Inflammablog3

Back to week 3: Birth control pill is linked to heart disease?

2010-05-04T22:37:00.002-06:00

Once again the "common folk" is a victim of the C-reactive protein (CRP) hype. A study done in 2003 showed pre-menopausal women that took birth control had twice as much CRP in their blood than women who did not take the pill. Since chronically high CRP has been linked to heart disease and inflammation and is believed to play a key role in narrowing and hardening of the arteries, it would be easy to believe the pill promotes inflammation (had we not all recently learned CRP is not the best indicator of inflammation)! However the pill has also been studied to reduce the risk of ovarian cancer due to the estrogen present.. But that's a whole other story. Pros and cons, pros and cons.

The same study revealed that even though levels of CRP were twice as high in the women who took the pill, both group's levels were considered to be in the "normal" range.

So what do we get from all this... Women currently on birth control pills shouldn’t throw them out strictly based on the fear of increased CRH levels and heart disease. Remember, heart disease is most commonly linked to other important factors such as SMOKING, diet, and genetics. Also, there are other important risk factors associated with the pill that we should be concerned with (as discussed in the discussion about stroke and blood clots linked to the pill). In conclusion, More research is necessary on this topic and hopefully next time it will include more factors besides good ol' CRP.

SOURCES: American Physiological Society annual meeting, San Diego. Darlene M. Dreon, DrPH, director of clinical research, Galileo Pharmaceuticals, Inc, Santa Clara, Calif. Trent MacKay, special assistant for obstetrics and gynecology in the Contraception and Reproductive Health Branch of the National Institute for Child Health and Human Development, National Institutes of Health.

Statistics on Countries using turmeric in food VS those that don't and the incidence of RA in these countries.

2010-05-04T03:54:00.003-06:00

So, I was very curious after reading about turmeric being used as a spice in many Asian cultures, is there evidence showing a lower incidence in RA in these types of countries compared to the United States. I found an article with statistics of how many people are affected by RA in each country. The US has upwards of 2 millions, while some rural Asian countries are in the low thousands. I have to speculate this being because of the population difference, but it would make sense if these countries show a lower incidence of RA. The article I presented in class today shows that the curciminoids in the turmeric are very effective at inhibiting the inflammatory response causing RA problems before the RA has infected the patient. After the onset of RA there is no evidence shown that turmeric curciminoids will have any affect. So if the rural Asian countries have used turmeric as a spice in their cuisine for centuries then why wouldn't they be more prone to be effected by the inflammatory responses to RA. Maybe we should take this into account and start using more spices with turmeric. This could help our problem of millions of people in the US that suffer from RA. We could reduce this risk of RA in the US simply by putting this into our foods. This is not a totally proven way of decreasing RA but it seems to sure help. My only concern is that the turmeric curciminoids could have other effects on our body with it's inflammatory inhibitor response. It could cause us to inhibit inflammation when we really need it and just cause more problems for us. I guess this is always the issue when dealing with new ways to deal with inflammation and other diseases though.

2010-05-03T15:10:00.003-06:00

Hey guys check out this link to an article that states that high altitude wines are more beneficial in repairing arteriole walls than low altitude wines!

http://www.jancisrobinson.com/articles/jr876

I only researched this because I recently sat next to a metabolic surgeon on an airplane and we talked the entire flight about inflammatory diseases and their relations to metabolic surgery. He was the one who informed me of the latest trends of wine drinking.

Polypharmacy

2010-05-03T12:58:00.002-06:00

A random note about the topic of polypharmacy that we went over briefly last class:
I work at an optometrist office and sometimes I enter patient history information into the computer system, especially if we have a new patient. One of the questions on the patient history form asks the patient to list out any medication they are currently taking. This patient that I was working with needed help with that portion because she said she did not know all of the medication she was on. She said she was on "hundreds," and although that was an exaggeration, it is a good example of polypharmacy. When asked if she had some sort of list, she said "no."
Even though the likeliness of a complication arising when dealing with an eye exam is very slim, it was just a good example showing that if a patient is taking more medication than they can remember, they should always carry around a list with them.

Herbal Medicine

2010-05-02T20:47:00.002-06:00

Herbal medicine relies on active plant chemicals with biological properties. Many conventional medicines are synthetic compounds designed to mimic the action of plant chemicals. For instance, the heart medication digoxin is derived from the foxglove plant. In herbal medicine, active chemicals are extracted from the plant parts (stems, seeds, roots, or leaves) that are the richest sources. The active chemicals can be quantitatively measured and prepared in the form of capsules, tinctures, teas, tonics, oils, or poultices. Aromatic herbs such as lavender can also benefit the immune system when used topically or as healing oils.

Inflammation is a key feature in autoimmune disease. In some conditions, such as Hashimoto's thyroiditis, inflammation contributes to the disease process. In other conditions, such as Crohn's disease, inflammation may occur as a result of the disease. Inflammation occurs as the immune system reacts to injury, infection, environmental agents, malignancy, and cellular changes. In skin, inflammation is most visible because it causes noticeable swelling, redness, discomfort and pain. The process leading to inflammation, which is known as the inflammatory response, also induces changes that aren't seen but influence the effects of inflammation and their severity.

The inflammatory response is a complex cascade of steps that include an activation of white blood cells, the release of immune system chemicals such as complement and cytokines, and the production and release of inflammatory mediators and prostaglandins. Inflammation may be acute or chronic or relapsing-remitting depending on the disease course. Most conventional treatments for autoimmune disease, including corticosteroids, work by reducing or suppressing inflammation.

Many herbs also possess anti-inflammatory (also known as antiphlogistic) characteristics. Herbs can be used as the sole therapy in autoimmune disease or as complementary corticosteroid-sparing therapies allowing patients to take smaller doses or shorter courses of corticosteroids. Treatment protocols today often rely on both alternative and conventional treatment options in a discipline known as integrative medicine.

This article describes the use of plant chemicals with anti-inflammatory properties as complementary therapies for patients with autoimmune disease. Also this article I found it interesting because it gives another alternative to the consumption of NSAIDS or other drugs; the alternative way is the use of herbal products that will eventually treat the symptoms.

2010-05-01T17:11:00.004-06:00

While researching more of the scientific articles I came to find an interesting article relating to anti-inflammatory drug use and the risk for Parkinson's disease.

Evidence from studies suggests a role of neuroinflammation in the pathogenesis of Parkinson's disease (PD). This study takes advantage of the well established American Cancer Society's Cancer Prevention Study II (CPS-II) Nutrition Cohort, and was able to further examine the relation between NSAID use and PD risk with more detailed information on different types of NAIDs. The cohort is a study that was initiated in 1992 to investigate the factors for cancer. Participants were from a cohort who replied to a mailed survey in 1982. In 1992 they answered a questionnaire on four types of common used analgesics. Follow-up surveys were conducted in 1997,1999, and 2001. In 2001's survey a specific question on the lifetime occurrences of PD was asked. Follow-up started on the date of return of the 1992 questionnaire and ended on the date when the first symptoms of PD were noticed for PD cases or September 30, 2001 for participants without PD.

In the '92 questionnaire, participants were asked whether they took the following analgesics regularly during the past year: aspirin, acetaminophen, ibuprofen, or other nonsteroidal analgesics. They were also asked how many days per month they took each drug, how many tablets they took per day, and the duration of use. The '97 survey asked about "baby or low dosage aspirin" and "regular or extra strength aspirin". Four baby aspirin was counted as one tablet. Users were categorized according to dosage: fewer than 2 tablets/ week; 2 to 6.9 tablets/week; and 1 or more tablets a day. Results of the study showed significant inverse association was suggested between the cumulative updated dosage of ibuprofen use and PD risk. Overall, ibuprofen users had a lower PD risk than nonusers. Unlike ibuprofen, the use of aspirin and other NSAIDs, or acetiminophen was not associated with PD risk. Non aspirin NSAID users had a 26% lower risk than nonusers.

Results were consistent with previous findings that users of non aspirin NSAIDs but no aspirin, had a lower risk for PD than nonusers. This study also further suggested that only certain non-aspirin NSAIDs such as ibuprofen reduce the risk for PD. However there is insufficient information on the optimal dosage, and it remains uncertain whether this effect is mediated by COX inhibition or through other mechanisms specific to ibuprofen and possibly some other selected NSAIDs.

The full article can be found on PubMed, the title of the article is: Nonsteroidal Antiinflammatory Drug use and the Risk for Parkinson's Disease.

Aspirin Decreases the Risk of Breast Cancer Deaths

2010-05-01T12:49:00.001-06:00

It was revealed in February 2010 that the use of anti-inflammatory drugs such as aspirin (and other NSAIDs such as ibuprofen and naproxen) has shown to decrease the risk of dying from breast cancer. This information comes out of the Nurses’ Health Study which has followed 4,164 registered nurses who were diagnosed with stages I, II, or III breast cancer between 1976 and 2002 until their death or June 2006, whichever came first. This study has looked at a wide range of health issues in these women. In particular, they started in 1976 looking at which of the women took aspirin on a regular basis (often to reduce risk of heart attack and stroke) and have attempted to draw correlations in other health areas.

The researchers looked at the breast cancer mortality risk and the number of days per week of aspirin use (0,1,2 etc.). They found that women who took aspirin two to five days a week had a 60 percent reduced risk of their cancer spreading and a 71 percent lower risk of breast cancer death. Six to seven aspirins a week lowered the risk of spread by 43 percent and the risk of breast cancer death by 64 percent. In the end they concluded that among women living at least 1 year after a breast cancer diagnosis, aspirin use was associated with a decreased risk of distant recurrence and breast cancer death. The researchers state that more information is needed but the use of aspirin could affect tumor growth or recurrence through a decrease in inflammation.

Interestingly, it was revealed in January 2009 based on data from the Nurses’ Health Study that the use of aspirin or other NSAIDs does not decrease the risk of getting breast cancer among premenopausal women. The information from both of these papers is intriguing and points to the role of inflammation at different stages of a variety of disease states. It is likely that a baby aspirin does more than treat muscle pains, headaches and offer protection from heart disease. More information is needed however, it is promising that anti-inflammatories may have a beneficial role in decreasing mortality risk after cancer.

Holmes MD, Chen WY, Li L, Hertzmark E, Speigelman D, Hankinson SE. Aspirin intake and survival after breast cancer. J Clin Oncol 28(9): 1467-72, 2010.

Eliassen AH, Chen WY, Spiegelman D, Willett WC, Hunter DJ, Hankinson SE. Use of aspirin, other nonsteroidal anti-inflammatory drugs, and acetaminophen and risk of breast cancer among premenopausal women in the Nurses’ Health Study II. Arch Intern Med 169(2): 115-21, 2009.

Identical Twins and Multiple Sclerosis

2010-04-29T02:42:00.003-06:00

Using extremely fine-grained analytical tools, scientists compared genetic information in three sets of identical twins. One of each pair had Multiple Sclerosis, and the other didn’t — yet their genes proved essentially identical. The research cost $1.5 million, and the scientists took 18 months to sequence 2.8 billion DNA units in each twin, and determine whether they came from the mother or father. Most genomic comparisons look for differences in a just handful of suspect genes, and even whole-genome approaches don’t differentiate between parental contributions. The researchers also analyzed the twins' CD4 cells because of their central role in the development of MS. The absence of genetic differences doesn’t mean that genetics are irrelevant to multiple sclerosis. Identical twins, who are descended from the same egg, are six times more likely to develop MS than non-identical twins, who come from two different eggs. It’s still possible that some as-yet-unknown genetic factor, undetectable by even the most advanced tools, may explain the discordance in the study. However, geneticist Stephen Kingsmore thinks the culprit is probably an unknown environmental influence. This unknown factor could combine with other known genetic risks of developing multiple sclerosis. This study was a pioneering effort and the researchers are looking forward to studying more twins and other cells.

Head Trauma Linked To Alzheimer's Disease

2010-04-29T01:37:00.010-06:00

Researchers at the University of Pennsylvania in Philadelphia are working to find out more about Alzheimer's Disease. The findings back previous studies that suggested brain trauma increases the risk of Alzheimer's disease, a leading cause of dementia, later in life. Trauma to the head may trigger a cascade of biochemical events in the brain, in time resulting in neurodegenerative changes similar to those found in patients with Alzheimer's disease. Dr. Douglas Smith says his findings support "several epidemiologic reports (that have suggested) a link between a single episode of brain trauma and the development of Alzheimer's disease later in life." Smith's team induced brain injury in anesthetized pigs via very rapid acceleration/deceleration of the animals' heads without direct impact, similar to what humans often experience in an automobile accident. Brain trauma is one of the only environmental risk factor for Alzheimer's disease, so there is something about brain trauma that might initiate these insidious neurodegenerative cascades. The analyses of the brain tissue revealed a remarkable and consistent accumulation of amyloid beta and tau proteins in damaged brain cells following trauma. In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells disintegrating the neuron's transport system for nutrients. In the study animals, these changes were evident as early as 3 to 10 days post-injury. The team concluded that microscopic injury to the brain caused by trauma can be linked to the development of Alzheimer's disease many years after the injury. The findings may also lead to new drugs aimed at preventing the process. "This study adds to the body of knowledge that might aid us in the development of an anti-plaque-making compound," Smith said in a statement.

8 Alternative ways to reduce Inflammation without the chance of adverse effects of NSAIDs.

2010-04-28T06:53:00.004-06:00

These are all ways of reducing inflammation without using NSAID's or other anti-inflammatory drugs. We talked about in class how COX-2 inhibitors could be linked to increased MI, and COX-1 inhibitors cause damage to you gastrointestinal system. So, why take the chance when you can just eat the right things to help you out. Omega-3 fatty acids can be consumed by taking in fish oil. There have been many studies done that show the omega-3 fatty acids make the precursors to prostaglandins, which can start or inhibit inflammation. But, remember to reduce you omega-6 fatty acid intake or you increased omega-3 fatty acid intake will not work for inflammation. The second food for you to consume is ginger. It has been proven to be a slight anti-inflammatory and helps with stomach aches and pain. The third is to take bromelain enzymes. These are seen in pineapples or you can buy them as a supplement. They are a naturally occurring anti-inflammatory. Another is Cetyl Myristoleate oil, which is seen in butter and fish. It will help with lubricating your joints and also is a natural anti-inflammatory. There was a study conducted with this oil and 63.5 % of the patients that did not respond to NSAID's for arthritic pain responded to this oil. Number five is Boswellia, which is boswellic acids that ares said to reduce inflammation. This was agreed with in a study of 175 patients with rheumatic disorders and 122 patients found reduced stiffness and inflammation in four weeks. Evening Primrose Oil was used in a study with 37 rheumatoid arthritis patients and significantly reduced tenderness swelling of the patients when only taking 1.4 g a day. Cayenne Peppers in a cream form can reduce pain by depleting a chemical component of the nerve cells that give signals to the brain about pain. The last one is White Willow Bark, in which aspirin is made out of. It gives mild pain relief and does not have the adverse effects on the gastrointestinal tract as aspirin does.

So, there's eight more things you can try to reduce inflammation before jumping the list and going straight to the medicine cabinet for your NSAIDs.

CHERRIES as treatment for inflammatory diseases

2010-04-27T17:43:00.007-06:00

We've blogged this week about the anti-inflammatory diet, complementary and alternative medicine, and the use of NSAIDs in the treatment of inflammatory diseases... but now CHERRIES??

While looking more into the new and upcoming treatments of inflammatory diseases I was shocked to see cherries as one of these remedies!

On April 27th, 2010 a team of Michigan researchers presented a new study at the Experimental Biology annual meeting sayig there is more evidence of tart cherries' powerful anti-inflammatory benefits.

Using a "whole fool" approach, reseachers found that a cherrt-enriched diet not only reduced overall body inflammation, but also reduced inflammation at key sites (belly fat, heart) known to affect heart disease risk in obese, at risk rats. At risk obese rats were fed a cherry- enriched "Western Diet" characterized by high fat & moderate carbohydrate- in line with the typical American diet- for 90 days.

Cherry-enriched diets, which consisted of whole tart cherry powder as 1 percent of the diet, reduced risk factors for heart disease including cholesterol, body weight, fat mass and know markers of inflammation. This study offers further promise that food rich in antioxidants, such as cherries, could potentially reduce inflammation and have the potential to lower disease risk.

A 2nd study found similar results in humans. Ten overweight or obese adults drank eight ouncesof tart cherry juice daily for a month. At the end of the trail, there were noteworthy reductions in quite a few markers of inflammation, in addition to lower levels of triglycerides, another key risk factor for hear disease. Researchers say both studies are encouraging and will lead to further clinical studies in humans to explore the link between diet, inflammation and lowering disease risk.

This is the latest linking cherries to protection against heart disease and inflammation. Researchers believe it's the anthocyanins- powerful antioxidant compounds in cherries- also responsible for the fruits bright red color, that connect cherries to reduced inflammation, even inflammation related to muscle recovery post-exercise. Since cherries are available year-round in dried, frozen and juice forms, they say it's easy to incorporate them into one's daily diet to help manage inflammation.

I'd personally like to see further research in this area. I could add cherries to my oatmeal or to my yogurt as preventative care, until its confirmed factual across the board. Why not?

Just a thought...

Article can be found at:

http://www.eurekalert.org/pub_releases/2010-04/wsw/-nrr042620.php

Use Complimentary and Alternative Medicine in the Treatment of Inflammatory Diseases

2010-04-26T13:53:00.003-06:00

In the assigned review article Anti-Inflammatory Actions of Acupuncture, the authors discussed the use of acupuncture in the treatment of inflammatory diseases. Acupuncture is one type of complementary and alternative therapy used in the treatment of various diseases. Other types include use of herbal supplements, massage, chiropractic manipulation, hypnosis, and yoga. According the National Institutes of Health, 38.3% of American adults used complementary and alternative medicine approaches and spent $33.9 billion dollars out-of-pocket for these treatments in 2007. Interestingly, the number of Americans using complementary and alternative medicine therapies has been increasing across several years despite the limited evidence to support the use of these therapy approaches. What do you think might be the reason that these therapy approaches are utilized despite the lack evidence to support their use?

Role of IFN-gamma in Alzeihmers

2010-04-25T21:47:00.001-06:00

Reactive gliosis surrounding amyloid beta (Abeta) plaques is an early feature of Alzheimer's disease pathogenesis and has been postulated to represent activation of the innate immune system in an apparently ineffective attempt to clear or neutralize Abeta aggregates. To evaluate the role of IFN-gamma-mediated neuroinflammation on the evolution of Abeta pathology in transgenic (Tg) mice, murine IFN-gamma (mIFN-gamma) was expressed in the brains of Abeta precursor protein (APP) Tg mice using recombinant adeno-associated virus serotype 1. Expression of mIFN-gamma in brains of APP TgCRND8 mice results in robust noncell autonomous activation of microglia and astrocytes, and a concomitant significant suppression of Abeta deposition. In these mice, mIFN-gamma expression upregulated multiple glial activation markers, early components of the complement cascade as well as led to infiltration of Ly-6c positive peripheral monocytes but no significant effects on APP levels, APP processing or steady-state Abeta levels were noticed in vivo. Taken together, these results suggest that mIFN-gamma expression in the brain suppresses Abeta accumulation through synergistic effects of activated glia and components of the innate immune system that enhance Abeta aggregate phagocytosis.

Anti-inflammatory drugs (NSAID's)

2010-04-25T14:53:00.002-06:00

During class the following two weeks we are going to talk about anti-inflammatories. Many of all, if not all of us, have used over the counter drugs to reduce unpleasant symptoms such as pain. NSAIDS work by blocking the enzymes COX-1 and COX-2, these enzymes are responsible of the production of prostaglandins. Prostaglandins are produced in the cell and promote inflammation, pain and fever. These chemicals also play a role in blood clotting and help support the lining of the stomach. However, only the enzyme COX-1 produces prostaglandins to support platelets and protect the stomach lining. Since most NSAIDS block the COX enzymes, the excessive use or chronic use of these NSAIDS can lead to stomach ulcers and bleeding. The effect of NSAIDS is determined by the amount of time it takes to be eliminated from the body and how strong it inhibits the COX-1 and COX-2 enzymes. Thus, the more a drug blocks COX-1, the greater the chance of developing stomach ulcers. Not all NSAIDS will block the COX enzymes, for example "Celebrex" will block COX-2 and will have little effect on COX-1 blockage, then reducing the chance of developing stomach ulcers or bleeding; these types of drugs are called selective COX-2 inhibitors.

Dr. Weil: The Anti-Inflammatory Diet

2010-04-24T22:21:00.003-06:00

This week’s topic is anti-inflammatories. Many of you may have heard of Dr. Andrew Weil. He is a Harvard Medical school graduate who has been at the forefront of popularizing Integrative Medicine. He is the program director of the Arizona Center for Integrative Medicine here at the University of Arizona which he founded in 1994. Since his undergraduate career he has been interested in botany and the role plants can play in health. Interestingly, he wrote his thesis on the narcotic properties of nutmeg. However, in recent years he has concentrated his focus on different lifestyle interventions that may assist in medical treatment. One of these is the Anti-Inflammatory Diet.

Dr. Weil credits the Anti-Inflammatory diet as more of a lifestyle than an actual diet. However, he claims that “it is the blueprint for optimum nutrition”. He continues to say that simple changes in eating habits can counteract inflammation which is at the root of diseases such as: heart disease, Alzheimer Disease, Parkinson Disease, age related disorders including cancer and autoimmune diseases such as rheumatoid arthritis and lupus. At the heart of his diet plan is variety and a balance. The diet strives to balance omega-6 fatty acids (said to promote inflammation) and omega-3 fatty acids (anti-inflammatory). It recommends that we eat less meat and poultry which contain omega-6 fatty acids and eat more fish with have omega-3 fatty acids. It also aims to decrease refined and processed foods which often contain pro-inflammatory compounds called AGEs (advanced glycation end products) and have a high glycemic index. Dr. Weil’s modified version of the food pyramid depicts the Anti-Inflammatory diet’s key points very well.

