaily.com/releases/2011/04/110404111048.htm

Prevention... after the insult?

In multiple previous studies evaluated by this class and blog, I have been critical of research methods that involve the administration of a drug or other treatment option before introducing the disease agent or disease state, such as in subjecting mice to stroke. I felt that while those studies may have cast new light on certain fields as proofs of concept, their clinical applications were minimal. The Candelario-Jalil et al. paper gives an incredibly thorough example of an inflammatory process that is affected differently by drugs given 30 minutes previous to an incident versus the same drugs given 6 hours after a transient global cerebral ischemia.

The adverse effects of global cerebral ischemia are biphasic, with a marked hike in hippocampal prostaglandin E2 (PGE2) 2 hours after the insult and another notable jump in PEG2 levels 24-48 hours after the transient ischemia. It was fortuitous that this study included so many animals and was planned with so many factors accounted, with administration of COX-1 and COX-2 inhibitors either before or after the ischemic event and in different doses, because their findings were significantly different for each drug at the different times of treatment. COX-1 inhibitors were more effective given before the ischemic event, as COX-1 was shown to play a stronger role in the hours directly following ischemia. In gerbils given COX-1 inhibitor six hours after ischemia, there was little improvement compared to sham gerbils. In contrast, COX-2 inhibitors exhibited better protection for hippocampal CA1 neurons at the 24-48 hour point following ischemia.

Had this study not looked at two different treatment timelines, would we have concluded that COX-1 inhibitors are entirely more effective at treating transient ischemia than COX-2 inhibitors? On the same note, two labs looking at the same drugs but with different timelines could publish diametrically opposed papers if they failed to evaluate the full course of disease progression. All this forces me to wonder if much of the conflicting material published in the scientific community is because of the narrow scope of certain studies which are then assumed to have wider application.

Candelario-Jalil, Eduardo, Armando Gonzalez-Falcon, Michel Garcia-Cabrera, Dalia Alvarez, Said Al-Dalain, Gregorio Martinez, Olga Sonia Leon, and Joe E. Springer. "Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia." Journal of Neurochemistry. 2003, 86, 545-555.

A general PPAR-gamma diagram...

PPAR-gamma pathway

I included this pathway to give a visual of the PPAR-gamma pathway presented...

it includes cytokines presented in the "Dietary Aloe Improves Insulin Sensitivity via the Suppression of Obesity-induced Inflammation in Obese Mice"

Roflumilast for treating COPD?

The paper titled “Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials” was studying the effects of Roflumilast on a particular subset of COPD patients. Though the authors state this is a double blind study are honest about their conflict of interest, I feel that the selection criteria for patients may have been chosen based on who they thought would have the best outcome from treatment with this drug. The paper seemed to be a follow-up to their original study to try and prove significant results from the use of Roflumilast, which did not lend to its credibility. Overall, the authors had a large sample size showing that lung function tests were generally improved with the use of Roflumilast.

As they state in the paper, chronic obstructive pulmonary disease (COPD) is a lung disease. It is characterized by a shortness of breath, fatigue, chronic cough, and increased respiratory infections. There are two main forms: chronic bronchitis or emphysema. One of the leading risk factors is smoking, but there are other causes such as air pollution. There is not a cure, but people can treat the symptoms using an inhaler with either bronchodilators or steroids.

Roflumilast itself is a Phosphodiesterase-4 (PDE4) inhibitor. When PDE4 is inhibited, cyclic adenosine monophosphate (cAMP) is not broken down as readily in cells. Increased levels of intracellular cAMP help to suppress TNF-alpha, IL-2, and INF-gamma production. PDE4 inhibitors also lower cytokine production along with degranulation by neutrophils and inflammatory cell adhesion.

In this paper, they were studying the use of oral Roflumilast to treat COPD. However, most drugs currently in use to treat COPD are from inhalers, so as to directly contact the most affected area. Therefore, I think that in the future it would be really interesting to look at PDE4 inhibitors such as Roflumilast in an inhaler to treat COPD. In fact, some researchers are looking into non-steroidal anti-inflammatories that can be inhaled. A paper I found called “Inhaled non-steroidal anti-inflammatories for children and adults with bronchiectasis” looked at NSAIDs that can be inhaled. The results of this recent paper show a great deal of promise for using these inhaled NSAIDs in the treatment of different lung diseases such as bronchiectasis or COPD.

Anti-inflammatory Agents: Present and Future

This is an overview of the “Anti-inflammatory agents: Present and Future” paper similar to the handout that was given in class. Overall, the paper was somewhat repetitive and, as was mentioned in class, did not go into some of the serious issues associated with the use of some of these therapies.

-COX inhibitors:

• COX enzymes synthesize prostaglandins and thromboxanes, which participate in vasodilation, blood clotting, cell growth, and many other functions
• COX-1 is constitutive while COX-2 is inducible
• COX-2 inhibitors have decreased GI effects but increased cardiovascular effects

-Resolvins:

• Products of omega-3 fatty acid oxidation
• Lower infiltrating neutrophils and macrophages
• Decrease gene expression of TNF-alpha and IL-1beta

-Glucocorticoids:

• Suppress expression of cytokine-induced genes, T-cell growth factors, INF-gamma, NOX synthase, COX-2, and intracellular adhesion molecules
• Increase expression of anti-inflammatory molecules
• Chronic use is associated with organ toxicity

-Biologicals:

• Anti-cytokine therapies (block IL-1, TNF, IL-6, IL-12, IL-17, IL-18, or IL-23) are used to reduce inflammation by preventing responses such as T-cell activation
• Cytokines are more potent than hormones and can be produced by many cells
• Chemokines drive migration of immune cells while promoting angiogenesis, and can also be blocked to reduce inflammation
• Issue is innate immune response is important in defense against illness and cytokines can help with repair
• Synergistic action of cytokines means inhibiting only one is sufficient
• Effective at very low doses

-B cell depletion:

• Prevents antigen presenting and therefore T-cell activation

-Protease inhibitors:

• Proteases break down proteins and can activate cytokines
• Reduce inflammation by preventing proinflammatory cytokines from activating

-Small-molecule inhibitors of signal transduction:

• Kinases phosphorylate intracellular proteins to activate
• Example is to inhibit p38, which is important in cytokine, chemokine, COX-2 and NOX synthase production
• Tyrosine kinase inhibition reduces dendritic cell activation and proinflammatory cytokine production
• Possible renal or hepatic toxicity

-Statins:

• Reduce cholesterol levels
• Some work better than others in reducing inflammation
• Lower CRP and cardiovascular events were lowered
• Reduce cytokine production, adhesion molecules, and dendritic cell maturation
• Increase IL-10 production

-Histone Deacetylase inhibitors:

• Histone deacetylase maintains nuclear histones in deacetylated state to hold DNA
• Prevent transcription of certain genes and reduce production of cytokines
• Effective at very low doses

