Immunity From Mom

We've discussed in class how important it is for mother's to breast feed their baby because it's a good method to pass along immunity to the infant. Breast feeding passes along IgA from the mother to the baby providing protection in the gut against microbes. Since babies don't start making their own IgA until after birth, breast feeding is important for the baby to get their source of IgA until they can make enough of their own.

Studies lead by teams from BYU, Harvard, and Stanford found the molecule CCR10 to be an important player in the ability to pass along immunity from the mother to the baby via breast feeding. This study was done in mice and they found that mice that lack this CCR10 molecule had 70 times fewer cells that produce antibodies in the mammary gland.

In essence, the mechanism underlying breast feeding as a means to pass along immunity to our infant is more complicated than I thought. Without the CCR10 molecule, good breast feeding practice wouldn't be any good in providing IgA protection.

References:
Breast Milk Molecule Gives Mom's Immunity to Baby -http://www.nlm.nih.gov/medlineplus/news/fullstory_70850.html
Breast-feeding, infant formulas, and the immune system -
http://www.ncbi.nlm.nih.gov

miRNA regulates immune system

MicroRNAs (miRNA) are transcribed in the nucleus and exported into the cytoplasm to control gene expression by binding to messenger RNAs (mRNAs) and cleaving or reducing their translational efficiency. They are considered to play a substantial role in gene regulation of cellular proliferation, differentiation, cell fate, apoptosis, signal transduction, and organ development; however, with the numerous miRNA identified scientist still remain to be fully understand their mechanism. miRNA’s role in post-translational modification in addition to other post-transcription modification can express a gene in varying ways, affecting proteins’ conformational fold and function. With this in mind, miRNAs have recently changed the view of immune development and regulation. It has been established that miRNA contribute to immune cell fate, regulation of Toll-like receptor and cytokine response. In addition, miRNAs have been found to contribute to inflammatory diseases., regulate hematopoiesis, immune responses (innate response, T cell activation and differentiation), and antiviral immunity. With the dynamic and complex nature of miRNA, it is hoped miRNA will serve a use as therapy in treating diseases.

Seminars in Cancer Biology
Volume 18, Issue 2, April 2008, Pages 131-140
Postgenetic Oncology - MicroRNA and Cell Proliferation

Bird Flu

The avian flu strain H5N1 commonly known as the Bird flu made it's first biggest hit in Asia in 2004 claiming the lives of~30 people is now reemerging. To this year, ~300+ cases resulting in death have been recorded. The natural host of the H5N1 strain are ducks but the virus can cross the species barrier and infect humans as well. The most recent cases reported by WHO (World Health Organization) in December 2008 occurred in Indonesia and Cambodia. In two of the three cases, the victims are confirmed to have been around birds.
Since we've talked about vaccines in class, I wonder how much Baxter would help out if people in this area are vaccinated with it? I don't know if these countries (people within these countries) are able to afford this vaccine.

References:
http://www.who.int/en/

The Varicella-Autoantibody Syndrome

Varicella (Chicken Pox) was a very common virus that many children from our generation were infected with. Although most of us had to deal with the typical symptoms, some children also developed life threatening blood clots. A very interesting phenomenon that we discussed in our Immunology class was to blame; Cross-reactivity. The varicella virus produced an immune response that cross-reacted with a protein found in blood called Protein S. The purpose of Protein S is similar to that of an anticoagulant. It basically helps regulate clot formation by deactivating pro-coagulant proteins. Three study groups were analyzed to determine the cause of this antibody and why some children were forming life-threatening clots.

The study groups consisted of 52 children without acute varicella virus exposure and 43 patients with varicella (VZV) exposure. The second group was further broken down into 17 children with thromboembolism (blood clots) or purpura fulminans and VZV and 26 with uncomplicated VZV exposure. There were significant differences between the group without VZV exposure and the group with VZV exposure. Those exposed to VZV frequently developed a lupus anticoagulant (measured by dilute Russel Viper Venom Time dRVVT) and several other antibodies to phospholipids regardless of whether they had uncomplicated exposure or if they developed thromboembolism. Although there was no difference between the two groups when it came to antibodies made in the acute phase, the difference came in duration of antibodies and their effect on Protein S. Those that developed a thromboembolism or purpura fulminans had significantly lower Protein S levels and significantly higher levels of antibodies to Proteins S.