I can definitely see the benefit in eating a healthy diet in order to maintain balance in our body and optimum functioning. I would say that the Anti-Inflammatory diet is a wonderful lifestyle to promote. However, I as being “anti-inflammatory”, I am still on the fence. But, it is all comparative: it is anti-inflammatory compared to the fast food nation we have become with diets high in saturated fat. Looking over the pyramid, the way of eating appears to be much more similar to our hunter/gatherer past with a greater emphasis on fruits, vegetables and fish and sparse consumption of poultry, red meat and sweets. Take a look for yourself and let me know what you think: http://www.drweil.com/drw/u/ART02012/anti-inflammatory-diet

Medications Used in the Treatment of Alzheimer’s Disease

2010-04-22T00:52:00.000-06:00

I had discussed in the class the research that is being conducted regarding the relationship between fibrin and Alzheimer’s Disease. I was interested in finding the current medications that are used in the treatment of AD, and came across an article from a PhD student, Carrie Hill. We know that there is no current cure for AD, which is why studies like I discussed in class are being performed. There are, however, medications that improve symptom management of the disease. When developing treatment plans, the cognitive and behavioral symptoms are considered.
I wanted to focus on cognitive symptoms, which include problems with thought processes like memory, language, and judgment. Cholinesterase inhibitors and Namenda are two kinds of medications that have been approved by the FDA for treating these symptoms. Cholinesterase inhibitors increase the levels of acetylcholine in the brain, which plays a key role in memory and learning. Surprisingly, this alone can postpone the worsening of symptoms for 6 to 12 months in about half of the people who take it. Cholinesterase inhibitors are most commonly prescribed for mild to moderate Alzheimer’s disease. Namenda, known as memantine, regulates glutamate in the brain, which plays a key role in processing information. This drug is used to treat moderate to severe Alzheimer’s disease and may delay the worsening of symptoms in some people.
Cholinesterase inhibitors can be started as soon as Alzheimer’s symptoms appear, and are most effective in the early stages of disease. When a physician determines that the cholinesterase inhibitor is no longer effective, memantine is usually introduced. Sometimes, memantine and a cholinesterase inhibitor are taken simultaneously during the moderate stage of the disease. I wonder if this combination with the addition of anti-inflammatory drugs would show a decrease in the progression of Alzheimer’s Disease?

http://alzheimers.about.com/od/treatmentofalzheimers/a/treatments.htm

Multiple Sclerosis: A Causative Analysis

2010-04-21T20:51:00.004-06:00

As we've already read in class, many researchers are looking at what they believe is/are the cause/s for the development and full expression of multiple sclerosis. We read a paper on microglia changing its phenotype to a cell somewhat identical to a phagocyte, and past research focuses have been on T cells. This condition is commonly referred to as an autoimmune response to some protein of the myelin sheaths, though this is still debatable. Current treatment can attenuate the response and lesson the symptoms, but there is no way to target any chemical treatment to the nervous tissue without effecting the entire immune system and its cells--so attenuating the cells of the immune system pharmacologically if a patient with MS also attenuates any immune response (depending on the compound used). The research of MS is further confounded by research models. Currently, rate or mice are generally used; however, since the cause of the disease is unknown, we cannot accurately say that the animal models are expressing the disease to the same or similar extent.

The affected tissue lies deep within the brain, forbidding any manual intervention that would not cause unknown irreversible consequences. Recent research has been done on the assumption that MS spontaneously begins with auto-reactive T cells, and this is supported by the mice models which much be injected with nervous tissue to develop the disease. Countering this idea is a group of scientists who have developed a murine which spontaneously develops MS. All murine models of MS have not been able to show B cell involvement, except this new model. The group found that yes, T cells are active in the model, but they are not actually inducing disease...B cells induce MS (shown by general good health in these models when B cells are removed). This is not to say that B cells are the prime player. T cells can do plenty of damage in the brain, but antibodies may be needed to sustain and develop the disease.

I just found this research interesting, and linked the paper's title above. I still feel it's important to take this with a grain of salt, simply because this is one study, published recently, in a species other than our own with a disease that is still not understood fully and may not completely represent how we express the disease. There's obviously a lot of research to do, but it's so very interesting to read about these finds which go against what the topic's body of research says.

The role of glial cells in Parkinson's Disease

2010-04-17T14:12:00.001-06:00

The glial reaction is generally considered to be a consequence of neuronal death in neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In Parkinson's disease, postmortem examination reveals a loss of dopaminergic neurons in the substantia nigra associated with a massive astrogliosis and the presence of activated microglial cells. Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, suggesting that toxic substances released by the glial cells may be involved in the propagation and perpetuation of neuronal degeneration. Glial cells can release deleterious compounds such as proinflammatory cytokines (TNF-α, Il-1β, IFN-γ), which may act by stimulating nitric oxide production in glial cells, or which may exert a more direct deleterious effect on dopaminergic neurons by activating receptors that contain intracytoplasmic death domains involved in apoptosis. In line with this possibility, an activation of proteases such as caspase-3 and caspase-8, which are known effectors of apoptosis, has been reported in Parkinson's disease. Yet, caspase inhibitors or invalidation of TNF-α receptors does not protect dopaminergic neurons against degeneration in experimental models of the disease, suggesting that manipulation of a single signaling pathway may not be sufficient to protect dopaminergic neurons. In contrast, the antiinflammatory drugs pioglitazone, a PPAR-γ agonist, and the tetracycline derivative minocycline have been shown to reduce glial activation and protect the substantia nigra in an animal model of the disease. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in Parkinson's disease.

AD-Cholesterol Connection

2010-04-14T15:04:00.000-06:00

As I had mentioned in class, there has been an establishment of cholesterol as a risk factor in the pathogenesis of Alzheimer’s disease (AD). This is a major focus of current research for AD. I came across a review article from PubMed titled, Alzheimer’s disease: the cholesterol connection, and found that in the past few years, this link has been supported through genetic, epidemiological and biochemical data. The review was from Harvard Medical School’s Neurobiology of Disease Laboratory and Genetics and Aging Research Unit.

In all forms of Alzheimer’s disease (AD) there is an abnormal accumulation of the beta-amyloid protein in specific brain regions, which is regulation by cholesterol. It was found that elevated levels of cholesterol increase the beta-amyloid protein in cellular and most animal models of AD, and that drugs that inhibit cholesterol synthesis lower the beta-amyloid levels. Recent studies have shown that the total amount and distribution of cholesterol within neurons impact the beta-amyloid biogenesis. I mentioned in class the role of the apolipoprotien E gene, the identification of a variant of this gene as a major genetic risk factor for AD is consistent with a role for cholesterol in the pathogenesis of AD.

The review describes its recent findings concerning the molecular mechanisms underlying the cholesterol-AD connection. Drugs that lower cholesterol levels are currently being considered and tested as potential therapies for the treatment of AD. Statins, which are relatively safe and have been used for a long time against high cholesterol levels, are now being directly tested in clinical trials for efficacy against AD. Some of the potentially beneficial effects of statins might also represent improved cardiovascular health, resulting in a reduction in ischemic events that are also considered risk factors for AD. An effective therapy for patients whose cognitive function does not benefit from statin treatment may ultimately consist of a combination of lipid regulating products, perhaps in combination with statins. Alternative products for cholesterol management so far include extended-release niacin, cholesterol absorption inhibitiors, ACAT inhibitors and cholesteryl ester transfer protein (CETP) inhibitors. Results from in vitro studies suggest that ACAT inhibitors are good candidates for regulating beta-amyloid biogenesis, but more research is needed to understand the exact molecular mechanisms underlying the AD-cholesterol connection. Also, it is necessary to gain an in-depth understanding of brain cholesterol metabolism. With new technology that is developing, we may be able clarify how plasma and brain cholesterol contribute to AD.

Full PDF text found at EBSCHOhost:
Title: Alzheimer's disease: the cholesterol connection.
Author: Puglielli, Luigi; Tanzi, Rudolph E.; Kovacs, Dora M.;http://web.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=2&hid=106&sid=86523406-21ed-4ee6-8f03-87d50b8af3df%40sessionmgr110

Sunlight (UV) and Multiple Sclerosis?

2010-04-12T20:06:00.004-06:00

As I mentioned in class, the 2010 CDC study found a correlation between areas of highest MS prevalence and greater UV exposure. I've chosen to explore this idea and I've found an article which I've referenced below which discusses an exploration of this trend:

For some time now, the observation that MS prevalence increases with latitude, meaning the further from the equator one gets, the higher likelihood of MS in the environment. Researchers in this article therefore look at Vitamin D and how its levels may in these different latitudes may help explain the differences in prevalence.

The article notes that 400,000 people in the U.S. have MS, of nearly 309, 055, 803 people in the U.S. (U.S. Census Bureau). UV exposure, as well as vitamin D levels can effect immune responses, but the question which arises is whether immunoregulation is done via UV exposure, or indirectly via vitamin D levels, or the two? As referenced in the article, research somewhere (not cited) has shown that increased levels of the active form of vitamin D can "block" the disease in animals.

The experiment uses mice which are genetically predisposed to an MS-like disease state, and the mice are injected with nerve antigen to initiate the disease. After initiation, one group of animals were exposed to "moderate" UV strength (equal to 2 hours of direct summer sun) for one week and the other group was irradiated every 2nd or 3rd day. They found that the exposure reduced the expression of symptoms for MS, but not the prevalence, especially in those mice irradiated every other day. The researchers also deduced that although vitamin D levels were increased with UV exposure, that factor alone could not explain the results.

The groups next area of study is to see what role skin may play with UV exposure to the production and expression of compounds involved in inflammation and the inflammatory response. The article identifies two possibilities of usefulness:

1. In the short term, if they can identify the specific active wavelength at which these same results can be obtained, this can be used as a therapy for those people suffering from MS.

2. In a more long term goal, if the group can discover the compound or compounds that the skin may be producing, the may be able to isolate or synthesize the compound and market a drug treatment.

The group does caution that this information is in the early experimental stages of development, and that results of a similar treatment may not lead to intentions.

Article

Food Allergies linked to RA???

2010-04-12T09:49:00.002-06:00

In class we discussed the possibility (mentioned in one of our lay articles) that RA may be linked to an "allergic" type of response to certain foods.

I did a little bit of research on the subject and found an article that suggests that RA symptoms may be caused by an "allergic" immune response to foods such as milk and other dairy products. The basic premise of the study the article mentions is that your body may produce antibodies to certain foods. These antibodies form immune complexes in your intestines and from there, these complexes can travel throughout your body and become inflammatory mediators.

This article mentions a study done by an individual doctor who noticed that up to a third of his RA patients felt improvement in their symptoms when they eliminated most allergy-causing foods and reverted to a basic "Stone Age" diet of fruits, vegetables, fish, and plain meat.

Here is a link to the article :http://www.arthritistoday.org/conditions/rheumatoid-arthritis/healthy-living/ra-food-allergies-2.php

Neurodegenerative Disease

2010-04-11T20:52:00.005-06:00

This week, we will be discussing inflammation associated with neurodegenerative disease. Neurodegenerative disease is the umbrella term that encompasses diseases that involve progressive dysfunction and loss of neurons in the central nervous system. Some examples of neurodegenerative diseases include Parkinson disease, Alzheimer disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis or Lou Gherig's disease, and Friedreich's ataxia. These diseases may cause decline of motor functioning and cognitive functioning, and eventually death. The impact of these diseases can be devastating to patients and their family members, not only functionally and emotionally but also economically. Thousands of dollars are spent on medical care provided by physicians, nurses, pharmacists, physical therapists, occupational therapists, speech-language pathologists, dietitians, and social workers. Thousands of dollars are also spent on research focused on preventing or remediating these diseases.

The articles for this week's discussion indicated that, while researchers are making progress toward understanding the mechanisms behind these diseases, effective treatment approaches for these diseases have not yet been discovered. Even when treatment approaches seem to work in the early phases of research, they later prove to be ineffective and even sometimes result in lethal side effects. As economic times become even more challenging, fewer and fewer studies will be approved, and the progress toward finding effective therapeutic approaches will likely be stalled even more.

What are your suggestions for improving the system for research that we have now to facilitate progress toward finding effective treatments for neurodegenerative diseases?

Arthritis and Intereukin 1

2010-04-11T17:44:00.003-06:00

One of the presented articles this week compared anti-TNF treatments with anti-IL-1 treatments in the CIA model. The article showed many more benefits when using the anti-IL-1 treatment, but did not have much information regarding human clinical trials. This article was from 1999, so I was very curious to see what some of the current anti-IL-1 treatments were.

I found the review article "Actual status of antiinterleukin-1 therapies in rheumatic diseases," which reviews some of the current clinical options for arthritis and rheumatic diseases. The article summarizes the pathophysiologic role of IL-1 and also goes over the three major types of anti-IL-1 treatments including Anakinra, Canakinumab, and Rilonacept. Anakinra is a treatment which prevents the binding of IL-1 by occupying the IL-1 receptors. Canakinumab is a fully human monoclonal anti-IL-1 beta antibody, which works by binding and neutralizing IL-1 beta. This was recently granted orphan drug status in Europe and the United States for the treatment of systemic juvenile idiopathic arthritis. Rilonacept is a dimeric fusion protein that consist of the ligand-binding domain of IL-1RI and its accessory protein, which is designed to bind and neutralize circulating IL-1.

Many of the studies have so far concluded short-term benefits in terms of biochemical markers, joint damage, and inflammation, but data for long-term use is still being collected. The advancement of these types of treatments in the past decade has really helped fight arthritis by increasing therapeutic options, but continued observation for long-term effects and further advancement is still necessary.

The full article and description of the reviewed studies can be found here:

http://www.ncbi.nlm.nih.gov.ezproxy2.library.arizona.edu/pubmed/20150813

Biological Agents for Relief of RA

2010-04-10T11:09:00.002-06:00

Several people in my life (including my mother) have struggled with RA and have now found relief with so-called "biological agents." I was interested in finding out exactly what these "agents" are and how they work (immunologically speaking . . . . )

These treatments are currently marketed as Enbrel, Remicade, and Humira. They are each a slightly different type of TNF (tumor necrosis factor) blocker. As we all know, TNF is a pro-inflammatory cytokine. These medications (which must be given as an injection or as an intravenous infusion) work by completely blocking the action of TNF. This provides great relief to many RA sufferers. For some, it even stops the progression of rheumatoid arthritis.

This may seem to be a perfect treatment! But . . . A major downside to this type of treatment (an issue that we discussed on Monday) is that our immune systems manufacture TNF for a reason. By blocking TNF completely, the immune systems of the RA patients are compromised and the patients are therefore highly susceptible to infectious diseases. I suspect that research in this area will continue until a treatment is found that inhibits progression of RA without compromising the immune system in the process.

Vitamin D and Rheumatoid Arthritis

2010-04-08T19:40:00.002-06:00

So I was looking around at studies done on treatments for arthritis and ran across this article on Vitamin D. The article is called "Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study". The point of their study was to evaluate the association between vitamin D intake and incidences of rheumatoid arthritis. They picked women between 55 and 69 who previously had no history of rheumatoid arthritis. Their diet and vitamin D intake were evaluated using a questionnaire. The women were then followed up for 11 years to check possible cases of the disease. Their results showed that a greater intake of Vitamin D lead to a decreased risk of RA.

An issue with this study is that it was only done on women. We really have no data then on how Vitamin D intake affects men. It might also be interesting to see what affect Vitamin D has on people who already have rheumatoid arthritis.

http://www.ncbi.nlm.nih.gov/pubmed/14730601

Psoriatic Arthritis

2010-04-06T23:11:00.002-06:00

Many articles about arthritis mention that there are hundreds of types of arthritis. The most common types that we have been discussing in class are rheumatoid arthritis and osteoarthritis, which are also the only 2 out of hundreds that I have heard of before. So I decided to learn about another type of arthritis.

I found an article containing information about a type of arthritis that occurs in people with psoriasis, called psoriatic arthritis. It is defined as "an inflammation of the joints that occurs in 10 to 30 percent of patients with psoriasis. It is not a type of psoriasis, but a symptom of psoriasis which is classified as a type of arthritis." The article I found stated that "Approximately 1 million people in the United States suffer from psoriatic arthritis. Most of them are adults between the ages of 30 to 50. However, psoriatic arthritis can affect juveniles and young people." I thought that it was very interesting that this type of arthritis is known to occur in children, because arthritis is usually said to occur in older people.

Psoriatic arthritis is suspected to be caused by genetics, but the cause is unknown. Therapy for this condition includes psoriasis treatment and progress that is being made in a type of medication made from human and animal proteins, called biologics.

http://www.omnimedicalsearch.com/conditions-diseases/psoriatic-arthritis.html

Arthritis and Heredity?

2010-04-05T19:58:00.000-06:00

One of you asked whether arthritis is hereditary so I decided to try to find some information on it. Discovery Health posted an article titled “Arthritis and Heredity” in which it talked about the many forms of arthritis and which ones tend to run in families. The most common varities of arthritis are osteoarthritis and rheumatoid arthritis with arthritis affecting one in seven Americans. While the article did not talk very much about the heredity of arthritis too much it did provide a lot of information on how arthritis can develop and what types of people are most affected. In osteoarthritis may be due to inactivity caused by muscle weakness and obesity. This form of arthritis is more common in women and in older people. Rheumatoid arthritis involves the body’s immune system attacking its own tissues. Women are much more likely than men (2 times more) to have this form of arthritis. Unlike osteoarthritis, rheumatoid arthritis tends to affect people of all ages and can travel throughout the body.

Here is the link to the site:

http://health.discovery.com/centers/arthritis/arthritis_qa/arthritis_hered.html

Hydrotherapy and Tai Chi effects on Osteoarthritis

2010-03-30T11:18:00.002-06:00

As I was looking around for arthritis related topics to blog on, I came upon an interesting study that looked at two different activities and their effect on symptoms of OA.

The study done in 2007 ran a 12 week test, with a 12 week follow up, on 152 elderly sufferers of osteoarthritis of the hip or knee. Subjects needed to be about 70 years of age and classified as inactive. 55 subjects were placed in a 12 week hydrotherapy class, 56 subjects were placed in a 12 week Tai Chi course and, 41 were placed in a control (wait list). Each session was 1 hour long and held twice a week, making a total of 24 classes.
Results showed a decrease in joint pain for patients in both hydrotherapy and Tai Chi groups based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. Physical function also improved in these two groups and was tested using the "Up and Go" test, 50-foot walk time, and timed stair climb. The "Up and Go test" is a measure of a patient's ability to get up out of a chair without arm support, walk several paces out and back, and sit back down without arm support. These improvements were sustained by most subjects for an additional 12 weeks after the classes.

http://www.arthritiswa.org.au/documents/PAFORMmainresultsACR.pdf

2010-03-28T23:10:00.002-06:00

The article "What A Pain," from The Boston Globe, referenced the Arthritis Foundation a few times, so I decided to learn more about it. I went to the website and found that it was actually very helpful and informative about arthritis. The website has information about many types of arthritis, events to raise awareness, and current research.

One of the topics that is currently being researched that I found interesting was in an article called, "Clarifying the Role of Fat in Osteoarthritis." It mentions how obesity is thought to increase the risk of arthritis due to increased weight and force on joints. The article goes on to say, "excess fat may take a toll in another way, too. Fat is a metabolically active tissue that secretes cytokines, or signaling molecules, that can trigger inflammation. An increase in cytokines may help to explain why, for example, obesity increases the risk not only for osteoarthritis in the knees, which would be directly impacted by the increased load, but also in the wrist, which is not a weight-bearing joint."

Research is currently being done on this topic. Here is the website to the Arthritis Foundation webpage
http://www.arthritis.org/

Different Categories of Crohn's Disease

2010-03-28T13:57:00.002-06:00

Interestingly I stumbled on a website that contained alot of really interesting information about Crohn's Disease. A lot of the material was, more or less, a review of things that we have seen in the various papers we have read; however, I did find a couple of interesting things that we have not really talked about. The first is different categories of Crohn's. The following table was taken from the website Crohns.net and lays out various forms of the disease mostly based on the origin of the symptoms.

Subcategory	Area Affected
Ileocolitis	The most common form of Crohn's Disease, affecting the ileum and colon
Ileitis	Affects only the ileum; fistulas or inflammatory abscesses possible
Gastroduodenal Crohn's Disease	Affects the stomach and duodenum; bowel obstruction possible
Jejunoileitis	Patchy areas of inflammation in the jejunum; fistulas possible
Crohn's (Granulomatous) Colitis	Affects only the colon and anus; anal fistulas, abscesses, and ulcers possible

Adapted from Crohn's and Colitis Foundation of America, Inc. 2004
http://www.ccfa.org/research/info/aboutch

There is also some interesting information about diseases that can arise from Crohn's. Of these one of the most common is osteoporosis. This comes about for two reasons; the first is a lack of nutritional absorption of vitamins d and k and the second is the treatment of the disease with corticosteroids. Both of these lead to decreased bone density and thus the condition of osteoporosis. Some other major medical problems that could occur either as a result of the different therapies or the disease state itself are colorectal cancer, infertility, bacterial infections, even a higher possibility of ischemic stroke. The increase in risk for stroke is thought to be because of a vitamin B deficiency and a hypercoaguable state brought on as an effect of the disease.

If you would like to to read more about this or see more about Crohn's in general visit crohns.net.

Information taken from
http://www.crohns.net/Miva/education/articles/Potential_Sequelae_of_Crohns_Disease.shtml\
http://www.crohns.net/Miva/education/articles/Crohns_Disease_Table_1.shtml

Stress and IBD

2010-03-28T03:07:00.004-06:00

There was an interesting correlation mentioned while I was researching about inflammatory bowel disease (IBD). This article examined the association between stress and IBD. In the past, there were several studies done that illustrated how IBD is affected by psychological components such as stress. With recent findings, research has shown that stress does not induce IBD; however, because of the past association between stress and IBD, the general public believes this false correlation. Often times, diseases such as IBD bring about stress and manifest effects through symptoms. In IBD, irritability, depression, or panic attacks can occur due to stress making IBD worse.

Another article I found on PubMed looked into the psychological aspects of inflammatory diseases and mentioned that stress does play a factor in IBD. Not only does it aggravate IBD, some believe that stress can cause IBD. Stress can affect the functions of secretion, vascular structure, and motility of the GI tract.

To examine if stress is associated with IBD, another case study evaluated stress by life even occurrences in Crohn’s disease and ulcerative colitis patients along with two control groups. Various questionnaires were utilized to assess stress in patients. It was concluded in this paper that stress such as life event is not considered an independent risk factor for the cause of IBD.

It appears to me that there is varying knowledge of the association of stress and IBD. The general public seems to relate the two as one causing the other while medical researchers do not categorize it as a risk factor but a factor that aggravates onset of the disease.