-Anti-coagulants and Thrombolytics:

• Activated protein C is the only approved therapy for sepsis
• Reduce cytokine production and endothelial activation by thrombin

-Activated Complement inhibitors:

• Reduce cytokine, chemokine, and adhesion molecule production

-PPARs (Peroxisome proliferator-activator receptors):

• Reduce expression of proinflammatory cytokines and adhesion molecules
• Used to treat type 2 diabetes
• Could increase cardiovascular events

-Prostaglandin (PGE) Agonists and Phosphodiesterase-4 (PDE-4) inhibitors:

• PGE2 is also immunosuppressive by inhibiting INF-gamma and IL-2
• Inhibitors of PDE-4 prevent breakdown of cAMP and are therefore anti-inflammatory
• Increased levels of cAMP lowers TNF-alpha

-Using small RNA molecules to downregulate gene expression holds promise

The paper “Anti-inflammatory Agents: Present and Future” stated the benefits of many treatments without listing the adverse effects. However, there can be serious side effects to using these various methods to treat inflammation. TGN1412 is a medication that binds to, and is a strong agonist for, the T-cells’ CD28 receptor. It was created with the intention of treating B cell chronic lymphocytic leukemia and rheumatoid arthritis. The disastrous Phase I clinical trial for this drug is an extreme example of the damage some of these therapies can cause. The clinical trials for this medication began in 2006, and were halted when many of the subjects had to be hospitalized with multiple organ dysfunction. These same effects were not seen in the pre-clinical trials on rabbits and monkeys, further proof that animal models do not accurately predict efficacy or safety in humans. Here is an article that I found about the clinical trials for this drug: http://www.i-sis.org.uk/LDTC.php

Anti-Inflammatory Agents

After class last week I was curious to the extent to which common anti-inflammatory drugs like Tylenol and Advil are taken by the general public. In one report produced by the FDA it was noted that over 100 million people consume products containing acetominophen annually, and that there are over 600 products that contain this substance on the market today. When I looked up Advil, I found that the sale of Advil generates 498 million dollars in revenue in a nine month period---that's a lot of anti-inflammatory power. While we were informed of the risks of taking these medications, I wonder to what extent are the majority of Tylenol and Advil users familiar with the product they pop everytime they have a headache. It seems to me like this would be a great area to introduce a placebo study.

NSAIDs and Antidepressants...

The study presented investigates how concurrent intake of antidepressants and anti-inflammatories modulate p11 levels in the body. p11 is a small regulatory protein of selective serotonin reuptake inhibitors (SSRIs). Past studies have linked low p11 levels to depressive like symptoms and higher levels of p11 to antidepressant activities. This was shown using p11 knockout mice and mice that were induced to express more p11.

In the context of the paper, they claim that p11 regulates some sertonin receptors by modulating their respective cell trafficking and localization in cell membranes. Doing such actions lead to different behaviour
The anti-depressants citralopram and fluoextin were shown to increase levels of p11 in mouse models. Coadministration of an NSAID with citralopram and fluoextine did not increase p11 levels.

Furthermore, the Tail suspension test (TST) and the forced swim test (FST) were administered to determine any change in depressive behavior in mice. Mice that were taking NSAIDs in addition to antidepressants scored more poorly than those that did not take NSAIDs.

The authors also investigated what cytokines are linked to increased levels of p11. TNF-a and IFN-g were injected into the frontal lobe of mice brain and western blot analysis revealed that mice injected with these cytokine yielded higher p11 levels compared to controls. This supports the idea that inflammation is involved with depression.

Based on the data, the authors feel that concurrent treatment of pain with NSAIDs and SSRI antidepressants minimizes the improvement of depressive symptoms.

Paper title: Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans

paper published online 4-25-11
link to paper: http://www.pnas.org.ezproxy2.library.arizona.edu/content/early/2011/04/20/1104836108.long

Revisiting the "Spicing Up" article...

The study investigated whether curcumin could be allosterically used to modulate HIV-1 (HIV-1P) and HIV-2 protease (HIV-2P) activity and (in vitro). They say that curcumin is a “modest inhibitor” of HIV protease but that complexing boron with curcumin increases inhibition by almost 10 fold.

Curcumin was complexed with boron in a variety of ways (see diagram) and each complex’s inhibitory activity was monitored. The researchers also investigated whether boron effects HIV-1P independently from curcumin and the results show that HIV-1P activity was not modulated.

So the article that we read in class last week advocated curcumin because it is all- natural. In the study that I just described the researchers acknowledge that curcumin’s activity is “modest” yet the “Spicing” study makes it seem as if curcumin in its natural form is a significant inhibitor. Clearly, in the study above curcumin is modified so the “spicing” authors (I think) poorly explicated the cited results and should have mentioned synthetic modifications of curcumin that may yield potential therapeutic benefits.

So, I would agree that Spicing up authors may have overhyped curcumin in some cases but I do think that curcumin consumption is a great herb that has a variety of useful purposes.

Sui, Z., Salto, R., Li, J., Craik, C., & Ortiz, . M. P. R. (January 01, 1993). Inhibition of the HIV-1 and HIV-2 proteases by curcumin and curcumin boron complexes. Bioorganic & Medicinal Chemistry, 1, 6, 415-22

The Strange Powers of the Placebo Effect

Placebos are powerful in that they can have real physical effects on the body without the risk of introducing foreign toxins that could have detrimental side-effects down the road. These physical effects can be attributed to the usually underestimated ability of the mind. The ability to influence physiological changes through the power of thought shouldn't be overlooked as a treatment for a variety of disease states including inflammation.

This is an interesting video I found that explains the placebo effect and really gets you thinking about how easily our brains can be manipulated to get the desired physiological response.

MENINGITIS

While I was researching online about anti-inflammation I came across Meningitis on the kids health website, a bacterial or viral disease. Meningitis is an inflammation of the meninges. Meninges cover the brain and spinal cord. Bacterial meningitis is very rare and can lead to death. Viral meningitis is less serious and more commonly seen. I have witnessed this disease twice in my life and have seen the viral and bacterial side affects. Meningitis is extremely serious with symptoms varying depending on the infection and the age of the person. The common symptoms include skin rashes, seizures, headache, photophobia, stiff neck, headache, irritability, lethargy, and fever. Viral meningitis being less serious can be treated at home by resting, getting enough fluids and over the counter pain medication. Bacterial meningitis being very serious is diagnosed by first giving an IV with antibiotics as soon as possible. Fluids may also be given. For inflammation reduction corticosteroids may be given depending on the cause. Wanting to know more about corticosteroids I proceeded to look them up on the mayo clinic website. These steroid hormones act as the hormones in the adrenal gland and are involved in many systems such as inflammation, carbohydrate metabolism, protein catabolism, immune response and stress response. The inflamed tissue around the brain can cause pressure within in the brain. Steroids reduce the inflammation causing the pressure to decrease. The sooner they are administered the faster they can work to reduce inflammation and improve chances of survival.
http://kidshealth.org/parent/infections/lung/meningitis.html#
http://www.mayoclinic.com/health/steroids/HQ01431

The Mind is an Amazing Healer

Acupuncture, bee stings, placebos: all treatment methods that are accepted by some and rejected by others. One common theme resonates throughout these types of treatments, and that is the power of believing in healing. Eastern cultures have been practicing spiritual healing for a very long time. The book "The Healing Power of the Mind" by a Tibetan Buddhist named Tulku Thondup Rinpoche explains some of the ideology of "awakening out inner wisdom." The main idea of the book is that when we hold onto the negative things that happen in our lives as well as the pain and suffering that comes with illness, we foster further pain and stress. However, when we open our mind to the warmth and sunlight all around us, we enable our body to release the pain and stress and begin to heal. According to "The Power of the Healing Mind," meditation is a technique that many western doctors have begun to adopt. There are quotations from several doctors:
Bernie Segal M.D., a surgeon and professor at Yale makes this statement: "It tends to lower and normalize blood pressure, pulse rate, and the levels of stress hormones in the blood."
Herbert Benson M.D. from Harvard states: "If you truly believe in your personal philosophy or religious faith-if you are committed mind, soul, and body to your world view-you may well be capable of achieving remarkable feats of mind and body that we may only speculate about."

While it would take a lot to convince our society as a whole that meditation can actually heal people, I feel that we should take it into consideration as a reasonable option. After all, before epidurals were available, women giving birth had to utilize meditation in order to get through the pain of childbirth. If it works for that, whose to say what other healing and protecting factors the mind may hold.

The Role of CD40 in Neuroinflammation

After going over the different factors that can lead to Alzheimer's Disease, I was interested in learning more about the role CD40 plays. The study, by Laporte et al, that I found looks at a transgenic mouse model that have an over-expressing tau phosphorylation, which leads to amyloid plaques and deposits. The study argues, if one genetically disrupts CD40, this will decrease cdk5 levels in mice, which will reduce tau phosphorylation. This is important, because this study alludes to that tau hyperphosphorylation is directly correlated with neuroinflammation, and that the dysregulation of cdk5 will lead to hyperphosphorylation of tau. The results of this study, looking to see if one disrupts CD40 will this decrease amyloid deposits, showed that by disrupting CD40 there is a relative loss of tau phosphorylation. So the study concludes by stating that, CD40 does not act directly on amyloid deposits, however there are inflammatory pathways, such as CD40, that have a direct effect on the phosphorylation of tau.

I thought this was a really good study and good article. It was very easy to understand what they were trying to do, and what their results were. Figure 3, which showed amyloid deposits in dystrophic neurites, was an excellent figure, it showed exactly what was going on, and pointed out where the amyloid deposits were. Overall, this was a good paper, I would be interested to see what you all thought of it.

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6SYR-4SSY8XV-1&_user=9555371&_coverDate=09%2F22%2F2008&_alid=1733205199&_rdoc=4&_fmt=high&_orig=search&_origin=search&_zone=rslt_list_item&_cdi=4841&_sort=r&_st=13&_docanchor=&view=c&_ct=10&_acct=C000055186&_version=1&_urlVersion=0&_userid=9555371&md5=51a840abea7981ff101fc887e3f726fc&searchtype=a

Placebos and Nocebos

Hey Everyone!

When I was reading Jeff’s blog I realized he brought up an excellent point when asking about placebos and if they actually demerit a treatment such as acupuncture. I thought it was an interesting question and decided to look up some information about placebos. According to the American Cancer Society placebos have an effect in every 1 in 3 patients. Scientific research involving placebos has shown that these patients in particular have a change in brain activity due to the placebo. I think that in itself is pretty interesting and hopefully further research will determine its implications. While I don’t think a placebo necessarily demerits a treatment, I do think the treatment needs to be investigated and then explained as to what it truly does…not just what it is thought to do.

On another note, in addition to the placebo effect there is a nocebo effect. I was unaware of this and thought it was somewhat interesting. The placebo effect results in the positive outcome someone was hoping for, while the nocebo effect results in unpleasant symptoms as a result of the placebo. Together they are referred to as the expectation effects. If the patient expects to feel sick from a particular medicine they most likely will, and if they expect to gain relief from pain, they will most likely find their symptoms eased. I don’t think we can demerit placebos and the affect our brain, and our faith, have on our healing.

Brianna Cosentino

http://homeremedies.ygoy.com/updates/1753/home-remedies-for-inflammation-of-the-kidney/

While surfing the internet, I stumbled upon this little gem of a miracle cure. It discussed naturopathic ways in which nephritis can be cured. Nephritis is inflammation of the kidneys and has a 15/100k mortality rate. In addition, the condition has been steadily on the rise since the 1970's.

This websites recommends home remedies to combat inflammation of the kidneys through the consumption of avocados, coconut milk, and carrot juice with lime concentrate. While these may provide some placebo-type affects, no studies have been performed that connect these remedies with decreased inflammation. Furthermore, nephritis can cause permanent kidney damage that may result in death if not treated correctly. Therefore, if a reader does not read critically about a very serious condition, poor consequences may result. This website is another case-in-point of highly unverified websites disseminating information that may harm readers that do not take it with a grain of salt.

How Olive oil helps switch off genes which lead to conditions including heart disease and arthritis

After reading the article "How olive oil helps switch off genes which lead to conditions including heart disease and arthritis" I was very interested in all of the different kinds of foods that can help inflammation. When looking through many different articles I found similar foods in each and these foods are part of the Mediterranean diet which is stated in the article. They do not go into detail about the mediterranean diet so I thought this diagram would clearly illustrate the foods that can help inflammation http://www.drweil.com/ecs/images/anti-inflammatory-food-pyramid.jpg.

I really enjoyed reading about how olive oil can help inflammation but I feel as if the article need more information about monounsaturated fat (MUFAS) because this would allow for the general public to understand even though it has a lot of fat it is necessary for the body. Monounsaturated fat is a fat which is found in many different foods and oils. It has been shown through many different studies that monounsaturated fat improves blood cholesterol levels which can decrease your risk of heart disease. Like olive oil it does this by controlling LDL(bad) cholesterol levels while raising HDL (good) cholesterol levels. Studies also show that MUFAS may benefit insulin levels and blood sugar control which will help if you have type 2 diabetes. By adding this information the article would have had more supporting data.
What did everyone think about the information regarding omega-6 fatty acids after reading the article "Anti-inflammatory Agents: present and Future" ??