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=3765643&ordinalpos=237&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=3765643&ordinalpos=237&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Some Interesting and Recent Studies on IBD

2010-03-26T00:26:00.001-06:00

Today, as I was searching the web for some fun facts we may not have touched on regarding IBD, I came across a recent news article that caught my attention. Published only yesterday, the lay article citing a very recent study on IBD spoke of a vaccine currently in development which, “can delay IBD development, control inflammation and thereby reduce the risk of future cancers.” The vaccine targets the MUC1 protein produced by the body which is found in large amounts in a patient with IBD. When tested in animal models the vaccine was shown to delay the onset of IBD symptoms which then reduced the risk of colon cancer. This recent finding could lead to a possible therapeutic option to lesson or delay the symptoms of IBD in a patient. I attempted to find the original article published in Cancer Prevention Research but was unable to do so due to the recent date of the publication.

Here is the link to the lay article I found online:

http://news.xinhuanet.com/english2010/sci/2010-03/25/c_13223568.htm

Here is a website with more information and specifics about the MUC1 protein:

http://www.genecards.org/cgi-bin/carddisp.pl?gene=Muc1

Also when I was scouring the web for different IBD tid-bits I came across a nice question and answer site with a good general overview of what is known today about IBD. It contains much of the terminology covered throughout the articles we have read over the past two weeks. Here it is:

http://www.ittakesmorethanguts.com/media/faq.htm

The final article that caught my eye on my search proposed a connection between IBD and venous thromboembolisms. The study shows that patients suffering from IBD are sixteen times as likely to have a venous thromboembolism than people who do not have IBD. The study followed 13,756 patients with IBD and 71,672 healthy controls. Of the subjects, 139 IBD patients reported a venous thromboembolism and 165 reported cases in the control group.

Here is a link to the lay article:

http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/18362

Here is a link to the journal article:

Grainge M, et al "Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study" Lancet 2010; DOI: 10.1016/S0140-6736(09)61963-2.

The main page where I found this article has quite a few articles about IBD. Here is the link to that if you would like to read more:

http://www.medpagetoday.com/Gastroenterology/InflammatoryBowelDisease/

IBD Management

2010-03-16T00:53:00.003-06:00

While going through my daily browsing through Yahoo Health, I stumbled upon an article relating to Inflammatory Bowel Disease (IBD). Since many of the articles we read touched upon treatments targeting the initiation of inflammation before tissue damage occurs, I thought it would be interesting to read about various treatments. Treatment is individualized based upon each patient. The physician and the patient work closely to develop which treatment goal is most effective. The goals are developed based upon the intensity of IBD and the side effects of a treatment. Managing IBD serves to improve quality of life by either reducing symptoms or eliminating them. This article discusses the use of corticosteroids for IBD to reduce the inflammatory response in ulcerative colitis and Crohn's disease. Typically, corticosteroids are used by people with severe symptoms because they stop symptoms by putting patients in remission. Long term use is not encouraged because they have side effects which limit treatment. Using systemic corticosteroids causes side effects such as acne and severe mood changes, adrenal insufficiency, visual changes, cataract formation, and aseptic joint necrosis.

Pregnant women use corticosteroids to manage IBD as well. They are considered as a safe means of treatment when symptoms flare up. Before, women with IBD were advised not to have children because they are more at risk for having a miscarriage, to deliver prematurely and to have a low birth weight infant. Medications have been used to help manage this problem in order for women to have a more successful pregnancy.

One common factor that develops with IBD is depression. This coexistence further decreases the “fair and poor” quality of life many IBD patients have described. Nearly 30-50 percent of people with IBD also suffer from depression and of these people, 30 percent develop a dependence on medication and alcohol.

Sources:
http://www.aafp.org/afp/980101ap/botoman.html
http://health.yahoo.com/digestive-medications/corticosteroids-for-inflammatory-bowel-disease/healthwise--hw40876.html;_ylt=AhI4dhx_I93e9ODpBwFreVFLvs8F

UA Live Fit

2010-03-15T22:51:00.004-06:00

During several of our class discussions regarding inflammatory diseases, we have mentioned the importance of diet and exercise in preventing and remediating some of these diseases. We have also discussed the lack of education in the U.S. specifically about diet and exercise. I just learned that UA Campus Health is introducing a new web-based program to educate students about living healthy, active lives. Apparently, everyone with a UA net ID and password will have access to this web-based service, which is described in the UA News (see link below) as “kind of like having an online personal trainer and nutrition adviser that’s available to you 24/7.” The website provides information about preparing nutritious food with limited resources, finding nearby restaurants that serve nutritious food, implementing new exercise programs, and even tracking fitness goal progress. For more information, follow this link to the UA news article:

http://uanews.org/node/30533

Surgical Options for Crohn's Disease/Ulcerative Colitis

2010-03-12T14:48:00.003-07:00

Alright so we talked about many of the different treatment options available for people suffering with Ulcerative Colitis or Crohn's Disease including immunosuppressants, steroids, anit-inflammatories, and probiotics; however I thought that I would post about the surgeries available for these people. The problem with surgery is that the Crohn's & Colitis Foundation of America have found that about 50% of patients that have surgery will see a recurrence of the disease, but they do state that medication (like the ones listed before) taken after the surgery can help the patient avoid, or at least delay, a recurrence.

There are really three options depending on the severity of symptoms. The first surgery is called a strictureplasty. This procedure is used to widen the narrowed diseased areas of the small intestine. FYI the diseased areas are called strictures and are a result of scarring brought on by the chronic inflammation of the disease. The surgery is as simple as cutting open the stricture then sewing it back up crosswise.

The second option is called a resection. This surgery is used when strictures are very long or there are many of them within a close vicinity and simply cuts away the diseased section then the healthy ends to the intestine are reattached. Finally if the damage done by Crohn's is really bad then a colectomy or proctocolectomy may be needed. The colectomy procedure removes the whole colon while the proctocolectomy does the same but also removes the rectum which means that another procedure (ileostomy) would be needed to create a stoma that would allow the patient to pass stool.

There are two quality of life issues that are presented to a patient; especially with a surgery like the proctocolectomy. The first is that a colostomy bag is needed when the rectum is removed; which means that it will have to be emptied multiple times a day and obviously would have to be worn all day. Also if too much of the intestine is taken it is possible to end up with short bowel syndrome. Essentially this can lead to malnutrition/dehydration and diarrhea. This happens because the decreased length of intestine does not provide adequate room for absorption of nutrients, minerals, and water. To counteract this people with short bowel syndrome have to take supplements and eat very small meals at a much more frequent pace then normal.

All in all it may seem as though surgery is a bad option; however it is essential when medications no longer control the symptoms.

Here are the websites where I found this info:
http://www.ccfa.org/info/surgery/surgerycd
http://digestive.niddk.nih.gov/ddiseases/pubs/shortbowel/
http://www.umm.edu/patiented/articles/what_surgical_procedures_crohns_disease_000103_10.htm

IBD in Children and the Difference Between IBD and IBS

2010-03-11T19:23:00.001-07:00

As a volunteer in the Pediatric Unit at the Tucson Medical Center over the past year something I find interesting is the communication between doctors and their child patients. It made me think about my topic this week and how I would go about explaining to a child who has IBD exactly what was going on inside of their bodies. The most common age range for this disease is 15 to 30, however, there are reported cases of even younger children who are affected. So how do you bring up a “sensitive” issue like this to a child? I have seen some pretty interesting techniques from the use of puppets to doctors addressing a child as if they were another doctor. You would be surprised what some kids can remember! So I found a couple of internet sites dedicated to the discussion of IBD in a way children would understand. The links are below:

http://kidshealth.org/parent/medical/digestive/ibd.html#

http://kidshealth.org/kid/health_problems/stomach/IBD.html

Here is also a site where kids explain their disease in their own words:

http://growingupibd.org/

The last link is important in that it shows the diversity of the symptoms present in a population of children. Each kid’s story is different and so are their needs as a patient. That is probably the biggest thing I have learned as a volunteer. What might work on one child may totally backfire with another. I have seen the puppet trick give a child a better understanding of their illness in one case while bringing a different child completely to tears. This is an important aspect of medicine to keep in mind for anyone in the field. The needs of patients both young and old should be examined on an individual bases. There is no one correct way to address a child about their illness.

------------------------------------------------------------------------------------------------------------

I also thought it would be good to address the difference between IBD and IBS for those of us who needed clarification. Both IBD and IBS have similar symptoms that may cause confusion to a patient. Symptoms of both include: alteration of bowel habits, pain, discomfort, bloating and increased urgency to use the restroom. The difference between the two illnesses is that IBS does not involve inflammation of the GI tract where IBD is identified by the inflammation of the mucosal tissue in the intestines. IBS is also known as a spastic colon or bowel and is an example of a functional disorder. A functional disorder is defined as “a disorder of physiological function having no known organic basis.” (http://medical-dictionary.thefreedictionary.com/functional+disorder). In other words there is an abnormality in the function of the GI tract but there are no physical signs of a problem. All in all, IBD is a more serious illness than IBS, The physical toll that the chronic inflammation can take on the GI tract can lead to ulcers as well as anemia from stool blood loss.

Probiotics

2010-03-08T13:50:00.004-07:00

One of the lay articles assigned for this week had said that Americans consume fewer fermented products that any other developed country and I agree with that author. Americans tend to turn to drugs when dealing with health issues, while Asian and European cultures stick to the more "natural" remedies. After reading that lay article that talked about probiotics in things like yogurt and fermented milk, I was curious because we had recently done an experiment to isolate microbes from yogurt in micro lab. So, I decided to try and search for the "best" brands of yogurt to eat. Instead I came across another article which talks about Kimchi, which is a spicy Korean dish that contains a strain of the probiotic Lactobacillus that was found to help reduce cancer cell growth. I'm not saying you should go and eat lots of Kimchi (because it's definitely not for everyone. I personally don't like it), but I just found this pretty surprising and interesting that such unexpected foods have promising health benefits, so I decided to share. Enjoy!

The full article can be found here:
http://www3.interscience.wiley.com/cgi-bin/fulltext/123206305/HTMLSTART.

Stroke Symptoms

2010-03-07T21:44:00.002-07:00

Hey guys! Here is a great way that I found from the National Stroke Association to remember the symptoms of a stroke! It's called "Act F.A.S.T."

FACE
Ask the person to smile.

Does one side of the face droop?

ARMS
Ask the person to raise both arms.

Does one arm drift downward?

SPEECH
Ask the person to repeat a simple sentence.

Are the words slurred? Can he/she repeat the sentence correctly?

TIME
If the person shows any of these symptoms, time is important.

Call 911 or get to the hospital fast. Brain cells are dying.

An additional method that can be used when one suspects a stroke is as follows: SUDDEN numbness/weakness of the face, arm, or leg, especially one side of the body. SUDDEN confusion, trouble speaking/understanding. SUDDEN trouble seeing in one or both eyes. SUDDEN trouble walking, dizziness, loss of balance or coordination. SUDDEN severe headache .

I also found some surprising statistics including the one which stated that twice as many women die from stroke every year than from breast cancer. I also found it interesting that strokes are preventable. Here are the guidelines offered on how to prevent a stroke:

Stroke Prevention Guidelines

All this information came from www.stroke.org.

"Deadly Inflammation, But No Sign of Infection"

2010-03-04T21:14:00.005-07:00

Not necessarily relevant exactly, but interesting nonetheless:

A paper in the journal Nature published evidence that during systemic inflammatory response syndrome (SIRS), blood plasma was found to have large amounts of mitochondrial DNA (1000 times more than in normal plasma).

The study suggests from the data that when there is damage to many cells, they will release "mitochondrial debris" and the body will respond to these debris as if it were a foreign pathogen. The study tested the neutrophil response to increased mitochondrial debris in the plasma and found a similar response to the debris as one would see toward foreign invaders . If you choose to read, the study further tests the idea that these mitochondrial debris elicit an immune response by the neutrophils.

Link to Nature Article

Cardiovascular Disease

2010-03-04T13:02:00.002-07:00

The four most common types of cardiovascular disease are coronary heart disease (which includes heart attack and angina pectoris or chest pain), stroke, high blood pressure and heart failure. Smoking, unhealthy diet, lack of physical acitvity, and over use of alcohol increase the risk for CVD. In 2000, CVD claimed over 945,000 lives, that’s one in every five deaths. In 2006, CVD claimed 831,272 lives which was 34.3% of all deaths or more than one of every four deaths! That’s way more than deaths due to cancer (559,888), accidents (121,599), and AIDS(12,113) combined. CVD occurs almost equally in men and women however, after menopause women have an increased risk.

Cardiovascular disease is the number one killer of people with diabetes, even when glucose levels are kept under control. People with diabetes are two to four times more likely to develop cardiovascular disease due to a variety of risk factors including high blood pressure, lipid disorders, high LDL, high triglycerides, low HDL, smoking, obesity, or high blood sugar levels. Recent studies have also shown that insulin resistance may be another risk factor.
Engaging in physical activity for at least 30 minutes every day, eating at least five servings of fruit and vegetables a day, and limiting your salt intake to less than one teaspoon a day of the week will help to prevent CVD.

Diet and Cardiovacular Disease

2010-02-25T18:18:00.002-07:00

As we all know by now cardiovascular disease is a pretty important topic in today’s health news being THE top cause of death in the U.S as well as worldwide. It accounts for 40% of all deaths in the U.S. which is more than all forms of cancer combined! Not that this should scare people because it seems scare tactics rarely work but I just wanted to list a few top risk factors for CVD (as in introductory):
Age
High Blood Pressure *
Diabetes*
High cholesterol*
Cigarette smoking*

When I started background research I couldn’t help but keep going back to how four of the five of these are modifiable or manageable(*). Three are commonly linked to one’s diet and the other is smoking which to me is a voluntary act. Sure, some of these have been found to have a genetic influence however even if you don’t smoke that would cut your risk factor by one! The main idea I’m trying to get across is diet can play such a large role in this very serious disease and killer. You can’t avoid getting older but you can try avoiding foods that lead to disease.

Fatty plaque of course is what we know causes the narrowing of coronary arteries leading to blocks causing Heart attacks and strokes. These plaques accumulate from adolescents which means what we have been eating all these years MAY eventually catch up with us later in life. This might be why they call CVD the “silent disease” with little to no symptoms besides high blood pressure and why heart attacks seem to happen out of now where.

Since fatty plaque accumulates from adolescents wouldn’t it seem logical to start our younger generations on healthy eating and educating them in order to make a dent in this possible health epidemic? Nutrition education to me doesn’t seem to be a fix all but I find it to be a step in the right direction for reducing High Blood Pressure, type 2 diabetes, and high cholesterol ultimately cardiovascular disease!

It gives me great joy to see some big names in America take on this task of educating children on making healthier eating choices. The biggest example is Michelle Obama’s campaign against childhood obesity. She targets implementing heather foods in school systems where children receive majority of their meals. Check out http://www.whitehouse.gov/the-press-office/remarks-first-lady-event-surgeon-generals-report for more information and her thoughts and goals for the campaign.

Another similar movement I’ve recently discovered is Jaime Oliver’s Food revolution. Take a look at this famous chief’s moving T.E.D talk (a bit long but worth it) where he talks about bringing in fresh foods from local farms into schools as well as nutrition education for American youth. On a side note: He’s not even American and he cares this much about a serious topic affecting so many Americans.

http://joshpremuda.com/2010/02/12/jamie-oliver-wins-ted-prize/

Connection Between Gum and Heart Disease

2010-02-25T13:25:00.003-07:00

Coronary heart disease is a narrowing of small blood vessels that supply blood and oxygen to the heart. It is usually caused by atherosclerosis, a condition which occurs when fatty material and plaques buildup on the walls of arteries. Its most common symptom is chest pain, however, in some cases no symptoms may be present. Treatment for heart disease can range from taking medication to surgery. Researchers have found that people with gum disease are almost twice as likely to suffer from heart disease. There are several theories that have shown a link between heart disease and periodontal disease. One theory is that oral bacteria effects the heart by entering the bloodstream and attaching to fatty plaques in the coronary arteries which contributes to clot formation. Another theory is that the inflammation caused by periodontal disease increases plaque buildup, which may contribute to swelling of arteries. There are more ongoing studies to further see the connection between gum and heart disease.

2010-02-22T10:58:00.003-07:00

Did anyone see the "Live Healthy" article about a link between gum disease and rheumatoid arthritis in the February issue of Shape Magazine? The article says:

At the end of a long day, it's tempting to cut corners on the whole floss-brush-rinse routine. But a new study from the University of Minnesota reveals that skimping on your dental care can harm your joints along with your teeth. Researchers found that people with gum disease are nearly three times as likely to develop rheumatoid arthritis - a condition that can cause stiffness, pain, and fatigue - than those with healthy grins. Since gum disease has also been linked to heart problems, it's worth spending a little more time on your mouth, starting tonight!

So brushing your teeth can prevent you from developing rheumatoid arthritis and heart problems?! Or is it just that gum disease is an inflammatory disease, and the presence of one inflammatory disease may indicate the presence of another inflammatory disease like rheumatoid arthritis or heart disease?

Stroke linked to Birth Control

2010-02-22T06:32:00.002-07:00

It has been noted that the 4th generation birth controls Yasmin, Ocella, and Yaz have had major side effects including strokes, heart attacks, deep vein thrombosis and other types of blood clots, pulmonary embolism, and gallbladder disease. These symptoms have been seen in women who were otherwise healthy with no known history of risks for the mentioned diseases. As I was searching for more information on stroke and heart disease, I stumbled across many pages of articles that warn women about the effects of these popular birth controls. One such article had the following warning:

If you or a loved one has taken Yasmin, Yaz, or Ocella for birth control or to treat symptoms of PMDD or acne and suffered gallbladder disease, stroke, heart attack, blood clots, deep vein thrombosis, pulmonary embolism, or other serious injuries, we encourage you to contact qualified legal representation today to evaluate your possible legal rights.

It is interesting to note that on the YAZ homepage, the list of side effects include all of the above diseases as risks for any woman taking any birth control. So I searched a few other commonly used birth controls and found this statement to be true.

Atherosclerosis

2010-02-21T21:44:00.001-07:00

Atherosclerosis is a disease in which fatty plaques, such as cholesterol, collect within the walls of arteries. Build up of these plaques can eventually occlude the vessel leading to a loss of blood flow; the location of this blockage will determine the severity of the disease. Though the end result of this disease is what is most commonly seen as the dangerous, the onset and progression can also lead to many complications as described by the various diabetes research articles. The progression of atherosclerosis, though gradual is thought to have a big effect on the secretion of C-reactive protein, a key inflammatory marker. Though these articles do not determine if the inflammation is causing the atherosclerosis, or if it is the other way around, they make clear the link between the two. There needs to be more research to determine if the treatment of inflammation can prevent diseases such as this. The effects of this information has the potential to be extremely profound.

Lipoproteins and Inflammation

2010-02-17T11:32:00.000-07:00

Lipoproteins are amphipathic molecules that encompass lipids and facilitate their transport in hydrophilic substances, such as the bloodstream. High-density lipoprotein (HDL), one of the five groups of lipoproteins, carries about 30% of blood cholesterol. High levels of HDL-bound cholesterol have been associated with a decreased risk of cardiovascular diseases, while low HDL has been linked to an increased risk for heart disease. All of the logic behind this is unknown, however the metabolic review article links this effect to its anti-inflammatory effects. Excess lipids undergo oxidation, and can induce inflammation in the liver and other organs. This can lead to many, many problems. Antioxidants and anti-inflammatory defense balance inflammation, however if overwhelmed can fail. HDL is very useful in maintaining the inflammation balance because it can increase anti-inflammatory effects and decrease genes with pro-inflammatory products, by decreasing their oxidation.

Beer Bellies Indicate a Healthy LifeStyle

2010-02-14T20:05:00.002-07:00

During Valentine’s Day weekend up to San Diego, my family and I stopped at a rest stop called Flying J. Flying J is basically a fuel-pit-stop for many road travelers, especially truck drivers. As I stood there pumping fuel into my parent’s vehicle, I observed the many truck drivers around my surroundings.

As each individual driver was busy loading their truck with fuel, sugar loaded or caffeinated drinks, and empty calories of junk food, I thought to myself that truck drivers are the number one people who struggle with obesity. As truck drivers carry our food, cars, and clothing from one location to another, their chances of eating a healthy diet and getting enough physical activity is basically slim to none.

However, I remembered reading in Journal of Inflammation for our class discussion, claiming that obesity in relation to insulin resistance is not claimed to support an association with body mass index, visceral or subcutaneous abdominal adipose tissue, and waist circumference but rather serum C-reactive protein and fibrinogen as well as spleen longitudinal diameter representing a reliable tool in confirming insulin resistance for the obese. Therefore, does this simply mean that normal-weight people might be at higher risks of obesity than truck drivers who appear to be “9-months pregnant”?

This then concluded, as I got back behind the wheel, that if it’s really what’s on the inside that counts then a lot of people who simply appear normal-weight are in big trouble.

Link between Diabetes and Obesity

2010-02-14T18:07:00.005-07:00

I found a very interesting article about possibly discovering a link between obesity and type II diabetes. A novel protein called pigment epithelium-derived factor (PEDF) which is released from fat cells is said to trigger the events that can lead to type II diabetes. A professor from the university states, "When PEDF is released into the bloodstream, it causes the muscles and liver to become desensitised to insulin"(Monash University). Their research shows that increasing PEDF in the blood causes diabetic reactions, but blocking PEDF reverses these actions to the point that the body starts to become responsive to insulin. Further research is still needed about this protein to eventually lead to a major breakthrough drug that can combat diabetes; but I thought this article was really cool and you all should check it out.

www.sciencedaily.com/releases/2009/07/090708090917.htm

Correlation Between Adipocytes and the Immunity

2010-02-11T13:18:00.005-07:00

Obesity is sometimes characterized by a low-grade systemic inflammation. This systemic inflammation is generally the cause of cardiovascular disease and type II diabetes in obese people. What causes these inflammatory response are adipose tissue partially composed of macrophages and lymphocytes. These adipose tissues release a wide variety of anti-inflammatory and proinflammatory factors, e.g. adipokines leptin, adiponectin and chemokines.

Adipocytes and macrophages both contribute to the stimulus of IL-6 and TNF-alpha, and high levels of IL-6 have been linked to CRP, which is a protein found in obese people. In addition, TNF-alpha can lead to insulin resistance by inducing serine phosphorylation of the insulin receptor, which can inhibit insulin signaling.

Although it is not clear on what causes these proinflammatory factors to be released from adipose tissues to produce the chronic inflammatory state of visceral diabetes, it is becoming a know fact in the research world that these inflammatory mediators are involved in the development of insulin resistance.