When Placebo Can't Be Controlled

Acupuncture has been practiced for thousands of years and with such age a practice gathers many strong believers. There are undoubtedly millions, possibly billions, of people in the world who believe that acupuncture administered by a knowledgeable practitioner can heal a wide variety of maladies... so how does the institution of Western intelligentsia scientifically evaluate a methodology that has produced results for millennia? There are plenty of theories concerning the pathway by which acupuncture effects its positive health results; some say acupuncture prevents pain perception by saturating certain neurological "gates"; others propose that stimulating the efferent vagus nerve elicits a parasympathetic down-regulation of inflammatory players like tumor necrosis factor alpha and proinflammatory interleukins; while always looming in the background is a crowd of critics screaming that acupuncture is pure placebo.

The majority of acupuncture research has been refuted by the scientific community as "poorly designed" or "biased." To be fair, it is not easy to put together a double-blind placebo-controlled study involving sticking people with sharp objects, but serious skepticism must be applied to every publication on acupuncture due to its inherently subjective nature. Challenges to the objectivity of testing acupuncture include the source which determines needle placement (Confucius says poke here versus Laozi says poke there), the concept of diffuse noxious inhibitory control (DNIC) set off by needle pricks at irrelevant sites, the possibility of a dose-response relationship, and the inadequate blinding via sham procedures.

DNIC is the scientific way of explaining counter-irritation, like when your dad offered to punch your arm to make your headache feel better. In acupuncture, it is proposed that needle pricks release endogenous opioid neuropeptides and monoaminergic neurotransmitters that send a message to the lower brain stem that result in anti-inflammatory actions. In the 1980's, Fauve et al. showed that in mice, local inflammation could reduce distant inflammation better than glucocorticoids. Cool concept... but there has yet to be a methodology set forth that is acceptable to the scholarly world as accounting for DNIC's potential reliance on the placebo effect. If acupuncture works because of DNIC, does needle placement matter? If placement doesn't matter, then any sham needle use will elicit a response that cannot be separated from the response to needle use in traditionally prescribed area.

Kavoussi's article begins with a quote from physicist/philosopher Thomas Kuhn, "There are many fields--I shall call them proto-sciences--in which practice does generate testable conclusions but which nevertheless resemble philosophy and the arts rather than the established sciences... incessant criticism and continual striving for a fresh start are primary forces, and need to be." So where is our fresh start on acupuncture? Is it reasonable to discard the obsession with ruling out placebo in our medical research paradigm? At some point, I think there has to be a concession by the scientific community that it cannot fully elucidate the incredibly complex interplay of physical, mental, emotional, and spiritual wellbeing in human subjects. The patient seeking acupuncture therapy must believe that acupuncture has some kind of power, be it physical or otherwise, but is that "placebo" necessarily a demerit to the efficacy of acupuncture?

Kavoussi, Ben, and B. Evan Ross. "The Neuroimmune Basis of Anti-inflammatory Acupuncture." Integrative Cancer Therapies. September 2007, vol. 6, no. 3. pp. 251-257.

Interestingly, after writing this article alongside a Licensed Acupuncturist, Ben Kavoussi has written extensively as a critic of acupuncture... a list of his articles can be found here: http://www.sciencebasedmedicine.org/?author=1346

Parkinsons Disease and Protective Nutrition

One theme that has been evident throughout most articles we read on inflammatory disease is that diet is of high importance when it comes to controlling and preventing increasing inflammation occurrence. There seems to be media coming from all angles on what type of foods help or hurt when it comes to all the inflammatory diseases. This made me wonder what research has been done on diet and Parkinson's and what type of diets are protective both prior to acquiring the syndrome and after.

One of the studies on Parkinson's and nutrition study the affects of nutritional urate in nueroprotection. The study started with 47,406 men of which 1,387 developed Parkinson's disease. It saw a protective effect with increased nutritional urate. It further explained the phenomena by adding, "Urate reduces oxidative stress primarily through its actions as an effective scavenger of peroxynitrite and hydroxyl radicals (1)." Increased urate is generally associated with causing gout and not commonly viewed as a positive nutritional aspect. This study believes that there are three mechanisms by which the urate was protective and states, "Possible mechanisms for a neuroprotective action of urate include suppression of oxyradical accumulation and preservation of mitochondrial function, inhibition of the cytotoxic activity of lactoperoxidase, and protection from dopamine-induced apoptosis (1).According to this study consuming more foods like fish and meat could decrease your chances of getting Parkinson's.

On the other hand, there is a study describing that increased protein ingestion while already having Parkinson's can be detrimental (2). The study explains that the reason for this is that there is a limited amount of transporters that cross the blood brain barrier. There is a dopamine protecting substance that competes with certain proteins to get transported (2). There was a correlation of decreased domapine protection with increase dietary protein after the onset of Parkinson's Disease.

Two other supplements that had a reverse relationship when it came to Parkinson's disease were Iron and Vitamin C. While heme-iron found in red meat products showed no association to Parkinson's in this studied fortified Iron products seemed to increase the instance of Parkinson's among individuals, and even more so in those who had Vitamin C deficiencies (3). The study also pointed out that grains from cereals fortified with Iron had a strong correlation with Parkinson's disease(3).

There were other dietary elements that were studied in relation to Parkinson's disease, however most had no strong correlations. Dairy specifically high fat dairy, is somewhat linked to increase risk of Parkinson's disease (2). Another slight correlation what found in the arachidonic acid, an Omega-6 fatty acid commonly found in peanut oil, was found to increase Parkinson's disease(2). Diets rich in fruits and vegetables like that of the Mediterranean diet seemed to decrease the incidences of Parkinson's (2). All and all it seems the best information on Parkinson's and diet says to eat natural fruits, vegetables,vitamins, proteins and leave out high fat foods to protect against getting Parkinson's Disease. Lastly, if you do get the disease it is better to lower your intake of Proteins.

References

(1)Gao, X., Chen, H., Choi, H. K., Curhan, G., Schwarzschild, M. A., & Ascherio, A. (January 01, 2008). Diet, urate, and Parkinson's disease risk in men. American Journal of Epidemiology, 167, 7, 831-8.

(2)Kones, R. (January 01, 2010). Review: Parkinson's Disease: Mitochondrial Molecular Pathology, Inflammation, Statins, and Therapeutic Neuroprotective Nutrition. Nutrition in Clinical Practice, 25, 4, 371-389.

(3)Logroscino, G., Gao, X., Chen, H., Wing, A., & Ascherio, A. (January 01, 2008). Dietary iron intake and risk of Parkinson's disease. American Journal of Epidemiology, 168, 12, 1381-8.

Updating Outdated Alzheimer's Diagnosing Techniques

I was on NPR and I stumbled upon a story published April 19, 2011 (serendipitously during Neurodegenerative week) about updating guidelines of diagnosing patients with Alzheimer's. Previously diagnosing those with the disease was done after the fact without any indication if a person was likely to develop the disease. Now an initiative being backed by the National Institute on Aging and the Alzheimer's Association, is urging doctors to tell patients whether or not they are likely to develop Alzheimer's by monitoring brain shrinkage, plaques in the brain, and modifications of CSF.

I think there are pros and cons.

One pro that is mentioned in the article is that those who are deemed highly likely to develop the disease, have more time to setup healthcare arrangements (i.e. hiring an at-home medical attendant, saving money, etc.). That way patients and their families will have more time to prepare for the subsequent series of unfortunate events.

Another pro mentioned in the article is that those who are placed in the "highly likely" category may be targets for experimental approaches at dealing with the disease down the road.

One con mentioned was that if people are labelled highly likely, then they may go through some deleterious psychological events.

Another con that I thought of, relates to insurance coverage. If someone is deemed highly likely to develop the disease he or she may be denied healthcare insurance coverage. This is extremely unfortunate but because of the recent economic decline, companies are trying to cut costs wherever they can and implementing stricter coverage guidelines. As a result, implementing this system of earlier Alzheimer diagnosis could potentially prohibit some patients from receiving care.

http://www.npr.org/2011/04/19/135548317/scientists-update-alzheimers-guidelines

T Regulatory Cell Therapy

I found the following review articles on T Reg cell therapy which pertains to the basic science article that we just read on Parkinson's Disease. I especially like the title: "Human T Regulatory Cell Therapy: Take a Billion or So and Call Me in the Morning". I have attached the link to the reviews so check them out. Basically, researchers believe that T reg cell transfer is a promising therapy for the treatment of many autoimmune, neurodegenerative, and inflammatory diseases due to the T reg cell's ability to suppress over-reactive immune states. They propose that a patients own T regs can be collected, proliferated ex-vivo and then reintroduced into the patient to increase the regulatory ability of the body's immune system. They also found that in some disease states, a patient's T regs have decreased ability to suppress immune responses, making it hard for adoptive transfer to have useful effects. It is still unknown why there is a depressed response from Tregs in many diseases. To overcome this, the authors propose using stem-cell therapy to create a new line of T regs that are functionally sound and can act to regulate autoimmunity. Most importantly, researchers are hoping that T reg therapy can be used following organ transplantation to suppress that immune response in Graft-Versus-Host Disease. Overall these review articles gives the pros and cons of research thus far into the area of T Regulatory Cell therapy.

http://www.cell.com/immunity/abstract/S1074-7613%2809%2900192-7

http://www.nature.com/nri/journal/v5/n4/full/nri1574.html

Memantine has been shown to be ineffective in the treatment of AD patients

Good afternoon All, a study was recently conducted that showed the drug memantine, or Namenda by its brand name, is ineffective for patients with moderate Alzheimers disease. The majority of doctors prescribe memantine coupled with a cholinesterase inhibitor, which prevents the breakdown of neurotransmitters which have been associated with memory, while memantine blocks NMDA glutamate receptors. The authors of the study argued that the combination of these drugs do not slow down the progression of the disease. Ultimately, there is no known cure for AD, the aforementioned medications are meant to help minimize the severity of symptoms and work differently for different people according to the study.

http://edition.cnn.com/2011/HEALTH/04/11/alzheimer.drug.ineffective/index.html

--I wanted to learn a little more about memantine, I was able to track down a very lengthy review article that discusses memantine in relation to AD and cholinesterase inhibitors. Memantine is a uncompetitive NMDA receptor antagonist. The overexcitation of these neurons is just one of many hypotheses that can explain the progression of AD. So the weak firing from low levels of glutamate will be blocked by the memantine and lead to overall improvement but will not effect stronger synaptice responese which are required for normal functioning. Overall, the review argues that memantine protects against neurodegeneration brought on by AB, however these were results from a mouse model. Overall, I liked the figures that the review included, the writing seemed straight forward, however while reading the review, the authors make a strong push for their medication. Even though this medication was cleared by the FDA, and showed strong results in mouse models, but from the study mentioned above, memantine has not been effective. Should they go back to the drawing board to research for other ideas on treating AD, or do you think uncompetitive NMDA receptor antagonists and cholinesterase inhibitors are the right direction we should be going?

http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2003.tb00254.x/pdf

More MS alternative therapies

Hey Everyone!

So after reading the article on bee sting therapy I decided to look up more alternative therapies for Multiple Sclerosis. Before I list these I should reiterate that none of them have been supported by any scientific findings, much like the bee sting therapy. Also the majority of these were described as “co-therapies” and were not meant to be the main course of treatment. The first co-treatment was massage. According to some massage therapy helps relieve stress and depression, which are both thought to progress MS. However, several websites cautioned against this form of treatment, since many of the mainline MS treatments can lead to bone thinning and osteoporosis. Depending on the severity of bone thinning, massage therapy has the possibility to be quite harmful. The next therapy suggested was acupuncture. According to some patients acupuncture relieves pain, lessens muscle spasms and helps with bladder and bowel control. However there is some research surfacing that acupuncture can actually be harmful. There is no hardcore scientific research pointing either way. The third alternative therapy was evening primrose oil also known as linoleic acid. Of the four studies I found, three of them were torn on the affects of linoleic acid and believed longer studies needed to be created to truly observe its affects on the myelin sheath. The last two alternative therapies were magnetism and marijuana. The magnetism studies I found were horribly designed and completely unscientific. Most of the information I found on marijuana strongly warned against its use since many MS patients already have cognitive impairments.

Possible drug targets for IBD and MS

I found an article that was covering new treatment possibilities for Inflammatory Bowel Disease (IBD) that were recently discovered. This possibility arose when the cytokine IL-23 was identified as playing a large role in the pathogenesis of this disease. It was found that IL-23 was being expressed in many different types of cells from the peripheral blood and intestinal mucosa of patients with IBD, demonstrating that new treatments of IBD may be aimed at limiting the damage caused by IL-23.

Having not heard of IL-23 as being a contributor to the disease in any of the articles we read in class, I did a little research on the cytokine. What I found out was that IL-23 assists in the pathogenesis of autoimmune inflammation as it induces CD4+ T cells which subsequently produces IL-17 and IL-6, both of which are known to act as proinflammatories. Interestingly, I also came across another article which stated IL-23 was also discovered in increased amounts in dendritic cells in patients that have Multiple Sclerosis. In the same article, it was shown that when inhibiting IL-23 along with IL-12, increased amounts of IL-10 and a decrease in TNF-α production were noticed; thus, presenting a possible drug treatment for MS aimed at IL-23 inhibition as well.