To see more about this topic visit:www.jacionline.org/article/PIIS0091674905004173/fulltext

The Role of Nutrition in Inflammation

2010-02-07T22:21:00.004-07:00

In the articles Inflammation and Metabolic Disorders and Inflammation in Obesity-Related Diseases, the authors indicated that high-fat foods can contribute to inflammation. Navab, Gharavi, and Watson (2008) further reported that foods which are characteristically "high fructose, high-energy density, low fiber, and low dairy" can lead to inflammation. There are some confusing contradictions in the nutrition recommendations in the lay articles, however. In the article that we discussed last week The Inflammation Age, the author indicated that whole grains, eggs, and poultry can result in inflammation. Whereas, in the article A Good Diet Can Defeat Chronic Inflammatory Illnesses, Garrison recommended eating sprouted breads, egg whites, and lean proteins like chicken. She also recommended eating fruits and vegetables, but also indicated that eliminating tomatoes and "nightshade vegetables like eggplant and bell pepper" can reduce the symptoms of inflammation. So what role do foods actually play in inflammation? Which foods should people avoid and which foods should people consume to minimize inflammation?

Spring Collection 2010, Style-Big and Bigger

2010-02-07T02:01:00.004-07:00

As the society continues to promote increased food intake, non-healthful foods, and physical inactivity, recent studies has shown that the American population has become more overweight. The percentage of being considered as overweight or obese in the United States is now 1 out of 3.

We confess that kids these days spend less time exercising and more time in front of the television, computer, or video-games. In addition, busy parents gradually have fewer “spare-time” with their kids and/or to prepare nutritional home-cooked meals. As we become more prone to quick and easy, individuals gradually adapt to a lifestyle that is comfortable as sweat-pants.

In the United States, the average dress size for a healthy woman has been considered to be an 8. For a healthy man, 40 was considered regular. However, nowadays people now consider the average dress size to be a 14 (the size at which “plus-size” clothing begins) for women and 44 for men. In other words, obesity has risen dramatically over the past few years in America.

From luxurious names to mass retail chains, clothing size labels have scaled down making consumers feel better. Therefore, by making the clothing bigger and the sizes smaller, are we slowly being brain-washed that a bigger size is the “normal-size”? Are we then programmed to easily choose the “deluxe value meal” at fast food restaurants? In that case, do clothing companies collaborate with fast food chains to promote better business?

This only led me to think about the Wendy’s $2.99 value-meal commercial. http://www.youtube.com/watch?v=j5Sz9Ms54ho Would the rates of obesity decrease if we didn’t get the amount of food that we paid for?

Measurement of airway inflammation in asthmatic children

2009-12-24T19:12:00.001-07:00

A group in Italy has been searching for a way to screen children for asthma, and get a reliable indicator of the level of inflammation in the airway. Initially the group looked into measurements of the temperature of exhaled breath to provide a marker of airway remodeling (1). The increase in the exhaled breath temperature (EBT) has been hypothesized to result from increased vascularity of the airway wall (1). Other studies have noted the correlation between inflammation and temperature and given mechanistic hypothesis (4). Previous studies also showed preliminary results that linked metalloprotineinase-9 (MMP-9) to the remodeling process. The preliminary data showed a correlation when children were exposed to allergens between the exhaled temperature and MMP-9, measured through enzyme-linked immunoabsorbant assays on sputum.

The same group abandoned the tempurature measurement to persue measurements of exhaled nitric oxide (eNO) and fractional exhaled nitric oxide (FENO). The measurements of FENO have been shown to correlate with eosinophilic inflammation in asthma patients. The studies indicated that allergen avoidance modifies inflammatory parameters and that the initial extracellular bioelectrical conductivity measurements provided a reliable non-invasive method to assess airway inflammation (2). The method was also tested for correlation against the Childhood Asthma Control Test (C-ACT), when used together produce a reliable diagnostic and predicting tool (3).

(1) Piacentini, G.L. , et. Al. Exhaled breath temperature as a marker of airway remodeling in asthma, a preliminary study, Allergy 2008:63; 484-485
(2) Peroni, D.G., et. Al . Bioimpedance monitoring of airway inflammation in asthmatic allergic children. Allergologia et Immunopathologia 2008
(3) Piacentini, G.L. , et. Al. Childhood Asthma Control Test and airway inflammation evaluation in asthmatic children. Allergy 2009
(4) Piacentini, G.L. , et. Al. Exhaled air temperature in asthma: methods and relationship with markers of disease. Clin Exp Allergy, 2007; Mar;37(3): 415-419

operational tolerance post liver transplants

2009-12-23T08:52:00.000-07:00

One of the interesting groups of patients that I have come across in the last 1 1/2 years are the patients who receive liver transplant and over time develop "operational tolerance" of their graft, meaning that they are able to wean off immunosuppressive agents over time. Operational tolerance is defined clinically as the "lack of acute or chronic rejectionn and graft survival with normal function and histology in an immunosuppressant-free, immunocompetent host."

Anectodally, we see this most commonly with teenagers who have become non-compliant with their immunosuppressive regiments. And of the solid organ transplants, liver transplants are most likely to become tolerated by the host's immune system. In general, children are more likely than adults to develop operational tolerance. In the literature, 3-20% of patients may be able to wean successfully off of immunosuppressants.

This brings the questions--why do some patients reject the graft and others become tolerant? How can we predict which patients will develop operational tolerance?

A study in Brussels observed that pediatric patients who developed operational tolerance had higher levels of IL-10 and decreased TNF-alpha and IFN-gamma levels soon after transplant (2 hours, 1 day and 4 days). This could potentially identify a cytokine profile that could possibly predict patients who would become tolerant. Other studies have suggested that there is an elevated number of T regs in patients who develop tolerance (this would correlate with higher amounts of IL-10, which is produced by T regs as we are aware).

T regs express CD4/CD25 and the transcription factor FoxP3. There are studies that suggest that FoxP3 can also be induced by peripheral T cells that are CD4+/CD25-.

This study (Pons et al) set out to monitor T cells in patients s/p liver transplant as immune suppression was weaned. They selected 12 adults who had: received a liver 2+ years prior to the start of the study, were 1+ years past a rejection episode, and had no evidence of autoimmune liver disease or viral infections. They were monitored prospectively as their immunosuppression (cyclosporine and prednisone) was gradually weaned. Flow cytometry was used to identify lymphocytes, and FoxP3 mRNA levels were detected by PCR. The researchers looked at populations of T lymphocytes (CD3+CD4+, CD3+CD8+, CD3+Vdelta+), B lymphocytes (CD19+), and NK cells (CD3_CD16+CD56+) prior to withdrawal of immunosuppression and then at various periods during withdrawal of immunosuppression. They compared these findings to another group s/p liver transplant who were immunosuppressant-dependant (ID) and another group who was healthy (H). There was a similar profile of T regs (CD4+CD25+) in all immunosuppressed patients.

Over the course of withdrawal of immunosuppression, 5/12 patients developed tolerance. The percentage of CD3+, CD4+, CD8+, CD19+, CD3-CD16+CD56+, CD8+CD28- populations did not change during withdrawal (in the patients who ended up becoming tolerant and those who ended up rejecting). However, in the group that became tolerant of their graft, T regs increased significantly during the withdrawal (beginning at the time of assessment pre-withdrawal and ending at the tolerance point). The group who rejected did not exhibit this increase in T regs. They noticed a similar pattern with FoxP3 mRNA expression.

This study was unable to predict (prior to immunosuppression withdrawal) which patients will become tolerant. However, they were able to determine that T regs and FoxP3 expression dramatically changes in patients who become tolerant.

Continued research in this area will greatly influence care of patients post transplant. In the past, it has been gold standard to continue immunosuppression, tolerating the side effect profiles of the medications. Identifying patients who will successful become tolerant will help to titrate medications, improve quality of life, and decrease harmful side effects of the immunosuppression medications.

Pons JA et al, FoxP3 in peripheral blood is associated with operational tolerance in liver transplant patients during immunosuppression withdrawal. Transplantation. 2008 Nov 27;86(10):1370-8.

Orlando G et al, Operational Tolerance after Liver Transplantation. J Hepatology 2009;50:1247-57.

Allogeneic Hematopoetic Stem Cell Transplantation for Sickle Cell Disease

2009-12-22T10:15:00.004-07:00

Background
Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease.
Methods
Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward.
Results
All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean ± SE) donor–recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3 ± 8.6% and 83.3 ± 10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0± 0.3 and 12.6 ± 0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient.
Conclusions
A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor–recipient chimerism and reverse the sickle cell phenotype. (ClinicalTrials.gov number, NCT00061568.)

As the authors note in their abstract, the myeloablative transplantation of allogeneic stem cells has been extremely successful (90-95%) in curing children with sickle cell disease. However, the myeloablation process has shown unacceptable toxicity in human adult patients, preventing clinicians from successfully treating these patients. The authors thus tested a nonmyeloablative procedure on a murine model to determine safety and efficacy, then progressed to this study on 10 adult human patients. Instead of attempting to block T cell activation as in normal myeloablative procedures, the drug combination used by this team inhibits T cell proliferation. The inhibition of T cell proliferation causes anergy in the host’s Tcells, limiting their reactivity to antigens, promoting T cell tolerance to the new graft tissue. With this treatment, the authors were successful at reversing the sickle cell disease phonotype in 9 out of 10 patients, and managed to prevent GVHD in all patients. This is promising research into being able to reverse the disease state in adults.

1. Hsieh, M. M.; Kang, E. M.; Fitzhugh, C. D.; Link, M. B.; Bolan, C. D.; Kurlander, R.; Childs, R. W.; Rodgers, G. P.; Powell, J. D.; Tisdale, J. F., Allogeneic Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease. N Engl J Med 2009, 361 (24), 2309-2317.

Cord Blood IgE as a Predictor of Atopy

2009-12-14T15:01:00.000-07:00

This longitudinal study was conducted with a group of mothers living in Vancouver and Winnipeg, Canada. Mothers of high risk children were recruited in their third trimester and ‘high risk’ was defined as having at least one parent with asthma or two parents with other IgE allergic diseases. Then house dust samples were collected and a questionnaire regarding health and exposures were completed before birth and at ages 1, 2 and 7. Additionally at years 2 and 7 allergy skin tests were performed on the following allergens: house dust mite, cat and dog dander, peanuts, eggs, cow’s milk, wheat and soy. Atopy was defined as one or more positive skin tests for any allergen. Also, cord blood IgE (CD-IgE) levels were collected at birth.
CD-IgE was detectable (≥0.5 KU/l) in 19.3% of the 285 children. A high percentage of children with detectable CD-IgE had a maternal history of asthma (p-value of 0.001), maternal atopy [adjusted OR 2.21 (1.01-4.84)], and were born in the winter months [adjusted OR 4.07 (1.68-9.83)]. Additionally at 7 years, detectable CD-IgE was associated with increased risks for atopy [OR 2.22 (1.11-4.41)], positive skin test reactions against any aeroallergen [OR 2.25 (1.13-4.47)] and recurrent wheeze [OR 2.51 (1.09-5.76)].
The data that they collected looks really interesting so make sure to look at the two tables they provided. Although this was a small study, the authors noted that this information can lead to targeted prevention efforts for infants who may be at higher risk for developing asthma. I think it’s most interesting that being born in the winter months was found to have a significant association with detectable CD-IgE. This is probably due to the increased exposure to inhalant allergens after birth but who knew the season you were born in may have that effect!
You can find the article at:
http://0-www3.interscience.wiley.com.impulse.ucdenver.edu/journal/123193720/issue
Elevated cord blood IgE is associated with recurrent wheeze and atopy at 7 yrs in a high risk cohort
Ferguson, Alexander A (12/2009). "Elevated cord blood IgE is associated with recurrent wheeze and atopy at 7 yrs in a high risk cohort". Pediatric allergy and immunology (0905-6157), 20 (8), p. 710.

RXR Activation: Hope for New Parkinson's Disease Treatment

2009-12-14T06:20:00.002-07:00

Parkinson’s disease is a neurodegenerative disease, which effects the dopamine-releasing cells in the brain. There has been a few experiments run attempting to rescue the dopamine neurons. This is done using chemicals that interact with the retinoid X receptor (RXR). The chemicals that will be investigated to interact with these receptors are known as RXR ligands. The article, which was published in journal BMC Neuroscience, describes the use of two cellular events which lead to the neuronal damage due to Parkinson’s disease. The two ligands examined in the experiment were the two RXR ligands LG268 and XCT. Specifically, they were studied to determine the neuroprotective function of the two.

Susanna Kjellander worked with a team of researchers from the Ludwig Institute for Cancer Research, Sweden, to test both the ligands and the two destructive Parkinson’s pathways. As a result she was able to make the following conclusion; "Nuclear hormone receptors like RXR and the Nurr1-RXR receptor heterodimer are emerging as interesting factors in Parkinson's research. It is unclear exactly how neurons are damaged in Parkinson's disease, but it is suggested that oxidative damage and energy depletion in the brain are involved. By activating RXR, neurons can be rescued from this degeneration."

In the study, there were two different dopaminergic cells (DA cells) to resemble the conditions present in persons with Parkinson’s. After studying these models, the researchers discovered the two RXR-activating ligands studied were able to selectively protect dopaminergic neurons from the stress induced in the model itself.

The results of this experiement were then confirmed to be accurate in a novel system in which dopaminergic neurons generated from mouse embryonic stem cells were treated with the neurotoxin. From this information they were able to theorize that "The regulation of RXR activity holds promise to contribute to a novel, alternative strategy to treat Parkinson's disease."

To reference the original article, it can be reached at http://www.sciencedaily.com/releases/2009/12/091210193158.htm. The article may also be searched by "RXR Activation: Hope for New Parkinson's Disease Treatment" ScienceDaily (Dec. 11, 2009).

Thiamine Found Important for Diabetics

2009-12-13T22:57:00.000-07:00

What was once termed “adult-onset diabetes” due to the fact that the vast majority of individuals with the disease were not in their youth, type 2 diabetes now effects people of all ages, and is one of the fastest growing health problems in the United States today. The most common procedure for treating an individual with type 2 diabetes is to simply limit the amount of sugars and refined carbohydrates in their diet. However, I came across an article, which proposed that a simple B vitamin referred to as Thiamine (B1) may play a key role in the treatment of the disease.

The complications that often accompany the disease are devastating to the effected individual, as they might include nerve damage, eye problems, cardiovascular disease, and kidney damage. Also, kidney failure usually occurs 15 to 20 years following the onset of the disease.

A major contributing factor to this grim prognosis lies in the fact that most people are under the influence that by tightly regulating blood glucose levels with diet, oral medication, or insulin, one would likely avoid any complications. However, recent studies have shown that while these things may in fact delay complications, it often does not prevent their onset. This was found to be especially true with diabetic nephropathy, which occurs when the capillaries inside the glomerulus are destroyed. This leads to thickening and scarring of the glomerulus, resulting in the drastic decrease in normal renal function. The first detectable symptoms of diabetic nephropathy are an increased level of albumin in the urine, known as microalbuminuria. Research led by Dr. Naila Rabbani and Professor Paul J Thornalley at Warwick Medical School, University of Warwick, in collaboration with researchers at the University of Punjab and Sheik Zaid Hospital, Lahore, Pakistan, discovered that high doses of Thiamine administered orally can significantly decrease the secretion of albumin, and reverse the progression of early kidney disease in type 2 diabetics.

The subjects (40) for the study were type 2 diabetics between the ages of 35 and 65, and administered 100mg of thiamine three times a day for three months. The control group was administered a placebo. Of those given thiamine, there was a 41% decrease in albumin excretion, and 35% of the subjects given thiamine returned to their normal levels after the thiamine treatment.

Another study led by Professor Paul Thornalley was able to prove that thiamine deficiency plays a significant role in a vast array of vascular complications, and even diabetic neuropathy, as a result of diabetes. They also discovered that thiamine levels in type 1 and type 2 diabetes were 76% and 75% lower than the control, respectively. This drastic decrease in thiamine levels is not due to a low dietary intake of thiamine, but a significant increase in urinary output, therefore supplemental thiamine for diabetics may prove essential.

Possibly one of the most beneficial thiamine treatments, although synthetic, is Benfotiamine, which is chemically similar to the allithiamines one would find in garlic. One of the reasons Benfotiamine is so effective is its ability to readily cross lipid bilayers. This allows the compound to reach relatively high levels in the tissues, while avoiding being excreted rapidly. Benfotiamine has been shown to block three of the four metabolic pathways responsible for the progression of vascular disease in diabetics, and also demonstrated an ability to reduce Advanced Glycation Endproducts (AGEs).

For more information, the article can be found at http://www.NaturalNews.com/025136_thiamine_diabetic_diabetics.html or search “Thiamine Found Important for Diabetics”; by: Patty Donovan, citizen journalist.

Transmissible cancers

2009-12-13T14:31:00.002-07:00

Came across a paper in Cell published in 2006 about the clonal origin of a transmissible cancer (CTVT) found in dogs. This was the first time I have heard about a tumor cell itself acting as the transmissible agent. The tumor cell itself was shown to be transferred as an allograft came from three different experiments: 1. CTVT can only be experimentally induced by transplanting living tumor cells, and not by lysates or killed cells. 2. The karyotype of the of the tumor cells is aneuploid but striking similar in tumors collected from various regions of unrelated dogs. And 3. A LINE-1 element upstream of c-myc was found in every tumor line examined. This tumor is passed from dog to dog usually by coitus but also can occur from licking and biting. This tumor is not fatal and usually is treatable. This cell has evolved into a parasite which represents the oldest somatic mammalian cell in continuous propagation.

For obvious reasons, Immunologists had a very hard time believing that the transmissible agent was the cell itself. The immune system is built to kill anything that is not recognized as self. So how did this cell evolve in such a way as to evade the hosts immune system? This was one of the questions that this paper sought to answer. As it turns out, MHC class I are downregulated in each of these tumors and class II are absent. Vertebrates has evolved NK cells to detect cells (typically tumors) that do not express MHC I and II and kill them because the normal acquired immune system would not be able to pick up these cells. These CTVT cells seemed to have evolved an expression level of MHC I that is high enough to keep the hosts NK cells at bay but low enough as to not illicit an immune response.

I found this paper really interesting and the authors and myself wonder why this isnt something that has occurred more often. At any rate, its amazing to see evolution in action, even at the cellular level. And we as researchers should look closely at this because it seems not a matter of 'if' but 'when' something like this will be seen in humans.

Murgia, C., Pritchard, JK., Kim, SY., Fassati, A., and Weiss, RA. Clonal Origin and Evolution of Transmissible Cancer. (2006) Cell 126, 477-487

Inflammation and the Host Response to Injury

2009-12-10T12:18:00.002-07:00

As we all learnt in this class inflammation is one of fundamental protection mechanisms in human biology. This is how we protect ourselves from foreign invaders as well as abnormal cell inside of our body. But gone awry inflammation that spreads beyond the primary locus or fails to subside poses serious chronic and acute health risks for millions of people.

Each year about 60 million Americans sustain injuries. Trauma accounts for more than 12% of all medical spending in America. After the first 24 hours following the injury the primary cause of death is Multiple Organ Failure (MOF). It presents as an excessive inflammatory response directed towards patient’s own tissues. It is closely related to Systemic Inflammatory Response Syndrome (SIRS) and Sepsis. Sepsis alone accounts for up to 215,000 American’s lifes every year, according to the National Institute of General Medical Sciences. We referred to SIRS in Immu 7630 course as cytokine storm.

Growing evidence suggests that genetic factors drive key aspects of an individual’s inflammatory outcome. Scientists studying inflammation are trying to identify the genes that drive inflammation as well as biomarkers from throughout the course of inflammation. Genomic studies, in addition to their proteomic and metabolomic cousins, aim to resolve an age-old mystery: namely, why some patients recover readily from inflammation while others suffer and die from it. Ideally, new gene based discoveries will provide diagnostic biomarkers to predict who among these patients will react poorly to inflammation and why. If doctors could reliably predict this outcome in advance, they might tailor antibiotics and other treatment options to a patient’s own inflammatory system, potentially saving lives.

Among the numerous programs moving inflammation research forward is an effort funded by a National Institute of General Medical Sciences “glue grant,” so named because it “glues together” multidisciplinary efforts to tackle biomedical questions beyond the means of any one research group. This program, called Inflammation and the Host Response to Injury, strives to determine why patients can have dramatically different outcomes after traumatic injuries and burns.

UCD and Denver Health Medical Center are part of this multicenter research study.

In order to find immuno-inflammatory biomarkers for developing MOF Glue Grant is using genomic and proteomic analyses:

mRNA Isolation for Protein Coding

The Glue Grant investigators nationwide are isolating messenger RNA (mRNA) from blood and other available tissues. Isolation of the mRNA molecule is key to finding expressed genes in the vast expanse of the human genome. Since mRNA is very unstable outside of a cell, we are using a special enzyme called reverse transcriptase to convert it to complementary DNA (cDNA) which is a much more stable compound than mRNA and is presumed to represent the sequences of the genes being expressed. Sequences contained in the cDNA are used to generate expressed sequence tags (ESTs) that code for the protein in question or represent non-translated regions. ESTs are powerful tools for gene mapping and gene discovery. In the search for known genes, they greatly reduce the time needed to locate a gene. ESTs provide sequences that can be generated rapidly and inexpensively, in that only one sequencing experiment is needed per each cDNA generated and ESTs do not have to be confirmed for sequencing errors.

Only a fraction of genes are turned on, and it is the subset that is "expressed" that confers the unique properties to each cell type. Gene expression is the term used to describe the transcription of the information contained within the DNA into mRNA molecules that are then translated into the proteins that perform most of the critical functions of cells. Gene expression is a highly complex and tightly regulated process that allows a cell to respond dynamically both to environmental stimuli and its own changing needs. This mechanism acts as both an "on/off" switch to control which genes are expressed in a cell as well as a "volume control" that increases or decreases the level of expression of particular genes as necessary.

Microarray technology is applied to the samples to collect gene expression data. This technology works through the ability of a given mRNA molecule to bind specifically to, or hybridize to, the DNA template from which it originated. By using an array that contains many DNA samples, we can determine - in a single experiment - the expression levels of thousands of genes within a cell by measuring the amount of mRNA bound to each site on the array. The amount of mRNA bound to the spots on the microarray is precisely measured, thus generating a profile of gene expression in the cell. Microarray expression analysis are performed on the samples to determine the level, or volume, at which a certain gene is expressed. The arrays used in this analysis are called expression chips or "Gene Chips". We use the expression chips to detect expression patterns, that is, whether or not a particular gene is being expressed more or less under certain circumstances, and to examine changes in gene expression over a given period of time.

Detection and Analyses of SNPs

A single nucleotide polymorphism (SNP) is a small genetic alteration that can occur in a patient's DNA sequence. An SNP variation occurs when a single nucleotide (adenine, cytosine, thymine, or guanine) is replaced by one of the other three nucleotides. Each patient's genetic material contains a unique genetic pattern that is composed of several different genetic variations, including SNPs. It is believed that SNPs can serve both as a biological marker for pinpointing a disease or condition and may be directly associated with or causative of a certain disease or condition.

Proteomic Analyses

Cytokine mediators, leukocyte phenotypes, and cell signaling intermediates (e.g., protein kinases, NF-ê B family) will be analyzed from blood and plasma of trauma patients. Of particular interest are investigations of changes in pro-inflammatory and anti-inflammatory cytokines in isolated populations of cells from these patients. There are several cytokines of interest that include TNF, IL-1, IL-6, IL-8, IL-10, IL-12, IL-18, IL-1ra, p55, and p75.

Glue Grant study is still underway and the final results are yet to be analyzed…

For more information please visit www.gluegrant.org or search PubMed for “Inflammation and the host response to injury: a Large-Scale Collaborative Project”.

2009-12-09T22:30:00.000-07:00

More news on my new favorite spice, tumeric! In a recent report researchers at the Univ. of Michigan found that the active ingredient in tumeric, curcumin, when applied to breast cancer cells in culture, was able to repress the growth of cancer stem cells, while not affecting the growth on non-stem cells. The same activity was seen with the active ingredient from black pepper, piperinem and was greatest when the two compounds were used together. Is this anti-stem cell activity a component in the anti-inflammatory mechanism used by curcumin, or perhaps an entirely separate effect?

This stem-cell specific growth inhibition may provide a better approach to limiting the growth of tumor cells in situ. Current treatments, such as standard chemotherapy or radiation, are thought to indiscriminately inhibit the growth of all cancer cells. But research has shown that many cancers are the result of cancerous stem cells driving the growth of tumors. And treatments that can specifically target these stem cells may provide better eradication than current treatments which are thought to often miss total irradication of the cancer stem cells.

Of note, the concentration of curcumin applied in culture is far greater (some 20 fold greater) than what could be obtained in the diet - supplementation would be required. Also, the study was an in vitro cell culture study, with all of the limitations inherent to cell culture models. But, the authors report that they hope to conduct Phase I safety trials as soon as next year.

1. Madhuri Kakarala, Dean E. Brenner, Hasan Korkaya, Connie Cheng, Karim Tazi, Christophe Ginestier, Suling Liu, Gabriela Dontu and Max S. Wicha. (2009) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Research and Treatment, Vol 66(3), p123-133

Hygiene Hypothesis goes in utero!

2009-12-08T13:54:00.002-07:00

On the blog and in class we have discussed the Hygiene Hypothesis. I was very interested to read today in a review article in JEM that there seems to be a growing body of evidence indicating that bacterial exposure in pregnant mothers can reduce the incidence of asthma and allergy in their children.

Of note, newborns of mothers exposed to a barn environment during pregnancy displayed enhanced Treg activity. A parallel study looking at PBMCs from 5-13 year-old children of farm-exposed mothers showed decreased sensitization. The really COOL thing is that the decreased sensitization was unrelated to the children's farm exposure at the time the PBMCs were taken. Instead the effects were exclusively related to the mothers' farm exposures during pregnancy.

This (and other data you can read in the article) suggests that during a child's development in the womb its immune system can be programmed to some degree. Why do you think maternal programming might exist? Is this exposure more relevant than the child's own exposure?

Soothing signals: transplacental transmission of resistance to asthma and allergy

Patrick G. Holt and Deborah H. Strickland

J. Exp. Med. 2009;0 200924691-20092469, Published online Dec 7 2009, 10.1084/jem.20092469.

Placebo Effect

2009-12-07T14:21:00.003-07:00

I thought the conversation about the saccharine water and the placebo effect in mice was very interesting. I was wondering if any studies have been done that can show that behavior can also negatively impact the immune system.

It seems that when pregnant women get sick from a certain type of food during pregnancy, they tend to feel nauseous or get ill from that food later on after the pregnancy. I've heard similar stories with people that get food poisoning. I wonder if this has to do with the body thinking that it will get sick from that same food because it has in the past. I would think that this would be a "reverse" placebo-effect in the sense that something that causes problems once in the body will be associated in the mind as always being a problem causer.

Aging, DNA damage, and chronic inflammation?

2009-12-07T04:24:00.002-07:00

Hi all,

Recently I found a research article that describes experiments that show for the first time a possible cause of the chronic inflammation that seems to be implicated in the etiology of so many chronic medical conditions. This chronic inflammation becomes more common and widespread as people age, or when they somehow sustain considerable damage to a particular tissue over time. One underlying cause of this age-associated inflammation turns out to be unrepairable DNA damage which accumulates in non-cycling cells of our bodies (either quiescent or senescent) as we age. This accumulation of DNA damage in cells as we age has been known for some time - but what this paper, by Campisi et. al. [1] at the Lawrence Berkeley National Laboratory, unexpectedly showed is that these damaged cells secrete a unique and powerful battery of inflammatory cytokines. As we age we constantly secrete more and more of these inflammatory cytokines in our tissues, which can lead to the development or exacerbation of all of the chronic inflammatory conditions which we have studied this semester

As an aside, I found this paper on the Faculty of 1000 Biology web-site (http://f1000biology.com/guardpages/evaluation/1145049//article/article.asp%253Fid%253D1145049%2526view%253D%2526style%253D). This web-site is a very cool service which provides a synopsis and critique of the most interesting current papers in biology, as judged by the "Faculty of 1000" - generaly recognized respected researchers in their fields. So, if you can afford the subcription fee, you can have the hottest papers in your research area identified and critiqued by experts and sent straight to your e-mailbox! You can also get a copy at the cool free-access Public Library of Science (PLoS) website, http://www.plosbiology.org/article/info:doi%2F10.1371%2Fjournal.pbio.0060301.

Anyways, back to the paper. In their experiments, the authors modified commercial antibody arrays to substantially improve their range and sensitivity, and then measured the proteins secreted by senescent cells in culture, as well as from tissue samples that were collected from prostate cancer patients both before and after completing a DNA-damaging form of chemotherapy. They found that different types of cells from different tissue all secrete a very similar set of proteins when they senesce in response to DNA-damaging radiation or chemotherapy. The authors propose to call this common response to DNA damage and senescence "senescence-associated secretory phenotype", or SASP. Importantly, they then showed that it occurs not only in cultured cells, but also to cells in vivo in response to exogenously introduced DNA damage (and by extension to normally produced endogenous oxidative DNA damage). The SASP develops slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. The SASP featured high levels of secreted inflammatory cytokines, immune modulators, and growth factors, all of which are associated with inflammation and malignancy (IL-6, IL-8, GRO-α, MCP-1, GM-CSF...).

Note: For those interested, the primary authors followed up this seminal line of experiments with further work clarify some of the molecular interactions involved in this inflammatory phenotype of aging and/or damaged cells, finding connections with the well characterized dna repair/maintenance genes ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb... [2]

- Brian P

1. Jean-Philippe Coppé, Christopher K. Patil, Francis Rodier, Yu Sun, Denise P. Muñoz, Joshua Goldstein, Peter S. Nelson, Pierre-Yves Desprez, Judith Campisi (2007) Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor, PloS Biology, www.plosbiology.org

2. Francis Rodier1,2, Jean-Philippe Coppé1, Christopher K. Patil1, Wieteke A. M. Hoeijmakers1,4, Denise P. Muñoz2, Saba R. Raza1,5, Adam Freund1,3, Eric Campeau1,6, Albert R. Davalos1 & Judith Campisi1,2 (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nature Cell Biology 11, 973 - 979.

Pharmacist's Letter Continued!

2009-12-06T10:15:00.005-07:00

For those of you in the UA course, I presented info from the pharmacist's letter database on turmeric. The database is designed to show any info that is related to medications including natural supplements that allow pharmacists to convey information including interactions, safety, and effectiveness. Recall that turmeric is only possibly safe when used orally or topically in medicinal amounts and likely safe when used in amounts commonly found in food. I found similar information using the same database regarding the scientific article from last Monday where they tested several active spice-derived components and how effective they were at being anti-inflammatories. This may be a long blog so sorry in advance. I just found it really interesting. I tried to bold anything related to inflammation to bring attention to them.

1. Black Mustard (allyl isothiocyanate)
-Uses: the oil is used for the common cold, rheumatism and osteoarthritis; orally - used to induce vomiting, a diuretic, and an appetite stimulant; topically - pneumonia, osteoarthritis, aching feet, and as a counterirritant (something that causes inflammation in one area to lessen it in another)
-Safety: likely safe when used orally in the amounts commonly found in foods; there is insufficient reliable information available about the safety of black mustard when used orally or topically for medicinal purposes
-Effectiveness: There is insufficient reliable information about the effectiveness of black mustard
-Mechanism of action: applicable part are the seed, oil, leaf, and powder; the powder contains glucosinolate sinigrin, which produces allyl isothiocyanate when mixed with warm water that has strong antimicrobial (bacterial and fungal) properties and can act as a counterirritant when diluted; seed, oil, and powder can have powerful irritant properties that can cause pain and increase inflammation of the skin
-Interactions with Herbs & Supplements, Drug, Foods, Lab Test, and Disease or Conditions - None known
-Adverse Reactions: Large amounts orally - vomiting, stomach pain, diarrhea, cardiac failure, breathing difficulties, coma, and possibly death
-The interesting thing I found was that this drug is such a potent so when applied topically for too long (longer than 10 minutes), it can lead to severe skin irritation and even burns and the concentrations as a counterirritant is 0.5% to 5% and used 3-4 times a day

2. Garlic (diallyl disulfide)
-Uses: hypertension, hyperlipidemia, coronary heart disease, earaches, chronic fatigue syndrome, prevention of colon cancer and other cancers of the breast, lung, prostrate, and bladder, osteoarthritis, allergic rhinitis, colds, flu, TB, whooping cough, and a lot of other random things; topically - oil is used for scalp diseases and vaginitis
Safety: Likely safe when used orally and appropriately; has been used safely in clinical studies lasting up to 7 years without significant toxicity; possibly unsafe when used topically - can cause severe skin irritation; possible safe for children in appropriate oral amounts and possibly unsafe in large amounts; pregnancy - likely safe when used orally in amounts commonly found in foods; possibly unsafe - orally in medicinal amounts
-Effectiveness: possibly effective to treat atherosclerosis at 300 mg per day, some evidence associated with decreasing the risk of developing stomach cancer, and come clinical research shows that taken orally, garlic can modestly reduce blood pressure
-Mechanism of action: bulb mostly used as an antihyperlipidemic, antihypertension, antifungal, and has also been reported to have antibacterial, antihelmintic, antiviral, antispasmodic, antithrombotic, and an immunostimulant
-Based on this info and other info that I found off the database, I didn't find any clinical evidence that suggests that garlic has no evidence of having anti-inflammatory properties. If it did, this database would discuss it because it talks about everything related in clinical terms regarding supplements.

3. Ginger (zingerone)
-Uses: Orally - motion sickness, morning sickness, dyspepsia, rheumatoid arthritis, loss of appetite, osteoarthritis, migraines, headache, anorexia, cough, bronchitis, stomachache, and others; Fresh ginger - orally for malaria, rheumatism, and toothaches
-Safety: likely safe - when used orally and appropriately; has been used in clinical trials (includes trial info in the database)
-Effectiveness: can reduce severity of nausea and vomiting in pregnant patients and postoperative patients and insufficient reliable evidence to treat chemo-induced nausea and vomiting; preliminary evidence shows modest benefits in OA - extract at 170 mg a day three times daily for 3 weeks is effective in reducing pain; some preliminary evidence shows that ginger might help in decreasing joint pain in patients with RA
-Mechanism of action: pharmacological properties - antipyretic, analgesic, anti-inflammatory, sedative, antibiotic, and other properties

4. Black Pepper (piperine)
-Uses: stomach upset, bronchitis, and cancer
-Safety: Likely safe when used orally in amounts commonly found in foods; possibly safe when used orally and appropriately in medicinal amounts; black pepper oil is used topically and is nonirritating and typically well tolerated; likely safe in children, pregnancy, and lactation
-Effectiveness: Insufficient reliable information about the effectiveness of black pepper
-Mechanism of Action: a typical diet provides 360 mg of black pepper provides about 60-110 micromolar of piperine that seems to increase oral absorption of drugs and other substances
-There doesn't seem to be much clinical evidence that black pepper works as an anti-inflammatory

In conclusion, only two out of the four anti-inflammatory agents mentioned in the article seem to have any clinical evidence. It will be interesting to see if new research sheds any more light on black pepper and garlic.

Does air pollution exacerbate asthma?

2009-12-05T14:51:00.003-07:00

A 2007 article in the Annals of Allergy, Asthma & Immunology asked the very salient question: does air pollution exacerbate asthma?

The objective of the article was to investigate associations between traffic and outdoor air pollution levels near residences and poorly controlled asthma among adults diagnosed as having asthma in Los Angeles and San Diego counties.

The authors estimated traffic density (TD) within 500 feet of 2001 California Health Interview Survey (CHIS) respondents' reported residential cross-street intersections. They then assigned annual average concentrations at government monitoring stations within a 5 mile radius of reported residential cross-street intersections of:

1. ozone

2. nitrogen dioxide

3. particulate matter (PM) 2.5 and 10 micrometers or less in diameter

4. carbon monoxide

In order to obtain the study population, 19,664 individuals were interviewed; 2,237 (11.4%) were diagnosed by a physician as having asthma. These individuals’ residence locations were entered into a database. The final study population was 1,609 adults (others were excluded because of missing data).

Exposure evaluation was evaluated by examining traffic density, which was based on a 500 foot buffer around person's probable home street segment. From the nearest measuring station within 5 miles of the respondent, the authors determined annual average concentrations of: ozone, nitrogen dioxide, particulate matter 2.5 micrometers or less or 10 micrometers or less, carbon monoxide.

For the statistical analysis, traffic density was divided into three tiers:

1. Low TD (20th percentile or less)

2. Medium TD (21-80 percentil)

3. High TD (> 80th percentile)

The results can be summarized in the following 4 main points:

1. There was a 2-fold increase in poorly controlled asthma among asthmatic adults (OR 2.11, 95% CI 1.38-3.23) in the highest quintile of traffic density after adjusting for age, sex, race, and poverty.

2. Similar increases were seen for nonelderly adults, men, and women. The strongest associations were seen in elderly adults (OR 3, 95% CI 1.13-7.91).

3. Ozone exposures were associated with poorly controlled asthma among two subgroups:

- elderly adults (OR 1.7, CI 0.91-3.18 per 1 pphm)

- men (OR 1.76, CI 1.05-2.94 per 1 pphm)

4. Particulate matter 10 micrometers or less affected primarily women (OR 2.06, CI 1.17-3.61), even at levels below national air quality standard.

The authors’ conclusion? Heavy traffic and high air pollution levels near residences are associated with poorly controlled asthma.

While this may seem like a relatively straightforward conclusion based on the data, this study had some very significant caveats to keep in mind:

1. Misclassification of exposures from stations:

- Traffic pollutants can have a strong spatial gradient, meaning levels detected at measuring stations might not reflect actual exposure levels of individuals.

2. Resident variability:

- The study did not take into account variables such as personal mobility, occupation-related exposures, or indoor exposures.

3. Temporal ambiguity

- This study was based on cross-sectional survey data, so the length of time any individual lived in a neighborhood was unknown.

4. Medication use

- Individuals’ use of medications was unknown; use could reduce symptoms and lead to underestimated prevalence of poorly controlled asthma.

Y-Y Meng, et al. Traffic and outdoor air pollution levels near residences and poorly controlled asthma in adults. Annals of Allergy, Asthma, & Immunology 2007;98:455-463.

Novel NF-Kb links inflammation and cancer promotion

2009-12-04T22:52:00.002-07:00

A recent paper by researchers at the University of California [1] reveals a novel mechanism by which chronic inflammation may play a decisive role in the promotion of cancer. This mechanism is a sort of molecular “cross-talk” between two processes in cells which were thought to be distinct – cell development and inflammation. This cross-talk comes through the actions of a protein, p100, which has been found to be crucial in a cell’s normal developmental metabolic pathways as well as in the cell’s response to inflammation. Novel cancer therapeutic treatments which target developmental pathways linked to chronic inflammation via p100 may prove effective in conjunction with the use of current anti-inflammatories such as NSAIDS.

NF-κB activity is inducible by a diverse range of stimuli including pathogen derived substances and intercellular mediators of inflammation. It is known that NF-κB is normally repressed by three different intracellular inhibitors (IκB-a,b,e proteins),and that during classical inflammatory signaling these inhibitors are released from binding NF-κB, resulting in its activation. A second, independent NF-κB activation pathway is thought to be activated in response to cell developmental signals rather than inflammatory signals. The molecular mechanism of this particular pathway has remained uncertain, but the results of this study show that a fourth IκB inhibitor (p100) is involved in the activation of NF-κB in developmental pathway signaling, such as during lymphoid organogenesis (see included figure).

This diagram reveals the cross-talk between NF-κB activation via inflammatory or developmental signaling – inflammatory signaling can activate developmental (cell reproduction and differentiation) pathways to some extent and vice-verse. And further work by the researchers showed that the “cross-activation” of developmental pathways by classical inflammatory signaling was much stronger, and of longer duration, than the normal developmental activation signal strength. For example, a 1 hr pulse of TNF-a stimulation resulted in an elevation of p100 protein of about 4-fold, that persisted for more than 20 hr. Remarkably, the researchers also showed that the strength of this cross-talk increased with repeated signaling – in other words, the longer cells were exposed to inflammatory signals via TNF-a, the more they were stimulated to reproduce! This is in marked contrast to the normally accepted role of TNF-a in signaling cell death.

The researchers speculate that in epithelial cells that are exposed to prolonged periods of inflammation, such as they might experience during chronic inflammatory diseases, the amount of cross-talk between the classic TNF-a mediated inflammatory cell death pathway and the p100 mediated developmental cell growth pathway may profoundly shift, with the inflammatory signals generating a stronger and stronger cell growth signal in place of the expected cell death signal. This could be the mechanism responsible for chronic inflammations being able to promote the growth of many types of cancers – after prolonged exposure, inflammatory TNF-a signals that were originally responsible for inducing cell death (and resolving inflammation and tissue repair processes) become instead growth stimulating signals that drive epithelial cells toward unrestrained cancerous growth.

1. Basak S, Kim H, Kearns JD, Tergaonkar V, O'Dea E, Werner SL, Benedict CA, Ware CF, Ghosh G, Verma IM, Hoffmann A.(2007) A fourth IkappaB protein within the NF-kappaB signaling module. Cell. Vol 128(2) p369-81.

NSAIDS and Cancer Prevention

2009-12-04T00:04:00.001-07:00

Over the last four decades dozens of epidemiological, clinical and experimental studies have established nonsteroidal anti-inflammatory drugs (NSAIDs) as promising epithelial cancer chemopreventive agents. The long-term use of aspirin and other NSAIDs has been shown to reduce the risk of cancer of the colon and other gastrointestinal organs, as well as cancer of the breast, prostate, lung, and skin. In a recent review, Harris[1] et. al. comprehensively reviewed the published research on NSAIDs and cancer incident. Data from 91 epidemiologic studies were analyzed for the dose response of relative cancer risk and level of NSAID intake for ten prevalent human cancers. The results showed a significant exponential decline in the risk with increasing intake of NSAIDs (primarily aspirin or ibuprofen) for 7 out of the 10 cancers, including the four major types: colon, breast, lung, and prostate cancer. Consistent daily intake of NSAIDs (primarily aspirin), produced risk reductions of 73% for stomach, 69% for esophageal, 63% for colon, 47% for ovarian, 39% for breast and prostate, and 36% for lung! NSAID effects became apparent after five or more years of use and were stronger with longer duration.

Despite general consensus as to the effectiveness of NSAIDs for cancer prevention, unresolved questions with regard to safety, efficacy, optimal treatment regimen, and mechanism of action currently limit the clinical application of NSAIDs to the prevention of cancer. Also, the development of safe and effective NSAIDs for chemoprevention is complicated by the potential that rare, serious toxicity may offset the benefit of treatment with these drugs given to healthy individuals who have a low risk of developing cancer. However, I believe there is growing support for the view that a full understanding of the role of NSAIDs in the prevention and treatment of epithelial cancers will be an integral part of the development of effective future treatments for reducing mortality and morbidity from most cancers.

1. Harris RE, Beebe-Donk J, Doss H, Burr Doss D. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review). Oncol Rep. 2005 Apr;13(4):559-83.

Chronic Beryllium Disease --going beyond HLA-DPB1?

2009-12-03T15:51:00.001-07:00

I have been working for several years with a doctor who does research with chronic beryllium disease (CBD). If you recall from our notes, this is a disease which is caused by inhalation of beryllium dust and an immune response which leads to granuloma formation in the lung. There is a known association between certain HLA-DPB1 alleles and CBD and we are always looking for ways to better understand what this means. The article “Electrostatic Potential on Human Leukocyte Antigen: Implications for Putative Mechanism and Chronic Beryllium Disease” describes how the authors constructed structural models of HLA-DP representing several distinct allotypes and how they calculated the electrostatic potential on the surface of these models. They determine that the higher the negative charge for the HLA-DPB1 alleles the more likely that the person would have chronic beryllium disease. These charges are then related back to certain alleles. I guess I have a question for anyone who may be reading this: Does the electrostatic charge give you any new meaningful information?

The article's link in PubMed.

H1N1 Influenza strains contain H5N1 genetic material...Are the young and healthy at risk of a massive cytokine storm induced by virus infection?

2009-12-02T14:33:00.000-07:00

Human infection with highly pathogenic avian influenza A viruses (HPAIV) such as H5N1 subtypes are characterized by inner bleedings and a massive overproduction of cytokines known as cytokine storm (Schmolke et al., 2009). Recent reports have linked the genomes of the last three pandemic influenza viruses as having emerged from gene reassortment events and possessing HA genes of avian influenza origin. Thus, these findings provoke the following question: If existing influenza strains (i.e. 2009 H1N1 influenza) undergo gene reassortment similar to H5N1 strains, is it possible that the resulting human adapted form could manifest itself as a deadly pandemic targeting healthy individuals by the onset of a massive cytokine storm?