The articles mentioned can be found using the following links:

http://www.sciencedaily.com/releases/2011/03/110331114844.htm
http://www.jleukbio.org/content/89/4/597.full
http://www.jimmunol.org/content/176/12/7768.short
http://www.signaling-gateway.org/update/updates/200502/nri1559.html

Alzheimers Current Events

Here is an article in the New York Times today about new guidelines for Alzheimers diagnosis issued by the National Institute on Aging and the Alzheimers Association. The article talks about the newly implemented changes that are based on some of the research that we have been reading about.

http://www.nytimes.com/2011/04/19/health/19alzheimer.html?_r=1&hp

Testing for Alzheimer's

After all this talk about Alzheimer's Disease, I was curious about the ways in which people are tested for it. An early testing device is the cognitive testing process. There are a few commonly used tests that physicians use:

• Three word delayed recall: the patient is told three words (ex: blue, dog, pen) and asked to repeat them. About 5 minutes later the patient is asked to repeat them. If the patient cannot remember all three words, even after hints like one is an animal, they may need further evaluation.


• Mini cognition test combines with three word recall: the patient is given three simple nouns and asked to repeat them. Next, the patient is asked to draw the face of a clock on a piece of paper and put the hands at a specific time. After the clock is drawn, the patient is asked to recall the three words. If the patient remembers only two, one, or none of the words, the clock should be evaluated. If the clock is abnormal, the patient needs further evaluation. Also is the patient remembers all three words but makes an abnormal clock they would need further evaluation.


• Coin counting: The patient is asked "If i give you a nickel, a quarter, a dime, and a penny, how much money have I given you?" If the patient cannot come up with 41 cents as the answer, they need further evaluation.

These are just a few ways in which a person's cognitive ability can be evaluated. Check out these links below to read more about the testing methods and warning signs for Alzheimer's Disease.

Cognitive Testing: www.alz.org/professional_and_researchers_14306.asp

10 Warning signs: www.alz.org/alzheimers_disease_know_the_10_signs.asp

Ethnicity and Alzheimers

In class there was a little discussion on how ethnicity and race may play into the diagnosis of alzheimers, but nothing too concrete. This article I found discusses how racial and cultural differences can impact how individuals with early dementia are diagnosed. It looked into how varied bereavement across cultures is and analyzed the differences between the diagnoses in dementia between people of different races; emphasis was placed on African Americans, Latinos, Whites, and American Indians. Just some interesting information!

http://www.usatoday.com/news/health/2010-07-13-alzheimersculture13_ST_N.htm

Mice on Treadmill

Hey Everyone,

Just so you can have a visual for the "Chronic Exercise ameliorates the neuroinflammation in mice carrying NSE/htau23" article.... here is a link on mice subjected to treadmill excises. I'm thinking it may lead to improved cardiovascular fitness; however looks like it could induce a little chronic stress as well.

Mice on Treadmill link

Deep Brain Stimulation

• In class I had Mentioned that one of the treatments for Parkinson's Disease is deep brain stimulation. While it seems easy enough to understand that electrodes are placed in areas of the brain to stimulate and control movement, there is much more involved as far as placement and consequences of the treatment. Upon further exploration I found many interesting facts involving deep brain stimulations and even some videos of how the procedure works.





• In deep brain stimulation electrodes are placed in the sub cortical areas of the brain. There is a battery connected to the electrodes that is generally located in the collar bone region. Using a CT or MRI to monitor the surgery, a hole is drilled into the skull and the electrodes are carefully placed as well as tested for nerve stimulation. The job of the electrode is to stimulate neurons that have become dormant or less active. There are studies that have show that the use of deep brain stimulation paired with the common Parkinson's medication Levadopa has a greater response toward decreasing the movement issue symptoms in Parkinson's disease. While there is great success with the invasive procedure it does not come without consequences. Patients who have this implantation have seen a steep rise in infections compared to the Parkinson's patients just on the medication. Other side effects of the operation include stroke, change in mood, and overproduction of scar tissue. Patients who opt for this procedure must be willing to make a long term commitment to maintaining and monitoring the progress of the units within their brain. The battery must be changed regularly through surgery, and because of the sensitivity of the area stimulated by the electrodes progress must be continually monitored.






• Deep Brain Stimulation not only is a treatment for Parkinson's Disease, but has shown great potential in treating psychiatric disorders as well. Disorders such as depression, obsessive compulsive disorder, and phantom pain have also been exploring the world of deep brain stimulation with some pretty good results. While Parkinson's disease is a disease characterized by neuron death in the substancia nigra primarily as a result of inflammatory disease, it is interesting that a treatment for Parkinson's is transitional in other areas of medicine.






• There are some interesting videos showing the deep brain stimulation implantation on youtube. The one following I found interesting in explaining the implantation process.





• http://youtu.be/WW-SWAnphFU





• This other video is interesting because it shows a study that target the elderly which are predominately affected by the disease.





• http://youtu.be/WYDoHmg9ECl







• Other Sources and interesting articles on Deep Brain Stimulation:




• Pluta, R.M., Perazza, W.G.D., &Golub, R.M. (Feb 16, 2011). Deep Brain Stimulation. Jama-Journal of the American Medical Association, 305-7.





• Deuschl, G., Schade-Brittinger, C., Krack, P., Volkmann, J., Schafer, H., Botzel, K., Daniels, C,... German Parkinson Study Group, Neurostimulation Section. (Jan 1, 2011). A randomized trial of deep-brain stimulation for Parkinson's disease. The NEw England Journal of Medicine, 355-9, 896-908.

Play at Your Own Risk!

Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease, can be caused by many different factors. But from all the pathologies we discussed in class this past week, the one thing that sparked my interest into doing more research was how some of these diseases can be caused by high impact sports. This may include sports such as Hockey, Boxing, and Football.

Back in 2008, Boston University School of Medicine and Sports Legacy Institute partnered up to begin an intensive look into how chronic head injuries may cause neurodegenerative diseases later on in a players life. Thus the Center for the Study of Traumatic Encephalopathy was formed.

This center conducts state of the art research on Chronic Traumatic Encephalopathy (CTE), which is a disease that leads to a highly progressive dementia. Some of the early symptoms that may appear during the athlete’s career are memory loss, depression and personality changes. All of these symptoms get worse and worse over the years and eventually leads to dementia.

The continual onset of trauma to the brain triggers a progressive degeneration of the tissue, including the build up of an abnormal protein called tau. When a brain sample has been collected after the person has passed away, the researchers can stain for that specific protein and can visualize where dead brain matter has occurred.

For more information on this ongoing research, go to this website http://www.bu.edu/cste/

Here they have a nice video explaining overall research findings and what they hope to do in the future. There is also a review article that discusses CTE in more detail if you click on the About tab and then What is CTE. Its near the bottom of the page.

Music Therapy in Alzheimer's

In one of my neuroscience class we talked about the benefits of using Music Therapy (MT) in treating Parkinson's disease and how it could be applied to other neurodegenerative diseases. First off, MT is a field of scientific research that observes how a trained music therapist uses music (both passive listening and active participating) to improve symptoms of various disease states.