Review of what the “cytokine storm” is: when the body’s normal immune system overacts to an intruder such as a virus, by overproduction of signaling chemicals (known as cytokines and chemokines) that help mobilize immune cells capable of removing infectious agents from the body. The extremely high levels of cytokines that are produced as a consequence of a healthy immune system are over-exaggerated and fatally damaging to tissues and organs. Death will usually result from multisystem organ failure.

I came across two articles I’d like to reference in regard to this blog. Below is a brief summary of each paper, highlighting the author’s findings which are relevant to this blog topic.

The first paper published in July 2009 in Science (Rebecca J.Garten et al., 2009) involved a large collaborative effort of many authors representing the WHO, CDC, NIH and various health organizations. The objective of this study was to characterize the antigenic and genetic variations of 2009 H1N1 circulating in humans. In their attempts to do this, they analyzed genome sequences isolated from 2009 H1N1 patients with previous strains of influenza including classical swine, human seasonal, American avian, North American and Eurasian swine strains. This paper examines the antigenic capabilities of influenza and how it has evolved overtime resulting in the emergence of pandemic flu strains. The paper provides the lineages and reassortment events that have taken place overtime and which gave rise to three pandemic influenza viruses (1918 H1N1, 1957 H2N2, and 1968 H3N2). The lineage suggests that all three strains originated from nonhuman reservoirs and the HA genes of all, originated from avian influenza virus. Now the most recent 2009 A/H1N1 strain contains a never before seen combination of gene segments which appear to be derived from Eurasian swine and classical swine lineages (Garten et al., 2009).

The second paper, by Schmolke M. et al., 2009 in the Journal of immunology by a group in Germany presents in accordance with numerous reports, the observation that the high fatality rate of avian influenza is a consequence of lethal cytokine storm induced by A/H5N1 virus both in humans and animals (Deng RM. et al., 2008; Claas EC. et al., 1998). The significance of the study is based on the concern of highly pathogenic avian influenza viruses (HPAIV) being directly transmitted to humans as a possible source of a new influenza pandemic. They performed mRNA profiling on human umbilical vein endothelial cells (HUVEC) infected with H5N1 based on the idea that endothelial cells are a major source of cytokines and chemokines, and relevant for systemic viral dissemination. Their results confirm clustering and upregulation of inflammatory/immune response which are accompanied by a massive systemic production of cytokines and chemokines, characteristic of a cytokine storm.

It’s frightening to acknowledge the ongoing threats of the 2009 H1N1 swine flu and the still present Asian avian flu virus (AAV H5N1) and its pandemic potential. In regards to the influenza strain reassortment and antigenic evolution, sequence variation in the gene segments of the H5N1 strain have been shown to contribute to viral virulence. It will be interesting to compare the updated sequencing of gene segment among the 2009 H1N1 strains with previously pandemic strains which could suggest whether it may or may not be likely to elicit such a strong cytokine response associated with highly virulent strains such as H5N1.

Based on the recent publications mentioned above I think it is obvious that 1) the new swine flu influenza A strain appears to be a combination of previous bird, swine and human genetic make-up. In addition, all three show lineage to have originated from avian flu. 2) H5N1 the highly virulent avian flu strain causes lethal cytokine storm in young and healthy individuals. These ideas together implicate that H1N1 viruses have pandemic potential and historically support the possibility that healthy young adults may be more susceptible to severe infection due to a strong immune system capable of eliciting a lethal cytokine storm. If uncontrolled, such a cytokine storm occurring in vital organs can lead to organ failure and death.

What would be the best approach in preventing an influenza pandemic or in addressing the potential damage it could elicit by inducing a cytokine storm in infected individuals? Should health officials stringently monitor strains of the 2009 A(H1N1) virus for any antigenic and genetic changes? In the case of infected patients, should the use of prophylactics such as immune suppressors or antivirals be used to minimize the possibility of the cytokine storm?

References:

Garten RJ et al., 2009. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science. 325:197-201.

Schmolke M, Viemann D, Roth J, Ludwig S. 2009. Essential impact of NF-κB signaling on the H5N1 influenza A virus-induced transcriptome. J Immunol. 183:5180-5189.

Deng RM, Korteweg LC, Gao Z, McNutt MA, Ye J, Zhang I, Gu J. 2008. Distinctly different expression of cytokines and chemokines in the lungs of two H5N1 avian influenza patients. J Pathol. 216:328-336.

Claas EC, Osterhaus AD, van Beek R, De Jong JC, Rimmelzwaan GF. 1998. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet. 351:472-477.

Genetic Variation In The Maintenance of HIV Seronegative Status Among High-Risk Populations

2009-12-01T23:18:00.002-07:00

Chemokine receptors have proved to be important in maintaining seronegative status among individuals who have a high risk for contracting the HIV virus. Cultures of lymphocytes and macrophages have shown that those who are relatively resistant to HIV infection secrete high levels of co-receptors CCL3, CCL4, and CCL5 when they are inoculated with this virus. It has been discovered that HIV resistant people are homozygous for an allelic, nonfunctional version of the CCR5 co-receptor, D32. In the Caucasian population, the prevalence of this frameshift mutation (coupled with a protein truncation) in the homozygous form is fairly high at about 1%. The heterozygous allelic form of this mutation may provide some modest protection against the sexual transmission of the HIV virus, and could even slow the progression of existing infections. In addition to this, variation in the promoter region of the CCR5 gene has been identified in both Caucasians and African Americans. Differences in promoter regions have also been associated with different rates of progression of the disease. This evidence shows that CCR5 is the major macrophage and T-lymphocyte co-receptor used by HIV to establish initial infection. Interestingly, this also offers hope that primary HIV infection can be blocked by anti-CCR5 receptors.

Janeway, Charles. Janeway's Immunology - 7th Edition / Kenneth Murphy, Paul Travers, Mark Walport. Garland Science. 2008.

Worm therapy available--legally?

2009-12-01T17:28:00.000-07:00

Scraping my net over the bottom of the Web, I found Ovamed GmbH, a company in a village near Hamburg that claims to be licensed by the Thai Ministry of Health to sell TSO (Trichuris suis ova) for treatment of Crohn's and UC in those "with a medical recommendation."

And another outfit, Autoimmune Therapies, will sell you a similar product. Here's what they say: "Helminthic therapy, nature's most powerful probiotic, harnesses nature to heal, restoring the helper organisms we co-evolved with and that our immune systems depend on to function correctly, and is based on sound science. Stop treating the symptoms, fix the problem." You can judge for yourselves the accuracy of those statements. They say they sell anywhere except the USA.

There are many more, springing up all over the world, wherever evidence-based medicine is not currently the fashion.

Aquagenic Urticaria (Physical Urticarias)

2009-11-30T21:24:00.003-07:00

Physical urticaria refers to a class of chronic urticaria, a hive or wheel type reaction, to a physical stimulus. The literature seems to indicate that for some patients the specific physical trigger results in hives, but in others the stimulus is the only common factor in the otherwise idiopathic condition. A large group of physical stimuli have been characterised and used as diagnostic criteria (1), which include: dermographism, delayed pressure urticarias/ angioedema, cholinergic urticaria, local heat induced urticaria, exercise induced urticaria, solar urticaria, vibrational angioedema, and aquagenic urticaria.

Though fewer than 50 cases of aquagenic urticaria have been documented in medical journals, relatively recent online tabloids and blogs have written articles about the condition (2,3). The clinical features of the condition include small perifollicular wheels on any skin region after contact with water (distilled, tap, or saline). For some patients characteristics of the water effected the condition, salinity, pH, and others factors (4,5). Many patients suffering from aquagenic urticaria have also been diagnosed with cholinergic urticaria or dermographism (6,7).

From the known mechanism of the immune system we have learned about this year it seems unlikely that water itself could be recognized by the immune system. However, a few hypothesis for the mechanism of the condition have been proposed. It is possible that the water acts to carry an antigen (possibly sebum) through from the epidermis to the dermis where it is recognized by mast cells causing the localized reaction (8). Further studies with this hypothesis demonstrated that organic solvents increased sensitivity to the reaction, and removal of the stratum corneum layer of the skin produced similar results. Another theory suggested cholinergic activation resulted in the reaction, scopolamine was shown to decrease reactions in two patients, but pre-treatment with atropine did not suppress reactions. The injection of methacholine, which usually elucidates cholinergic reactions for diagnostics was negative when tested on aquagenic urticaria patients (9). It may also be possible that the activation or involvement of the sensory neurons, perhaps presenting antigens from a latent virus could provide a possible mechanism, though no research has been done in this vein. Similarly, it is possible that ions in the water change an already present molecule of self into a recognizable antigen.

Elucidating a mechanism, or further understanding of aquagenic urticaria and other types of physical urticaria may provide immunologists new insights into antigen presentation, and inflammation.

1. Kontou-Fili, K, Borici-Mazi, R, Kapp, A, et al. Physical urticaria: classification and diagnostic guidelines. An EAACI position paper. Allergy 1997; 52:504.
2. http://www.dailymail.co.uk/news/article-520329/The-teenage-girl-allergic-WATER.html
3. http://abcnews.go.com/Health/AllergiesNews/story?id=7401149&page=2
4. Gallo, R, Cacciapuoti, M, Cozzani, E, Guarrera, M. Localized aquagenic urticaria dependent on saline concentration. Contact Dermatitis 2001; 44:110
5. Tkach, JR. Aquagenic urticaria. Cutis 1981; 28:454
6. Parker RK, Crowe MJ, Guin JD. Aquagenic urticaria. Cutis. 1992 Oct;50(4):283-4
7. Luong KV; Nguyen LT. Aquagenic urticaria: report of a case and review of the literature. Ann Allergy Asthma Immunol. 1998 Jun;80(6):483-5.
8. SHELLEY, WB, RAWNSLEY, HM. AQUAGENIC URTICARIA. CONTACT SENSITIVITY REACTION TO WATER. JAMA 1964; 189:895
9. utdol.com

CRP and COPD

2009-11-30T18:33:00.003-07:00

I found this article to be very interesting as I currently work in research looking at the association between COPD (chronic obstructive pulmonary disease) and CVD (cardiovascular disease). I found this article in the European Journal of Internal Medicine 19 (2008) 104–108.
Authors: Fisun Karadag, Sevin Kirdar, Aslihan B. Karul, Emel Ceylan

Title: The value of C-reactive protein as a marker of systemic inflammation in stable chronic obstructive pulmonary disease

In this article the authors sought to evaluate circulating CRP levels in order to determine the value of CRPas a biomarker of systemic inflammation and as an indicator of malnutrition or severity of COPD in stable COPD patients in comparison to the proinflammatory cytokines TNF-α and IL-6.

The study consisted of 35 male patients with stable COPD and 30 age and sex matched controls with normal pulmonary function. Serum CRP, TNF-α, IL-6. levels were taken from the subjects. It was found that CRP levels were significantly higher in stable COPD subjects than in control subjects however, TNF-α and IL-6 were not significantly different. When BMI was taken into account then it was found that COPD subjects with low BMI had a higher serum CRP and TNF-α levels compared to COPD subjects with normal to high BMI.

The authors came to the conclusion that the present study confirms that because circulating CRP levels are higher in stable COPD patients this may be regarded as a valid biomarker of low-grade systemic inflammation. Also, because CRP and TNF-α were higher in the COPD patients with a low BMI then this could be considered an indicator of malnutrition in COPD patients.
The results of this study could be applied to the current study in which I am working looking at COPD and CVD. Using CRP as an indicator of low grade systemic inflammation could be utilized when we are looking at the occurrence of coronary calcium development in those with varying severity of COPD and outcomes such as stroke or heart attacks. Based on these results, I would expect those with lower COPD severity (goldstage 1) to still be at increased risk for heart attacks and stroke. This would be contradictory to the current notion that goldstage 1’s are not really COPD thus the lack of contribution to cardiovascular disease. The other results identifying higher CRP and TNF-α indicating malnutrition could e applicable to studies looking at muscle/tissue wasting in COPD subjects.

Food allergies--peanut/tree nut

2009-11-30T14:56:00.003-07:00

Being one of the clinicians in this course, I thought I would share some information about food allergy (which is an issue we encounter with increasing frequency):

Food allergies are adverse immunologic reactions to food proteins and run the spectrum of IgE mediated reactions to cell mediated reactions such as food protein induced enterocolitis or contact dermatitis. However, IgE mediated food reactions are the most common.

Food allergies are prevalent with reproducible symptoms in 5% of young children and 1-2% of adults. More than 90% of food allergies are caused by milk, egg, fish/shellfish, wheat, soy, peanut/tree nuts. It is estimated that 1-2% of the U.S. and European population is allergic to peanuts and/or tree nuts.

Furthermore, reactions to nuts, particularly peanut are severe and often fatal. In fact, per the United States Food Allergy & Anaphylaxis Network (FAAN) registry, peanuts are responsible for a significant percentage of food-associated deaths. Unfortunately, accidental exposure to peanuts is common, noted to occur in 14.3% of Montreal schoolchildren, and exposure to doses as small as 100 micrograms may provoke symptoms (an average peanut weighs 300-500 milligrams). Approximately 20% of children will outgrow a peanut allergy (approximately 10% outgrow tree nut allergy).

Interestingly, nearly one-third of peanut allergic patients will become tree nut allergic and this trend seems to be true of tree nut allergic patients becoming peanut allergic, at least for some tree nuts, such as cashew. So, is it that nut allergic persons are predisposed to develop allergies to multiple different nut proteins? Or are they reacting to similar epitopes in the various types of nuts? The answer is unclear for several reasons. First, and most obviously, not enough work has been done between peanut and tree nut cross reactivity. Second, how do we assess cross-reactivity? Do we use methods that denature the protein and exposure linear, but not necessarily functional epitopes, such as Western blotting? Or do we use functional assays that use structurally intact proteins such as histamine release assays (human basophils or immortalized rat basophils)? Also, how do these studies correlate with the clinical history as well as measurements of peanut or tree nut specific IgE? This is the subject of some ongoing research being conducted here as well as a few other sites in the U.S. and Europe, and perhaps elsewhere.

As a final note, there are a few articles that demonstrate transfer of allergies in the context of transplantation. The first article by Bellou et al. involves bone marrow transplantion. The second article by Phan et al. involves liver transplantation. The third article, which did not have an abstract available online reports peanut hypersensitivity transfer via fresh frozen plasma. The mechanism responsible for the transfer of allergy is undetermined but ideas include adoptive transfer of primed donor B-cells or T-cells, or the transfer of donor mast cells sensitized to peanut specific-IgE or passive transfer of donor peanut specific-IgE.

Articles:

Bellou A, et al. Tranfer of atopy following bone marrow transplantation. Ann Allergy Asthma Immunol. 1997 May;78(5):513-6.

Phan TG, et al. Passive transfer of nut allergy after liver transplantation. Arch Intern Med. 2003 Jan 27;163(2):237-9.

Arnold DM, et al. Passive transfer of peanut hypersensitivity by fresh frozen plasma. Arch Intern Med. 2007 Apr 23;167(8):853-4.

References:

Sampson H. Update on food allergy. J Allergy Clin Immunol 2004;113:805-9.

Bock S. Prospective appraisal of complaints of adverse reactions to foods in children during the first three years of life. Pediatrics 1987;79:683-8.

Hefle S, Nordlee J, Taylor S. Allergenic Foods. Crit Rev Food Sci Nutr 1996; 36:S69–S89.

Sicherer S, Furlong T, et al. A voluntary registry for peanut and tree nut allergy: Characteristics of the first 5149 registrants. J Allergy Clin Immunol 2001;108:128-32.
Sicherer S, Sampson H. Peanut allergy: Emerging concepts and approaches for an apparent epidemic. J Allergy Clin Immunol 2007;120:491-503.

Yu JW, Kagan R, Verreault N, Nicolas N, Joseph L, St Pierre Y, et al. Accidental ingestions in children with peanut allergy. J Allergy Clin Immunol 2006;118:466-72.

Roux K, Teuber S, et al. Tree nut allergens. Int Arch Allergy Immunol 2003;131:234-44.

Fleischer D, Conover-Walker M, et al. The natural history of tree nut allergy. J Allergy Clin Immunol 2005;116:1087-93.

Burks K, Bock S. Natural History of Peanut and Tree Nut Allergy: Development of Tree Nut Allergy/Sensitization. J Allergy Clin Immunol 2008;121:S235.

Nicotine, Anti-Inflammatory H1N1 Cure

2009-11-30T09:34:00.003-07:00

With the recent global outbreak of H1N1, there have been many theories for different vaccines to cure H1N1. Lucky for us some of those theories have been approved by medical researchers and the FDA and vaccines have been produced to cure the people who are affected with the disease. Ironically, there is another theory that you all may find controversial, which I find interesting to blog about and read your comments.

Doing some research on Anti-Inflammatory drugs/remedies using the world wide web, I came across this article stating that Nicotine from tobacco has an anti-inflammatory affect via the vagus nerve which can block a variety of cytokines of the H1N1 virus. Last week in discussion, we talked about the "risk/benefit" theory, where taking an Anti-Inflammatory drug can initially be beneficial, but if that drug is overused, the risk is damage to the GI tract, liver, and can raise blood pressure.

In regards to this article, the "risk/benefit" theory can be applied as well. The article does mentioned that smoking is very toxic to the body, but the nicotine in tobacco can act as an anti-inflammatory and as long as nicotine is present in tobacco, the degenerative effects from inflammatory diseases will be moderately controlled.

Nicotine stimulates the cholinergic anti-inflammatory pathway. At the end of this pathway are immune cells that produce anti-inflammatory cytokines that block inflammation. Thus, nicotine, although one of the most addictive chemicals, can have beneficial effects on inflammatory diseases, such as arthritis, asthma, cancer, inflammatory bowel diseases and perhaps, H1N1.

Tobacco Smoke Is Toxic but also Anti-Inflammatory
Paradoxically tobacco smoke contains hundreds of toxic and carcinogenic chemicals that produce inflammatory reactions and numerous degenerative diseases, but it also contains nicotine that is anti-inflammatory. Smokers assault their bodies, but moderate and obscure the inflammatory degeneration and disease, until they stop the nicotine exposure.

Nicotine Withdrawal Is Inflammatory
The anti-inflammatory benefits of nicotine reveal the inflammatory basis of many unexpected diseases. Nicotine withdrawal is severe, partly because it leads to rebound release of inflammatory cytokines, inflammation and inflammatory disease symptoms that include depression and obesity. Smoking cessation may contribute to more severe symptoms of H1N1 infections.

Nicotine Acts via the Vagus Nerve
Attempts to augment bypass surgery for weight reduction have encountered the anti-inflammatory benefits of stimulating the vagus nerve. Vagus nerve stimulation via an electrode attached to the left branch in the neck by a device implanted behind the clavicle, reduces inflammatory cytokine production and is an effective treatment for obesity. Other types of vagus stimulation are being tested for efficacy in treatment of numerous inflammatory diseases, including arthritis, allergy, asthma, Alzheimer’s, etc.

Nicotine Blocks Cytokine Storms
Cytokine storms are a deadly consequence of inflammation that is out of control. These exaggerated host responses are targets for bioterrorism, because it takes very little toxin or a very minimal infection to be lethal, if it produces a cytokine storm. In mice, the ricin toxin, a bioterrorism agent, induces a cytokine storm that kills by multiple organ failure. Ricin-treated mice can be protected by nicotine prior or after the cytokine storm begins.Read more: http://diseases-viruses.suite101.com/article.cfm/nicotine_antiinflammatory_h1n1_cure#ixzz0YMYaYMWp

In my opinion from a person who does not smoke, I think when it comes to using tobacco whether it be from cigarettes or chewing to receive a source of nicotine to fight inflammation, the risks of smoking to receive a source of nicotine out weigh the benefits. Smoking can cause lung cancer, throat cancer, severely raise a person's blood pressure, effect a person's physical appearance, and can become addicting to where a person can't go through a day without having a smoke. There are other ways to fight inflammation that are less harmful to a person than using nicotine and I believe a person who smokes to fight inflammation should reconsider and look at other healthier treatments like changing their diet, exercising, etc.

Mabley JG, Pacher P, Szabo C. Activation of the cholinergic anti-inflammatory pathway reduces ricin-induced mortality and organ failure in mice. Mol Med. 2009 Feb 11. [Epub ahead of print]
Gwilt CR, Donnelly LE, Rogers DF. The non-neuronal cholinergic system in the airways: an unappreciated regulatory role in pulmonary inflammation? Pharmacol Ther. 2007 Aug;115(2):208-22.
Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth. 2009 Apr;102(4):453-62.Read more: http://diseases-viruses.suite101.com/article.cfm/nicotine_antiinflammatory_h1n1_cure#ixzz0YMchF3PY

Electro-acupuncture

2009-11-29T15:41:00.004-07:00

In our acupuncture discussion last week, I had briefly mentioned about “electroacupuncture”. It was my first time hearing this term so I looked up for more detailed information on this subject…if anyone’s interested in it as well!

We all have a general idea of how traditional acupuncture works…
Electroacupuncture stem from the same idea of using needles on the acupoints but with the needles attached to a device that generates continuous electric stimulation. Another term for electroacupunture is “Percutaneous Electrical Nerve Stimulations (PENS)”

There are three main benefits of using electroacupunture:
1. It substitutes for prolonged hand manoeuvring. It helps to assure that the patient gets the amount of stimulation needed in case of the acupunturist’s pause due to fatigue. It also helps to reduce the total treatment time by providing continuous stimulus as well as the chances for the acupuncturist to attend other patients.
2. It can provide a stronger stimulation without causing tissue damage. Strong stimulation may be necessary in difficult cases such as neuralgia or paralysis.
3. Electroacupunture makes it easier to control the frequency and the amount of stimulus in comparison with hand manipulation of the needles.

There is one disadvantage of electroacupunture --- the lack of direct acupuncturist participation. It limits the opportunity for the acpunturist to respond to changes that are taking place during treatment.
According to the Chinese literature, good results are expected from electroacupunture especially in treatment of neurological diseases, including chronic pain, spasm, and paralysis. However, the method should be used with caution in patients with serious cardiac disease. It’s generally recommended to avoid placing electrodes near the heart to prevent the adverse responses of the heart to electrical impulses. In addition, the path between any two electrodes should not cross the heart area as well. Some have also suggested avoiding placing electrodes to needles on both sides of the spinal cord no matter how low the current that’s being used, because of the possible effect of the electrical stimulus on the nervous system.

Similar to the traditional acupuncture treatments, the electroacupunture treatment experiments also revealed conflicting outcomes. The majority of journal articles from China on electroacupunture are devoted to laboratory animal studies. Those studies have limited relevance to humans due to the difficulties matching points on these animals with those on humans. Therefore, electroacupunture animal studies mainly provide a means of using an animal model to study acupuncture therapy in general.

This following short video provides the basic idea as well as demonstratio of both traditional and electroacupuncture!

Here is the link if the short video does not show on your computer.
http://www.youtube.com/watch?v=bvlxggeIG4E&feature=related

References

http://www.itmonline.org/arts/electro.htm Electro-acupuncture Subhuti Dharmananda, Ph.D, Director, Institute for Tranditional Medicine, Portland, Oregon
http://en.wikipedia.org/wiki/Electroacupuncture Electro acupuncture
http://www.youtube.com/watch?v=bvlxggeIG4E&feature=related Acupuncture treatment - the basics. Tom Kennedy

Ross River Infection causes arthritis in humans and mice.

2009-11-27T18:47:00.008-07:00

So, there haven't really been many pathogens discussed here so far, and I figured I'd write a little about a virus that's really unique in the way that your immune system clears it.

Ross River Virus (RRV), is a negative sense, enveloped, single stranded RNA virus in the family Togaviridae and was first isolated in 1959 from a mosquito in Australia. It is one of the members of the Old World alphaviruses, and symptoms in humans are usually a rash, followed 2 weeks or so later by various musculoskeletal symptoms in the extremities. These can include arthritis/arthralgia, as well as muscle pain. The interesting thing about these symptoms is that they do not go away in a matter of days as one would normally expect. They can instead persist for weeks to months, and in rare cases, years after infection. There are also currently no treatments, and no vaccine against this or any other arthritic alphavirus.

Figure 1. The Ross River is designated by the marker "A".

In comparison to encephalitic alphaviruses, very little is understood about arthritic disease cause by alphaviruses. It was not until 2006 that a mouse model of RRV infection was published. (Morrison et al, 2006) These preliminary studies showed that infection of mice with RRV resulted in massive inflammation of bone, joint, and skeletal muscle tissues in the hind limbs. Further analysis showed that the cells causing this inflammatory response were macrophages, NK cells, CD4+ and CD8+ lymphocytes. Current studies are looking at the which type of macrophage is involved, as well as how the virus is causing this massive immune response.

The greatest advantage to this model system is that the disease process in mice closely resembles that seen in humans, therefore, presumably, any advances made in understanding viral pathogenesis in the mouse can be transferred into the human disease with a fair amount of confidence.

Figure 2. Photograph of a patient infected with Ross River Virus.

As if that wasn't enough, an avirulent strain has been isolated which contains 45 amino acid substitutions when compared to the WT. This avirulent virus has been shown to replicate just as efficiently as the WT virus, however it does not induce any of the inflammation seen in WT RRV infection. Current studies on comparing these two genomes have identified 2 independent genetic virulence determinants in regions of the genome that contain only 11 AA changes. Site directed mutagenesis of each one of these 11 AA residues will hopefully identify 1 or 2 particular AA residues which are critical to viral pathogenesis.

Figure 3. Histology of Mouse quadriceps tissue. A. Mouse infected with wild type RRV. B. Mouse infected with avirulent strain of RRV. Both mice received the same amount of virus during infection.

The hope is that these virulence determinants might allow researchers to begin working on a possible therapeutic vaccine. The other hope is that these particular AA residues may be conserved across different species of alphaviruses such as Chikungunya and others, and that it might be possible to transfer any finding gleaned from RRV and incorporate them in the battle against Chikungunya. (If you're interested in reading about Chikungunya, feel free to check out: http://en.wikipedia.org/wiki/Chikungunya.)

References:

Characterization of Ross River virus tropism and virus-induced inflammation in a mouse model of arthritis and myositis.

Morrison TE, Whitmore AC, Shabman RS, Lidbury BA, Mahalingam S, and Heise MT.

Journal of Virology, 2006, 80(2):737-49.

No Finger Prints from Inflammation

2009-11-26T11:55:00.002-07:00

If you watch television then you’ve seen a drug commercial with a list of side effects. One commonly used cancer treatment drug, capecitabine, has a side effect which can get you into trouble at the airport – capecitabine can erase finger prints!

Capecitabine is prescribed regularly to prevent cancer from returning and is known to cause inflammation and blistering of the palms and soles of the feet. Using it a lot can cause swelling and blistering and leave patients without finger prints. Sometimes the swelling isn’t pronounced enough to affect patients and cause doctors to remove capecitabine from their drug regimens.

This is exactly what happened to one patient chronicled by the BBC. This patient was travelling to the United States where he was held by immigration officials for four hours. Their reasoning? The man’s finger prints had vanished!!!

Here is a link to more similar stories:

http://www.handresearch.com/news/cancer-patient-no-fingerprints-hand-foot-syndrome.htm

Tumor Immunology in the News

2009-11-25T13:43:00.004-07:00

I just stumbled upon this interesting article about an article by Mooney et al. that utilizes a sponge-like matrix coated with pro-inflammatory molecules (bacterial DNA), cytokines and crude melanoma lysates as an anti-tumor 'vaccination' for melanoma. The components of the matrix basically mimick a local pro-inflammatory environment and provide the infiltrating DCs with peptides of the melonoma which can then in turn be presented to antigen-specific T cells in the draining LN. The reason for the excitement about this approach is quoted as "[...] it has all of the molecular and cellular signatures of a strong vaccine reaction.[...]". As always, the detailed reasons of why this works so well are not known.

Maybe it is almost, but not quite yet, time for tumor immunology to shine.

P.S.: It seems that the original article is not in PubMed yet, as I could not find it. I will post a proper link once it is up.

Anti-Inflammatory Foods

2009-11-24T19:42:00.002-07:00

In the spirit of Thanksgiving and all the holiday food we will be consuming this holiday weekend, I was doing some research on Anti-Inflammatory drugs and all of sudden my stomach told me to go eat some dinner and then it hit me to search if foods can help reduce inflammation. I came across this article that explain which foods we all should eat or stay away from.

What is Inflammation?
Inflammation is defined as a localized reaction of tissue to irritation, injury, or infection. Symptoms of inflammation include pain, swelling, red coloration to the area, and sometimes loss of movement or function. We commonly think of inflammation as the painful component of arthritis. Inflammation is also a component of chronic diseases such as heart disease and strokes.

Avoid Pro-Inflammatory Foods
Pro-inflammatory foods will increase inflammation, increase your pain from the inflammation and may also raise your risk for chronic disease. Loading up on junk foods, high-fat meats, sugar and fast foods will increase inflammation in your body. This is partially due to the unhealthy fats used in preparing and processing these foods, especially trans fats and saturated fats.

Processed meats such as lunch meats, hot dogs and sausages contain chemicals such as nitrites that are associated with increased inflammation and chronic disease.
Saturated fats are also found in meats, dairy products and eggs. While all of these foods are important source of minerals and vitamins, you don't need the extra saturated fat. These foods also also contain fatty acids called arachidonic acid. While some arachidonic acid is essential for your health, too much arachidonic acid in the diet may make your inflammation worse. Be sure to choose low fat milk and cheese and lean cuts of meat, which will not promote inflammation.

Diets high in sugar have also been associated with inflammation, obesity and chronic disease such as diabetes. Eliminate high sugar foods such as sodas, soft drinks, pastries, pre-sweetened cereals and candy.

Choose Anti-inflammatory Foods

Fats and Oils
The right types of fats in your diet will impact pain and inflammation in a positive way. Omega-3 essential fatty acids are very powerful anti-inflammatory agents. They are found in cold water oily fish, walnuts, flax seeds, canola oil and pumpkin seeds. Adding omega-3 fatty acid supplements from flax oil or fish oil may also help reduce inflammation, just be sure to speak with a doctor or nutritionist before taking larger, therapeutic doses of any supplement, or follow label instructions.

Protein
Your body needs protein to build healthy body tissues. Good protein sources include lean poultry, fish and seafood, nuts, legumes and seeds. Red meats may trigger inflammation, so cut back on fatty red meats. When you do eat red meat, choose lean cuts of bison, venison and other game meats, or the lowest-fat cuts of beef, preferably grass-fed beef.
Soybeans, tofu, and soy milk are three great sources of soy proteins that may help to reduce your pain and inflammation.

Carbohydrates and Fiber
Most of your carbohydrates should come from whole grains, vegetables and fruits. The bread, cereal and pasta in your diet should be mostly be 100% whole grain products. Whole grains are excellent sources of fiber, and a high fiber diet will reduce your inflammation.

Choose green leafy vegetables, green and brightly colored vegetables and lots of fresh whole fruits. You should eat at least five and preferably more servings of fruits and vegetables each day. Green vegetables and whole fruits are also important as sources of dietary fiber.

Berries are also a great food choice, especially blueberries and strawberries which are packed with anti-inflammatory phytochemicals and anti-oxidants. The pigments in brightly colored fruits, vegetables and berries contain many phytochemicals that have anti-inflammatory properties. One example is quercetin, which is found in apple and red onion skins and has strong anti-inflammatory properties.

It was discussed in lecture this past week that altering one's daily life style can help with regulating chronic inflammation. We also agreed in class that in reality, it takes discipline and personal responsibility to conduct a routine that consists of the daily activities which helps a person reduce the risk of being diagnose with chronic inflammation. However, I commented that not everybody will take the necessary steps to alter their daily live activities to reduce the risk of chronic inflammation but maybe a person would be more willing to alter their daily diet? To be honest I think it depends on the each person, each person has their own beliefs to what is good for them and will do whatever makes he or she happy.

Are you a person who would be willing to alter your daily activities or alter your daily diet or both to help fight against being diagnose with chronic inflammation?

Photopheresis for GVHD

2009-11-24T12:23:00.007-07:00

This is an interesting immunological intervention that is approved by FDA, but the mechanism of action is not well known. I am surprised many treatments that are routinely used (empirical) but we do not really know why it works. Probably steroids were/are one of those medications which has long history without knowing the mechanism of action.

Extracorporeal photopheresis (ECP) is a relatively new technique used to treat immunological disorders and complications, such as cutaneous T-cell lymphoma(CTCL), graft-versus-host disease(GVHD), solid organ transplant, and Crohn disease. GVHD will be discussed mainly as the observation of what happens through ECP is quite interesting.

The procedure consists of: 1) the photopheresis system draws blood from the patient, 2) Blood is separated by centrifugation into its cellular components and plasma, and red blood cells are returned to the patient, 3) white blood cells are treated with 8-methoxypsoralen(8-MOP) and exposed to ultraviolet A(UVA) radiation, and 4) the phtoactivated white blood cells are returned to the patient.

ECP was believed to work due to DNA damage and subsequent lymphocyte apoptosis by 8-MOP in the presence of UVA. Then later, researchers started thinking that it doesn’t really make sense as only 5 to 10 percent of lymphocytes are treated during a cycle of treatment. Additionally, research found that induced production of TNF-alpha by monocyte, and a shift in the profile of cytokine production and the balance of Th1 and Th2 response after treatment. Currently a more plausible theory is that the apoptotic lymphocytes produced during ECP increased their display of tumor associated antigens, dividing monocyte activation and the maturation of dendritic cells. That mediates regulatory T-cell production and results immune tolerance.

One of the biggest advantage of ECP is that it doesn’t cause systemic immunosuppression. In actual practice, the ECP is combined with immunosuppressives anyway, and cautions are needed. However, utilizing ECP are expected to help less invasive and effective therapy to be used in organ/stem cell transplantation for GVHD. Again, it is going to be interesting to see what theory is going to fully explain the phenomenon.

References
Knobler, R., Barr, M., Couriel, D., et al. (2009). Extracorporeal photopheresis: past, present and future. Journal of American Academy of Dermatology, 61(4), 652-665.
Xia, C., Canpbell, K., and Clare-Salzler, M. (2009). Extracorporeal photopheresis-induced immune tolerance: a focus on modulation of antigen-presenting cells and induction of regulatory T cells by apoptotic cells. Current Opinion in Organ Transplantation, 14, 338-343.

Party with red wine and chocolate!

2009-11-23T23:45:00.002-07:00

Red Wine

The researchers from the University of Barcelona studied the difference between red wine and gin (gin represented for any other type of alcoholic beverage) and found that red wine contains many complex compounds including polyphenols which induces a much greater anti-inflammatory effect than other alcoholic beverages.
Dr. Emanuel Rubin, a distinguished professor of pathology at Jefferson Medical College in Philadelphia said that consumption of any form of alcohol will help in lowering inflammatory markers; however, red wine has a much greater effect.

Red wine has long been associated with a lowered risk of heart attack and stroke. An experiment was performed by the Jefferson-led team[1], they measured inflammatory biomarkers in the blood to compare the different effects of red wine and gin on heart health.
The results of this study confirmed that red wine significantly lowered the level of inflammatory molecules such as adhesion molecules (inflammatory markers), proteins that cause white blood cells to stick to the walls of the arteries, which can lead to the formation of atherosclerotic plaques.

The benefits of red wine to a person’s health have been well documented. Numerous research suggesting that a moderate consumption of red wine could help to reduce the chance of getting heart diseases, various cancers, as well as reducing blood pressure and cholesterol levels.

Red wine has a number of antioxidant compounds, one of them is resveratrol --- a compound which has been linked with cancer prevention.
Scientists have been doing research on resveratrol’s role as a potential treatment against sepsis, appendicitis and peritonitis. Severe sepsis is known to have few effective treatments and a high percentage of mortality; however, scientists and research groups have found positive effects of resveratrol and its role of down regulating inflammation. Although further understanding and research is required, resveratrol may play an important role as an effective anti-inflammatory drug in the future.[2]

Chocolate

There is a review article which discussed the anti-inflammatory impact of cocoa flavanols. The article mentioned that cocoa-based products are the richest functional foods based upon flavanols. Flavanols modify the production of pro-inflammatory cytokines, the synthesis of eicosanoids, the activation of platelets and NO-mediated mechanisms. There have been studies suggesting that the regular or occasional consumption of cocoa-rich compounds result in beneficial effects on blood pressure, insulin resistance, vascular damage, and oxidative stress.[3]

Similar to red wine, polyphenols are also found in chocolate which makes it beneficial for health as well. Polyphenols are found in beverages (wine, coffee and tea), fruits and vegetables (apples, broccoli, onions, blueberries, blackberries, cherries, strawberries, plums and red grapes). [4] Although the best way to get plenty of polyphenols is to consume lots of fruits and vegetables, having chocolate every once a while will not hurt!

MODERATE consumption of red wine + MODERATE consumption of chocolate = FUN anti-inflammatory protection

[1] Red Wine Has Greater Anti-Inflammatory Action Than Other Alcohols. NUTRA ingredients.
http://www.nutraingredients.com/Research/Red-wine-has-greater-anti-inflammatory-action-than-other-alcohols
[2] Scientists Uncork Anti-Inflammatory Secrets of Red Wine. Family Health Guide. http://www.familyhealthguide.co.uk/scientists-uncork-anti-inflammatory-secrets-of-red-wine.html
[3] Chocolate at heart: The anti-inflammatory impact of cocoa flavanols. Carlo Selmi, Claudio A. Cocchi, Mario Lanfredini, Carl L. Keen, and M. Eric Gershwin. http://www.worldcocoafoundation.org/scientific-research/research-library/documents/Selmi2008.pdf
[4] Cocoa in Chocolate May Be Good for the Heart. Bio-Medicine http://www.bio-medicine.org/medicine-news-1/Cocoa-in-Chocolate-May-Be-Good-for-the-Heart-59974-1/

FX125L

2009-11-23T12:28:00.003-07:00

Article: "New Anti-Inflammatory Molecule Safe" from Medpage Today.

I tried to do some research to find the original article that this article by Michael Smith from Medpage Today was referencing based on the citation at the end, but it turns out that it is actually an oral presentation by P. Wiesel and associates at the American College of Allergy, Asthma, and Immunology Conference in July 2009. This article describes a new and innovative drug, FX125L, that is considered an oral anti-inflammatory and is targeted for the treatment of mainly asthma and COPD. They claim that at even relatively high doses, the medication is safe. Based on the article, a very recent study was performed with 66 volunteers regarding the drug and doses ranging from 0.3 to 3,000 mg. I don't know about you, but that is a VERY large range of dosing. According to the abstract of the presentation, there were no serious side effects, but some effects were adverse with the most common side effect being headache (4 on FX125L and 2 on placebo), dizziness (1 on FX125L and 1 on placebo), and nausea (1 on FX125L and 1 on placebo).

According to the 6th edition of Immunology - A Short Course by Coico, et.al, asthma involves cytokine-induced recruitment of inflammatory cells (mainly eosinophils) that can cause tissue injury due to toxic substances released by these cells that can include oxygen radicals, nitric oxide, and cytokines. Cytokines released by TH2 cells and mast cells (IL-4, IL-13, and TNFalpha) upregulate expression of leukocyte and endothelial adhesion molecules such as ICAM-1 and E-selectin. Because of these adhesion molecules, there in an increase in eosinophil-endothelial cell adhesion that causes migration and prolonged survival within lung tissue.

So, what is FX125L? It seems to be a broad-spectrum chemokine receptor inhibitor. FX125L acts similar to a corticosteroid, but the article claims that it doesn't have as adverse effects as corticosteroids. According to theasthmacenter.org, corticosteroids (like Advair and Pulmicort) in asthma suppress the inflammatory reaction that causes swelling and narrowing of the bronchi. It is normally used when asthma can't be controlled with bronchodilaters like albuterol. The most significant side effects with corticosteroids is usually caused by a high daily oral dose over a period of months to years.

The exact molecular action of FX125L was hard to find. The only thing I could find was that it blocked migration of inflammatory cells. This would obviously prevent the inflammation from occuring if the cells associated with inflammation are unable to chemotax to the site. Also, according to the presentation abstract, FX125L inhibits neutrophil recruitment to the lung. Neutrophils are the first line of defense against fungal and bacterial infections, but when recruited to the lung, can release chemokines and cytokines that enhance inflammation such as IL-6, IL-8, IL-1beta, andTNFalpha.

The term "broad-spectrum" usually refers to being effective over a wide range. It would be interesting to know exactly how this is accomplished. If FX125L targets a specific receptor, how can it be broad-spectrum? I think about antibiotics and how there are broad-spectrum ones that are used to treat a number of strains of bacteria that cause infections so it can be prescribed for many infections. How does FX125L target chemokine receptors in general and manage to target a particular one? Maybe it targets a specific receptor that is associated with inflammation in general or in most to all cases. This is one of many questions that I hope will be explained soon as the research progresses.

"ACAAI: New Anti-Inflammatory Molecule Safe" Medpage Today. Ed. Michael Smith. 9 Nov. 2009. Web. 16 Nov. 2009. .
Presentation - Wiesel P, et al "First clinical experience with FX125L, an anti-inflammatory oral small molecule with an entirely novel mechanism of action" Ann Allergy Asthma Immunol 2009; 103(5)(suppl 2): Abstract 5
Corticosteroids - http://www.theasthmacenter.org/manual/part2-12.html
Neutrophils - http://www.springerlink.com/content/j71781x837m85n12/fulltext.pdf

Strenuous Exercise linked to memory Loss

2009-11-23T11:31:00.000-07:00

This study was presented at the Alzheimer’s Association 2009 International Conference on Alzheimer’s disease. Long-term strenuous physical activity has been shown to decrease lifetime exposure to ovarian hormones in women and has been found to play a protective role against breast cancer. However a decrease in ovarian hormone exposure has been associated with increased risk of cognitive impairment. Also, long-term physical activity is associated with improved cognition but the intensity required to preserve cognition is not known. Mary C. Tierney, PhD, and professor at the University of Toronto wanted to examine the relations between both long-term strenuous and moderate activity and cognition in recently postmenopausal women. The study had 90 women aged 50-63 years old who gave details on the amount of their strenuous and moderate physical activities from high school to menopause. Eight memory and brain function tests were administered to all participants. The researchers found that long-term strenuous activity was always associated with poorer performance on all eight of the tests. Moderate physical activity was always associated with better performance on all eight of the tests. The results suggest that long-term strenuous activity may increase the risk of cognitive impairment in recently postmenopausal women, but moderate long-term physical activity may improve later life cognition. Dr. Tierney says that further study is needed.

Don't Sneeze On Your Cat!

2009-11-21T20:43:00.002-07:00

As a self-proclaimed “cat lady” I decided that the recent confirmation of the transmission of the H1N1 influenza virus from humans to cats is appropriate to blog about. On November 4, 2009, it was reported and confirmed that a 13-year old cat in Iowa contracted the H1N1 influenza virus. Since then, more cats have been diagnosed with H1N1 and there has been one presumed, yet not confirmed, death.

When two members of an Ames, Iowa, family came down with the H1N1 flu, the family pet, a 16-pound orange tabby, became lethargic, lost his appetite, and was showing signs of respiratory discomfort. Fortunately they were able to call a family friend, Dr. Brett A. Sponseller, who is a specialist in large animal internal medicine and molecular virology at the College of Veterinary Medicine at Iowa State University. Dr. Sponseller and his colleague Dr. Albert Jergens conducted many tests and concluded that the cat indeed had H1N1 influenza.

This story is unique because it is the first case of a feline contracting influenza from a human, which has created concern for health officials and pet owners alike. There have been cases of companion animals acquiring the flu from other species. The canine influenza (H3N8) began in horses, and cats have been known to contract avian influenza (H5N1) from eating birds. However, the feline H1N1 case in Iowa remains the first time a cat has contracted influenza from a human. To date this virus has been confirmed in three pet ferrets, turkeys in Chile and Canada, and has also been transmitted between humans and pigs.

Since then, there have been more confirmed cat H1N1 cases. On November 17th 2009, a cat in Park City, Utah became the second confirmed H1N1 feline case. The owner contracted the H1N1 flu and noticed flu-like symptoms in the cat – similar to the Ames family. On November 18^th, 2009, the Oregon State public health veterinarian reported that a pet cat died from presumed H1N1 influenza virus infection approximately one week after a child in the household had flu-like symptoms. The cat shared a household with three other cats – all of which became ill with less severe sneezing and coughing symptoms.

Even though veterinarians and health care officials are uncertain of how the cats contracted the virus, it is known that the flu is easily transmitted between family members, and it is not surprising that a sociable cat would come into contact with the virus making it more susceptible. It is important to note that according to Dr. Sponseller, there is no evidence that a cat can transfer the H1N1 virus to a person because cats with flu typically don’t cough or sneeze.

This situation has fostered more “swine” flu panic and has raised many questions. How can a cat get H1N1 from humans? What makes this influenza virus transmittable to cats? Can a cat transfer H1N1 to humans? Can other companion animals such as dogs get H1N1? Will there be a H1N1 vaccine for pets? Until more is learned about the transmission of the H1N1 influenza virus, many of these questions will remain unanswered.