The article on AD observed the effects of passive MT, or the effects of just listening music on the behavior of patients with with moderate to severe Alzheimer's. The authors found that patients patients' daily activities were disturbed much less frequently, and that the patients displayed less aggressiveness and anxiety. The MT effects lasted for about a month after the therapy stopped.

While this therapy is clearly not going to cure AD, I think it is a great step in helping patients suffering for this disease to maintain a semblance of normalcy.

Alzheimer's Paper:

http://www.ncbi.nlm.nih.gov/pubmed/16618375

-Vinoo

Alzheimer's and DIet

So after learning about the different possible mechanisms that contribute to AD (described briefly below), it made me wondering what type of antioxidant intake research is out there regarding AD. Seems to be a mounting body of evidenced that flavonoids, particularly anthocyanin (responsible for the bright red/purple pigment in foods) maybe beneficial.

Possible mechanisms to produce AD:

1. reduced synthesis of acetylcholine (neurotransmitter)

2. hyperphosporlyation of tau proteins leading to neurofibrillary tangles

3. accumulation of amyloid beta plaques ---seems to be a connection to anthocyanins....

A paper published this past year looked at the affects of mulberry (ME), rich in anthocyanin ---(a flavonoid) on preventing AD in senescence-accelerated mice. Background evidenced indicated that antioxidant-rich berries can positively affect cognition and memory. Specifically, cyanidin-3-O-glycopyranoside (one of the most common anthocyanin) has been identified a "neuroprotective," by decreaseing amyloid beta peptide-medicated cytotoxicity in neurocytes. Other studies found that cyanidin-rich supplements improved lipid oxidation in the brain as well as spatial working memory tests in aged rats (via cAMP-response element).

This study examined 6-month old adult mice from SAMR1 (senescence-resistant) and SAMP8 (senescence-accelerated prone) strains. They found the following:

1. ME significantly improved memory deterioration

2. ME reduced oxidative stress-induced lipid oxidation (via isoprotane reduction)

3. ME improved MAPK cascade via lower levels of p38 and JNK as well as decreased nuclear Nrf2 levels (MAPK regulator), simular to that of the SAMR1 mice (control, not accelerated aging mice)

4. ME reduced the accumulation of amlyoid beta deposits in the hippocampus of the mice feed the extract.

Overall, they found the anthocyanins "promoted age-dependent antioxidant production and reduced oxidative stress-intduced damage."

Food for thought.

Shih P, et al. Antioxidant and cognitive promotion effects of anthocyanin-rich mulberry on senescence-accelerated mice and prevention of Alzheimer's disease. Science Direct. 2010;595-605

Psychoneuroimmunology

After reading more on stress and inflammation in the immune response I came across the term Psychoneuroimmunology which describes the relationship between the brain and the immune system. We had read a few lay articles on stress, particularly the study on how social stresses exacerbated the symptoms of Multiple Sclerosis. There is actually an organization committed to this specific field called the Psychoneuroimmunology Research Society and I have included their website below. Also, it seems that may medical schools and health care facilities have specific research units dedicated to this field. I have posted another paper on the concerns and difficulties that are involved in the field including measurement of psychological parameters and the effect of the environment on a subject.




http://en.wikipedia.org/wiki/Psychoneuroimmunology
http://www.apa.org/monitor/dec01/anewtake.aspx
pni.osumc.edu/KG%20Publications%20(pdf)/049.pdf

Living Long Time

Since we had the short discussion on longevity and ethics in medicine last time, I thought I would post this little quiz that I saw on Dr. Oz's website too.

http://inflammablog4.blogspot.com/

If you think about it most illnesses could be considered built in mechanisms to "weed out" or kill out certain disease states. Take diabetes for example. Too much visceral fat and intramuscular fat can (and more than likely will) lead to diabetes. This could be considered an evolutionary mechanism to decrease the prevalence of obesity in the human population. I know that sounds mean, but if you look at things from a biological and ecological standpoint, and it makes sense for other animals (remember the giant arthritic frogs)!

DR. OZ: Alzheimer's: Diabetes of the Brain

DR. OZ: Alzheimer's: Diabetes of the Brain

http://www.doctoroz.com/videos/alzheimers-diabetes-brain

Interesting points:

• Insulin is not only made in the pancreas, but also in the brain!
• As we know, the brain needs and metabolizes lots of glucose to function, and insulin helps it uptake that glucose into its cells. But in Alzheimer's, insulin function is impaired (insulin resistance)
• Since 1980, deaths of people with both diabetes and Alzheimer's have increased dramatically
• Visceral obesity is bad!!! LOL
• Processed foods are bad!!!

Not sure, but it seems like new treatments for diabetes have kept diabetics alive longer, and so now we see an increase in Alzheimer's in diabetic patients (especially elderly people). So would this link between diabetes and Alzheimer's be considered a coincidence???

Hey everyone!

So yesterday somebody posed the question of why MS is more common in women than in men. I found a few genotyping studies that confirmed the greater prevalence of certain MS-related genes in women, but it seems that the answer to this question is still largely unknown. Estrogen, though, seems to have some therapeutic effect on managing MS. Check these articles out: 
http://www.ncbi.nlm.nih.gov/pubmed/19539954
http://www.ncbi.nlm.nih.gov/pubmed/19591008
The second article is more recent, and even mentions various clinical trials that are currently testing the efficacy of estrogen therapy in MS treatment.

- Julia 

Homocysteine and its Role in Neurodegenerative Disorders

I stumbled across this article when doing some research for another course. I thought it was a relatively simple yet comprehensive article which addressed multiple components of disease that have been discussed in class (homocysteine levels, nutrient deficiency, etc.) in addition to corresponding with this weeks discussion of neurodegenerative disorders. Furthermore, upon reading this article, it brought to mind the discussion of stroke, which occurred at the beginning of the course. Increases homocysteine concentrations were directly correlated to an increase risk of stroke, which would subsequently exacerbate any cerebral vascular dysfunction experienced by the patient, causing further deleterious effects. As neurodegenerative diseases affect such a large group of people, and in my opinion impair one's quality of life, it would be amazing to decrease the severity of these diseases with something as accessible as a B-12 vitamin which can be found in any supermarket. However, it does appear that plasma homocysteine may not be a great indicator of a specific neurological disorder as it lacks specificity. In addition, use of homocysteine as a marker of disease my raise ethical questions, much like those discussed on Monday. Just though it was interesting! Note: While the abstract is listed below, the full article can be found at the provided link. Homocysteine: a biomarker in neurodegenerative diseases Abstract: Disease of the central nervous system are found in patients with severe hyperhomocysteinemia (HHcy). Epidemiological studies show a positive, dose dependent relationship between mild-to-moderate increases in plasma total homocysteine concentrations (Hcy) and the risk of neurodegenerative diseases such as Alzheimer's disease, vascular dementia, cognitive impairment or stroke. HHcy is a surrogate marker for B-vitamin deficiency (folate, B12, B6) and a neurotoxic agent. The concept of improving the patients clinical outcome by lowering of Hcy with B vitamins seems to be attractive. Recent B vitamin supplementation trials demonstrated a slowing of brain atrophy and improvement in some domains of cognitive function. Meta-analysis of secondary prevention trials showed that B vitamins supplementation caused a decrease in plasma Hcy and a trend for lowering the risk of stroke. HHcy is common in elderly people. Therefore, it seems prudent to identify B vitamin deficient subjects and to ensure sufficient vitamin intake. Therefore, recent evidence supports the role of Hcy as a potential biomarker in age-related neurodegenerative diseases. http://find.galegroup.com/gtx/retrieve.do?contentSet=IAC-Documents&resultListType=RESULT_LIST&qrySerId=Locale%28en%2C%2C%29%3AFQE%3D%28KE%2CNone%2C24%29Homocysteine+and+stroke+%24&sgHitCountType=None&inPS=true&sort=DateDescend&searchType=BasicSearchForm&tabID=T002&prodId=HRCA&searchId=R1&currentPosition=1&userGroupName=tusc83053&docId=A252447279&docType=IAC#