Parker-Pope, Tara, “The Cat Who Got Swine.” The New York Times. The New York Times Company. November 5th, 2009. Web. November 17^th, 2009. <http://well.blogs.nytimes.com/2009/11/05/the-cat-who-got-swine-flu>.

“2009 H1N1 Flu Virus Outbreak” AVMA. American Veterinary Medical Association. November 18^th, 2009. Web. November 20^th, 2009. <http://www.avma.org/public_health/influenza/new_virus/>.

Alzheimer’s Disease- Oral hygiene

2009-11-21T13:57:00.000-07:00

Disclaimer: This post may come off as insensitive.
I just finished reading an article titled “Trouble Thinking? Better See the Dentist” found here http://www.reuters.com/article/newsOne/idUSTRE5AC06O20091113.
Let me start off by saying I worked in a dental office for 2 years.
The patients who came in with the WORST cases of Periodontitis & Calculus were usually the most uneducated and apathetic patients we would see. For some, a lifetime of calculus would cake onto their teeth so badly that they thought their teeth were simply growing. That’s what I said: THEY THOUGHT THEIR TEETH WERE GROWING!
For these patients, the only thing more painful than seeing the dentist would be reading The Great Gatsby. But I digress.
The Amyloid Hypothesis associated with chronic inflammation has been questioned as a causative factor in the pathogenesis of Alzheimer’s disease. Granted, I saw plenty of inflamed gum tissue in my time working in a dental office. But these epidemiological studies are simply telling me that the less health conscious individuals are showing early signs of Alzheimer’s disease for the sake of being unhealthy. What frustrates me is the scientific spin on it “those with the highest levels of the gum disease-causing pathogen Porphyromonas gingivalis were three times more likely to have trouble recalling a three-word sequence after a period of time.” When a dentist assesses gum disease, they stick a probe in your gums and measure the depth. It takes 5 seconds, less if you don’t have gum disease. This article makes it sound like they cultured the Porphyromonas gingivalis and really narrowed it down as a pathogen for Alzheimer’s disease.
Growing up, my dad would always tell me “Sit mens sana in corpore sano”, which is Latin for “a healthy mind in a healthy body” (my mom is Latina; dad is from New York…he says it in Latin to look cool). I think we should continue looking into the Amyoloid Hypothesis as a pathophysiological factor in the progression of Alzheimer’s Disease. However, I think there are things we control on a day to day basis that can make our brains healthier and more useful.

Clean Pigs and Diabetes

2009-11-20T08:13:00.002-07:00

I came across this cool report in Science about a group looking to use pig pancreatic islet cells in human patients. You can check it out here:

Science 20 November 2009:
Vol. 326. no. 5956, p. 1049
DOI: 10.1126/science.326.5956.1049-a

Basically there are a few centers in the world raising pigs in sterile environments for islet cell harvest. By transplanting the pig islet cells into human autoimmune diabetes patients the hope is that the pig cells will not be susceptible to the autoimmune response to human islet cells. Hopefully, these cells will act as a near-term solution while the bugs are being worked out of a similar human stem cell approach.

Since pig tissue in a human will obviously mount a strong immune response the New Zealand group is "encapsulating the islets in material that willfend off immune attack while allowing insulin out. The Minnesotateam is still working on an immunosuppression regimen that willallow the use of "naked islets," says Schuurman, which the scientiststhink will have better access to nutrients. Further down the road, scientists at the University of Pittsburgh and elsewhereare working on techniques for shuffling pigs' genes or conditioningpatients' immune systems to narrow the species gap."

Obviously the biggest hurdles will be working out the regulatory issues related to grafting living pig tissue into humans to permit clinical trials. An interesting and kind of crazy idea.

What do you guys think about this? What are some of pros and cons you can think of with this approach?

Scale for the Severity of Disease State in EAE

2009-11-19T22:55:00.000-07:00

During our discussion on multiple sclerosis last class we discussed the animal model of multiple sclerosis called Experimental Autoimmune Encephalomyelitis (EAE) as a tool to determine the effectiveness of treatments for multiple sclerosis. In the paper by Tsutsui et al. it was mentioned that the animals were assessed daily for EAE severity but it did not elaborate on how this was quantified in a consistent manner.
By tracing back through the references I found in the journal Natural Medicine (Liu et. al.) that severity of EAE was determined on a scale from 0-5 according to function. A score of 0 indicates that the disease is not apparent in the mobility of the animal. A score of 1 indicates mild physical signs including weight loss and tail weakness. 2 indicates mild paralysis in the hind limbs, a 3 indicates complete paralysis of the hind limbs. A 4 indicates hind limb paralysis with fore limb weakness or paralysis and finally a 5 indicates moribund (approaching death) or death.
As useful as this scale is it is unfortunate that the limit to its usefulness is limited to very advanced degrees of disease state. In humans with multiple sclerosis we know that there is a range of other problems in the early stage that manifest themselves early before obvious motor problems are manifested that this model could not be used to investigate.

Stem cells and all Neurodegenerative diseases

2009-11-18T14:42:00.000-07:00

Knowing that stem cells can differentiate into multiple cell types or all cells of the body (depending on their origin), transplantation of stem cells into an adult brain has been proposed as a future therapy for neurodegenerative diseases.
In each type of neurodegenerative disease (Hunnington’s disease, Alzheimer’s disease, Parkinson’s disease, ALS), there are many different cell types involved in their pathology, thus, different types of neurons are required for replacement.
This article http://celleng.sjtu.edu.cn/pic/xq19.pdf analyzes many neurodegenerative diseases and their potential for stem cell therapy. They show the challenges in the way for stem cell therapy, for we need to know how to pattern stem cells to obtain a more complete repertoire of various cell types for replacement. How are stem-cell-derived neurons integrated into an adult brain’s existing neural and synaptic network? How can we modify stem cells appropriately to treat a particular disease?
To identify the self-repair mechanisms of the brain, we’ll require a new technology for genetically labeling stem cell progeny. The hope is this knowledge will allow us to figure out a strategy to deliver new molecules that can yield functional neurons/cells in damaged areas.

Converting RBC Blood Groups by Cleaving Terminal Sugars

2009-11-17T16:32:00.005-07:00

It struck me in class today that, with an enzyme to cleave either the A or B sugar from the end of the blood group glycolipid, you could create a 'O' erythrocytes from A, B, or AB individuals, expanding our supply of 'universal donor' blood while drastically reducing the risk of accidental mismatch.

As it turns out, I was not the first to have this idea - way back in 1983, it was demonstrated that a galactosidase derived from coffee beans is able to convert B RBCs into O, and that these cells are viable in people of any blood type (excluding the Bombay phenotype). Unfortunately, this method, and many others attempted for both A and B sugars, required a prohibitively large amount of enzyme and incompatable conditions, preventing its practical large scale use.

Recently (2007), researchers, doing a large scale scan of bacterial and fungal isolates, isolated two novel galactosidases which remove the A and B sugars much more efficently, and with identical, neutral pH, reaction conditions - allowing for the conversion of AB eyrithrocytes as well as A and B. Standard typing showed full conversion of any of the groups to O.

With a quick search, I wasn't able to find any more information on more progess towards making this a reality in blood banks, but hopefully someone's working on it...

References:

Liu Q, Sulzenbacher G, Yuan H, Bennett E, Pietz G, Saunders K, Spence J, Nudelman E, Levery S, White T, Neveu J, Lane W, Bourne Y, Olsson M, Henrissat B, Clausen H (2007). "Bacterial glycosidases for the production of universal red blood cells". Nat Biotechnol 25 (4): 454

Group B erythrocytes enzymically converted to group O survive normally in A, B, and O individuals. Goldstein, Jack; Siviglia, Geraldine; Hurst, Rosa; Lenny, Leslie; Reich, Lilian, Science (1982), 215(4529).

Sea anemone toxin may provide relief for MS patients.

2009-11-15T19:20:00.002-07:00

Having read, A randomized crossover study of bee sting therapy for multiple sclerosis by Wesselius & Heersema et al., I was interested in other possible applications of animal venom in treatments similar to the apitherapy frequently used as an alternative care source for MS patients. In my inquiry I found an article on a sea anenome toxin that may act beneficially in the relapse of MS patients.

By Norton, Pennington and Wulff, Potassium Channel Blockade by the Sea Anemone Toxin ShK for the Treatment of Multiple Sclerosis, provides an overview of interaction between the toxin and potassium channels, the role of potassium cell in T-cells and the changes in potassium expression during T-cell differentiation.

Norton et al., site studies which state provide evidence showing that ShK has been able to prevent and treat adopted experimental autoimmune encephalymyelitis (EAE) in rodent models. ShK subcutaneously injected prevented EAE in a study in which all control animals died. ShK was even proven to ameliorate symptoms when treatment with ShK was delivered until after the presentation of the first symptom.

Ultimately, this paper provides just another example of possible solutions to human diseases that may be lie latent and undiscovered in other species. I always try and look at the human body holistically when discussing diseases, thinking of how all the systems interact; however, I think this articles reassures the discussion about preserving as many endangered species as possible, as we may not truly understand the potential that those animals hold.

Reference for the article: http://web.ebscohost.com/ehost/pdf?vid=2&hid=8&sid=8f2a0a67-151f-49cc-8910-280672d21490%40sessionmgr13

Iron Accumulation in the Brain may lead to AD and PD.

2009-11-14T17:39:00.002-07:00

Multiple recent studies have been published pertaining to iron accumulation in the brain and a correlating incidence of neurological disorders. Many studies have been published particularly surrounding Alzheimer's and Parkinson's disease. Authored by Zecca et al., Iron, Brain Ageing and Neurodegenerative Disorders, focuses on this correlation.

Iron accumulation has been linked to multiple neurodegenerative diseases; it is believed that the build up iron causes an increased amount of oxidative stress which can be responsible for neurodegeneration. The iron accumulation in the brain increases preferentially in areas that are impacted by AD and PD. Some evidence seems to indicate that the accumulation of iron in the microglia induces the inflammatory response common amongst many neurodegenerative diseases.

In the case of Parkinson's Disease, increased iron accumulation is seen in the substantia nigra in extreme cases. Iron (III) specifically can be seen accumulated in the oligodendrocytes, astrocytes, microglia and portions of the substantia nigra of PD patients. In Alzheimer's Disease, iron seems to promote both deposition of amyloid-B and oxidative stress which are associated with plaque deposition.

This provides a unique link between metabolic needs, nutritional regulation and neurodegenerative diseases.

Reference for the article: http://www.nature.com/nrn/journal/v5/n11/pdf/nrn1537.pdf

New Clues to How Fish Oils Help Arthritis Patients

2009-11-14T17:17:00.002-07:00

I've always heard that fish oils are good at reducing inflammation. I thought this article was interesting I tried finding a more specific and in depth summary of how Resolvin D2 promoted edothlial cells to produce NO to prevent the macrophages from attacking the cells. I'd like to hear other opinions on the subject. I's sure we can all agree nutrition is very important for arthritis patients. maybe we can find a more detailed summary of the pathway.

Findings may boost treatments for other inflammatory diseases, researchers say

Posted October 28, 2009

WEDNESDAY, Oct. 28 (HealthDay News) -- Researchers think they now understand the way that fish oils benefit people with rheumatoid arthritis and other conditions linked to inflammation.

The body converts an ingredient in fish oils called DHA into a chemical called Resolvin D2, which reduces the inflammation that can lead to various diseases, the scientists from Queen Mary, University of London and Harvard Medical School explained in their study published in the Oct. 28 issue of the journal Nature.

"We have known for some time that fish oils can help with conditions like arthritis, which are linked to inflammation. What we've shown here is how the body processes a particular ingredient of fish oils into Resolvin D2. We've also looked in detail at this chemical, determining at least some of the ways it relieves inflammation. It seems to be a very powerful chemical and a small amount can have a large effect," Mauro Perretti, a professor of immunopharmacology at Queen Mary, University of London, said in a university news release.

"This research is important because it explains at least one way in which fish oils can help in different types of arthritis. We can also work on this chemical and see if it can be used not only to treat or even prevent arthritis, but also as a possible treatment for a variety of other diseases associated with inflammation," said Perretti, who led the U.K. research team.

Unlike current anti-inflammatory drugs, Resolvin D2 doesn't appear to suppress the immune system, the researchers noted.

In arthritis, the body's immune system attacks healthy tissue. An important part of this process occurs when white blood cells (leukocytes) stick to the inner lining (endothelium) of blood vessels. In lab tests, Perretti and colleagues found that Resolvin D2 prompted endothelial cells to produce small amounts of nitric oxide, which acts as chemical signal that discourages white blood cells from sticking to the endothelium, thus preventing inflammation.

More information

The American Academy of Family Physicians has more about rheumatoid arthritis.

Link Between Pain Thresholds, Inflammation And Sleep Problems In Arthritis Patients

2009-11-14T17:04:00.002-07:00

Link Between Pain Thresholds, Inflammation And Sleep Problems In Arthritis Patients

As a college student sleep is sometimes a luxury, I often find it difficult to find time to sleep with all the deadlines and daily activities. My concern for lack of sleep lead me to this lay article on RA and pain threshold for sleep disorders. I found it interesting and thought I'd share it with everyone. I thought it would be interesting to consider how sleep or more specifically sleep deprivation related to disease. can anyone think of any possible relationships between RA and sleep deprivation aside from increased stress and damage leading to increased inflammation?

Article Date: 29 Oct 2009 - 5:00 PDT

Despite recent advances in anti-inflammatory therapy, many rheumatoid arthritis (RA) patients continue to suffer from pain. Research published in BioMed Central's open access journal, Arthritis Research & Therapy found that inflammation is associated with heightened pain sensitivity at joint sites, whereas increased sleep problems are associated with heightened pain sensitivity at both joint and non-joint sites.

Researchers from the Division of Rheumatology and Pain Management Center of Brigham and Women's Hospital, and the Chronic Pain and Fatigue Center of the University of Michigan Medical School, assessed experimental pain sensitivity, disease activity, sleep problems and psychiatric distress in 59 women with RA. The researchers used questionnaires to assess the women's sleep problems and psychiatric distress and measured the levels of C-reactive protein as an indicator of disease activity. They also measured pain sensitivity with pressure pain threshold testing at joint and non-joint sites. Lower pain thresholds are indicative of higher pain sensitivity.

"Sleep problems were inversely associated with pain threshold at all sites, suggesting a defect in central pain processing", state the authors. This finding emphasises the need for research into the mechanisms underlying sleep disorders and pain in RA patients, particularly given the common occurrence of sleeping problems among these patients. This autoimmune disease, causing chronic inflammation, affects nearly 1% of the population and sufferers often report ongoing pain in spite of successful anti-inflammatory treatment.

"Since differences in pain sensitivity may shape the course of pain complaints and influence treatment decisions, it is important to understand the factors associated with enhanced pain sensitivity", lead author Yvonne Lee says, adding, "Physicians and researchers should consider both inflammatory and non-inflammatory factors when evaluating pain in research settings and in the clinic."

Notes:
The relationship between disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional study
Yvonne C Lee, Lori B Chibnik, Bing Lu, Ajay D Wasan, Robert R Edwards, Anne H Fossel, Simon M Helfgott, Daniel H Solomon, Daniel J Clauw and Elizabeth W Karlson
Arthritis Research & Therapy (in press)
http://arthritis-research.com/

Source:
Charlotte Webber
BioMed Central

Blood Brain Barrier Breakdown Precedes Infiltration in MS

2009-11-13T09:41:00.002-07:00

As we discussed in class, Multiple Sclerosis is currently an idiopathic disorder with no known precipitating cause. Clinically it manifests itself as demyelinated areas of the central nervous system called lesions that contain blood derived immune monocytes. Because the immune system and the central nervous system are normally separated the immune cells are unable to discriminate between brain antigens and foreign antigens.
It is for this reason Multiple sclerosis has been considered an autoimmune disorder and therapies have centered around attempting to modify the inflammatory response and try to depress what seems to be considered an overactive immune system response. In the review article from last class by Martino and associates, it was noted that the blood brain barrier showed enhanced leakiness around the sites of the lesions but it was unknown whether this preceded or was a result of an already initiated immune response. I see this as a pivotal question to answer in the quest for a treatment of multiple sclerosis. Obviously at some point damage is done by the blood born immune system but is this behavior due to an aberrant immune response in need of correction or is it simply working perfectly against antigens that it should never have had the opportunity to encounter in the first place?
According to a paper by Floris and associates in the journal Brain, they were able to determine that in animal models with allergic encephalomyelitis (EAE) MRI imaging with gadolinium showed that vascular leakage and onset of neurological signs occurred concomitantly BEFORE the infiltration of immune monocytes. This suggests that cerebrovascular leakage and monocyte infiltration are two distinct events in the development of the lesions. This may be a very important consideration in the direction of research and the development of new therapies for multiple sclerosis.

The 1976 Swine Flu Vaccination Program

2009-11-12T17:44:00.003-07:00

I recently read an article written by the David J. Sencer, the director of the Center for Disease Ccontrol in 1976. I found it interesting what with all of the recent publicity about the H1N1 vaccine. I have written a brief summary and added some links to the original article and to the CDC’s H1N1 factsheet.

http://www.cdc.gov/ncidod/EID/vol12no01/pdfs/05-1007.pdf
http://www.cdc.gov/h1n1flu/general_info.htm

In 1976 at Fort Dix Army base more than 200 soldiers became infected with a swine flu strain (H1N1) similar to the virus that caused the 1918 outbreak in which an estimated 50 million people died worldwide. It was decided that mass quantities of the vaccine would be needed to vaccinate the entire population to prevent a pandemic like that of 1918. The director of the CDC recommended that the federal government contract private pharmaceutical companies to produce the vaccine. A nationwide immunization program was launched by the federal government at a cost of $137million. Before any vaccine was released however, the vaccine manufacturers required that the federal government underwrite them against claims of adverse reactions prior to any vaccine delivery. The federal government agreed and the vaccinations began.

Soon cases of Guillain-Barré Syndrome were identified in patients days or weeks after receiving the vaccination. By December of 1976 more than 40 million people had been vaccinated against H1N1, of which about 500 people developed GBS. According to the NIH Guillain-Barré syndrome is a disorder in which the body's immune system attacks part of the peripheral nervous system by destroying the myelin sheath that surrounds the axons of many peripheral nerves. Sometimes it destroys the axons themselves. It usually occurs a few days or weeks after a viral infection. While there is no known cure for GBS there are treatments that can lessen the severity and speed recovery.

Statistically the number of GBS cases in the vaccinated population was higher than what would be found in the normal population in 1976 (according to the CDC about 1 more case per 100,000 that were vaccinated). As a result federal health officials decided that even the idea that GBS could be linked with the vaccine warranted ending the vaccine program immediately, so that the possibility could be investigated. In the Media the vaccination program was considered a debacle, and the director of the CDC was fired. In addition, the anticipated H1N1 pandemic of 1976 failed to happen.

According to the CDC the link between flu vaccine and GBS has been studied and in most cases no link was found. However in two studies it is suggested that 1 more person out of 1 million people vaccinated with the seasonal flu are likely to develop GBS. (http://www.cdc.gov/h1n1flu/vaccination/factsheet_gbs.htm )

Any thoughts?

More information on Guillain-Barré from the NIH at http://www.ninds.nih.gov/disorders/gbs/gbs.htm

Mystery Colors in Lymph Tissue

2009-11-12T15:51:00.009-07:00

Since we recently discussed tattoo inks that elicit type 4 immune responses, I thought I'd mention another interesting phenomenon that arises from tattooing:
A patient presented with a lump in the right armpit that had been there for 6 months. After investigation, there could be no conclusion made about the cause of the lump. This necessitated an excision biopsy. The resulting H&E stained sample is shown above. Beyond some hyperplasia, the only noticeable defect was a black "discoloration". Immediately, it was suspected that the black spots were metastases of malignant melanoma (which is notorious for its dark pigmentation). However, after more vigorous examination and a specific, stain-based testing, they determined that this was not a melanoma. In fact, this black color was due to a tattoo that the patient had gotten 30 years previously. It has been well documented that tattoo inks end up in spleen and lymph tissue. However, it had not previously been reported that such an old tattoo could cause enlargement of a lymph node (it had been assumed that such an effect occurs within the immediate timeframe of recieving the tattoo).

Presumably, the presence of tattoo inks in immune tissues is due to uptake in the skin by antigen presenting cells which then migrate to the lymph nodes or spleen. It is interesting to note that tattoos are not only sometimes the victims of attack by the immune system within the skin, but can also cause some interesting pathology within tissues of the immune system. Since tattoo inks are not regulated, its frightening to wonder what sort of unintended chemistry might find its way into some of your body's most important defensive tissues.

That said, I'll probably still get a tattoo when I pass my comprehensive exam.

CM Jack, A Adwani and H Krishnan. Tattoo pigment in an axillary lymph node simulating metastatic malignant melanoma. International Seminars in Surgical Oncology. 2005, 2:28

Are you choosing who you are attracted to or is it your MHC region?

2009-11-12T13:29:00.002-07:00

We know that there are many genes in the MHC I and II regions and that they are highly polymorphic. Combinations of these genes and polymorphisms are important because they are related to the number of peptides that can be presented to t-cells.
It has been shown in fish (arctic charr) that they can discriminate between MHC identical siblings and siblings with different MHC genotypes (Olsen, et al, 1997). Fish chose swimming in water scented with a sibling who had the same MHC genotypes over water in siblings who did not. In mice it has been shown that MHC genes influence individual body odor in mice and that mice also prefer MHC-dissimilar mates (Chaix, et al, 2008).
In humans, there have also been studies looking at odor preference and MHC region, although there have been no studies that have linked odor preference and attraction. In several “sweaty t-shirt” experiments women were asked their preference to smells found on t-shirts that had been worn by males with different MHC genes. Females significantly preferred the odor of males with dissimilar MHC regions to their own. Another study looked at the genetic similarity at the MHC region between spouses, which included 30 European American couples from Utah and 30 African American couples in which there was found an association between mate selection and MHC dissimilarity in the European American couples(Chaix, et al, 2008).
So if you have problems in your relationships it may not be your fault!

FACE	Ask the person to smile. Does one side of the face droop?
ARMS	Ask the person to raise both arms. Does one arm drift downward?
SPEECH	Ask the person to repeat a simple sentence. Are the words slurred? Can he/she repeat the sentence correctly?
TIME	If the person shows any of these symptoms, time is important. Call 911 or get to the hospital fast. Brain cells are dying.