Diacerin

Last week during the arthritis discussion we analyzed an article that tested the effects of the drug Diacerin on osteoarthritic cells. The drug is unique because it inhibits interleukin-1 rather than acting on the cyclooxygenase enzymes like non-steroidal anti-inflammatory drugs do. However, this particular study only looked at chondrocytes in vitro and was not a human study. It got me wondering if there have been any human clinical studies on this drug and if it has any negative health effects. I found this article:

http://onlinelibrary.wiley.com/doi/10.1002/art.23056/pdf

Looks like they found Diacerin to be safe and well tolerated. No serious or
previously undocumented adverse events were observed
during the study. I'm interested to see where this drug will go in the future.

One last note on Arthritis

Last Monday we discussed the final segment of our arthritis block and covered a research article looking into the treatment of RA by breaking from the norm and not going with anti TNF alpha treatment, but rather an anti IL-1 treatment. It was believed that TNF drives most of the IL production, thus by targeting and block TNF, IL-1 would be suppressed as well. However they found that anti TNF treatment was only beneficial in reducing inflammation and that too when administered before or at onset of the disease. In studying using anti IL treatment, it was found that there was a significant effect seen in decreasing joint damage and destruction, and that too when given at onset or after induced arthritis.

The study did a good job in demonstrating how using this form of treatment as compared to what was previously thought, would be more beneficial in treating and reducing the effects of arthritis. The well formed and easy to read figures and graphs even demonstrate that anti TNF treatment does indeed only reduce some inflammation at onset of induced arthritis but has no beneficial physiological effect as the disease progresses. However use of anti anti IL treatment was beneficial in relieving inflammation and reducing joint destruction; which brings about a question as to why there was no test done in testing administering both drugs to the animal models and seeing the effect of both. Allowing anti TNF treatment to work in the early stages, and IL to become of use in the later developing and later processes.

However Dr. Cohen mentioned that still Il-1 treatment inst being used, so what is it about the study that they're leaving out that we need to know, or is it that in the 12 years that have passed since this paper has been published, more research has been shown that anti IL-1 isn't the best treatment after all.

Keep in mind arthritis costs the US economy over $86 billion per year. Thus cutting edge research will continue to find the most effective drug administered in the lowest amount.

Multiple Sclerosis Overview-Neurodegenerative

Multiple Sclerosis is an autoimmune disease affecting the central nervous system (CNS), which includes the brain, spinal cord, and optic nerves. When the immune system begins to attack the CNS, inflammation occurs, causing damage to the myelin sheath surrounding nerve fibers. While the myelin is being attacked, the nerve cell itself also becomes damaged. In addition to this, the cell and myelin develop scar tissue, also known as sclerosis, giving the disease its name. This damage leads to disruption in the signaling to and from the CNS. This disruption ranges from a slowing in the signal, to a complete halt in signaling, or cross-talk between signals.

Multiple sclerosis is more common among women and is generally diagnosed between the ages of twenty and thirty. The symptoms vary from patient to patient based on the severity and location of immune system attack. The symptoms of MS range everywhere from fatigue, numbness, pain and depression, to walking problems, balance and coordination problems, bowel and bladder dysfunction, impaired cognitive function, and spasticity. Other symptoms that are less common include things such as respiration problems, swallowing problems, speech disorders, tremors, and seizures.

There are four main categories, or courses, of MS: Relapsing-Remitting MS, Primary-Progressive MS, Secondary-Progressive MS, and Progressive-Relapsing MS. Relapsing-Remitting MS is the most common form and is “characterized by clearly defined acute attacks with full recovery or with residual deficit upon recovery”(NMSS). Typically in the periods between disease relapses, there is no disease progression. Primary-Progressive MS is a progression of the disease from its onset without acute attacks. Roughly 10% of people diagnosed with MS have the primary-progressive form. Secondary-Progressive MS can be thought of as a combination of relapsing-remitting and primary-progressive MS. In other words the patient starts with infrequent relapses and remissions and then moves towards a progressive worsening of the disease without remissions. According to several MS studies, “of the 85% who start with relapsing-remitting disease, more than 50% will develop SPMS within 10 years; 90% within 25 years” (NMSS). The last form, Progressive-Relapsing MS, is characterized by progressive worsening from the onset of the disease, but also acute relapses. This is the least common form and accounts for roughly 5% of patients with MS.

Quick Blurb about MS Review Article:

In the “Inflammation and MS Review” the authors contend that inflammation may not be completely detrimental to MS, as commonly thought, but may have beneficial roles as well. The review article continues on to describe the CNS and explain particularly beneficial roles of inflammation. In the CNS the brain is protected by the blood-brain barrier, which is composed of cerebral endothelial cells and tight junctions. In patients with MS the endothelial tight junctions of the blood-brain barrier are abnormal. As one might expect this allows for mononuclear cells and other detrimental factors to enter the brain. This breakdown in the blood-brain barrier is a main suspect as to how demyelination and axonal injury begins. The continuous influx of these cells and the inability to clear them leads to the activation of local immune cells and inflammatory mediators. The researchers of this article contend that while initial inflammation seems to play a large role in demyelination, it may be beneficial in the long run. When studying mice with the animal model of MS, they found that the morbidity rate increased 20% to 80% when treated with antibodies against proinflammatory cytokines. There research finds that inflammation may also be responsible for clearing toxins that are responsible for progressing the disease. There are clearly many details to the benefits and detriments of inflammation in MS so read the article and enjoy! Its very interesting!

(NMSS) "What Is Multiple Sclerosis? : National MS Society." Home : National MS Society. Web. 10 Apr. 2011. .