The interesting question that I brought from this paper is: what the difference is between these two groups of children? They both are producing a cross-reactive antibody to VZV and Protein S, but only a small portion develop low levels of Protein S and high levels of antibodies which lead to thromboembolism. Could this be a problem with T cell regulation in these patients? If not, what is different with these patients?

Pubmed:
http://www.ncbi.nlm.nih.gov/sites/entrez?otool=uchsclib&term=the%20varicella-autoantibody%20syndrome&cmd=search&db=pubmed

DVT - Deep Vein Thrombosis

In class last month Dr. Cohen briefly mentioned vein blood clots. Where could that clot dislodge to? Answer: the lungs.

That week my dad was diagnosed with a DVT - Deep Vein Thrombosis in his leg. He had been active and couldn't figure out why. He hadn't been on a long flight or anything similar that month. We were very concerned about a Pulmonary Embolism. Yes, the dislodged clot could travel to the lungs!! (capillaries) This is what killed young reporter, David Bloom, in Iraq.

Well, a couple of months earlier, my dad was recovering from eye surgery. He was told to stay on the couch until his detached retina healed. His doctor did mention that my dad should, however, get up every 30 minutes or so to "get the blood moving." This was great advice, but it wasn't quite enough exercise to prevent a DVT. (My dad's blood test was normal and he was on a low dose aspirin regimen before this.)

I just want to express how important exercise is --even when we are cramming for a test or finishing a long experiment. Anyone up for running the stairs at lunch break?

http://en.wikipedia.org/wiki/Deep_vein_thrombosis

Fake Blood Real Stokes

I ran across these articles while looking up biotech experiments. These articles talk about doctors using a perflurocarbon to supply oxygen to patients that suffer from brain injuries such as head trauma and stroke. Since the substance is "oily" it can squeeze through inflammed vessels more easily than blood can and carries much more O2.

Since one of the functions of inflammation is to increase blood flow, do you think supplying all this O2 can curtail some or any of the swelling and the potentially harmful effects of an inflammed brain?? Does the property of increased Oxygen delivery decrease the length of time it takes to bring down swelling, in effect speeding up the healing process? I think this chemical is lacking in anti-inflammatory properties and that O2 delivery just might be the only, yet important, characteristic, would you agree? Comments?

http://www.thescizone.com/news/articles/1481/1/Synthetic-Blood-Announces-Oxycyte-Development-Strategy/1.html

http://hamptonroads.com/2008/03/type-artificial-blood-may-be-key-surviving-brain-injury

Inflammatory Bowel Disease and the Hygiene Hypothesis

After visiting Liberia, West Africa, (before the civil war) I can see how people in Rwanda have nearly no occurance of Inflammatory Bowel Disease. The children actually get to play on the land! They are exposed to parasitic worms. It is normal for the worms' eggs to contaminate food, water, air, faeces, pets and wild animals. Women still wash the clothes in streams and wildlife is all around. Yes, I nearly ran into a dead deadly green mamba snake (I didn't know it was dead while I was running). I believe in the Hygiene Hypotheis and feel that too many Americans are too fearfull of germs.... and worms!

Anyway, I think the University of Iowa study is right on. Thanks Dr. Cohen for telling us!
Here is the publication:
Helminths and harmony
http://gut.bmj.com/cgi/content/full/53/1/7

Protecting virus

An article I read a while back discusses a novel method of controlling flu virus infection using a protecting virus. The concept was developed for influenza type A and involves a genetically modified version of the virus that has an 80% deletion on one of the 8 RNA strands. This deletion renders the virus harmless and interferes with the ability to reproduce once inside a cell. When it is joined by another normal influenza virus, the protecting virus replicates much faster than the normal influenza virus thereby crowding it out resulting in a slowed rate of progression. This delay allows the immune system time to develop and mount an immune response.

The implications of such a cascade are that any strain of influenza that you encounter will become it's own vaccine by giving the body time to recognize the virus and develop an effective response. Thus, protection is conferred against unforeseen strains and mutations that vaccines have a lesser ability to deal with. This is especially desirable for a virus that mutates often leaving vaccines that cannot protect against all variations. In addition, by using a live infection, you are creating a better immune response than by using peptides of the viral products alone. Current research shows that protection from infection happens immediately upon administration and can even be given 24 hrs after exposure while maintaining effectiveness.

Some experiments have been done to show that by putting the protecting virus in drinking water of animals they have gained protection from various strains of influenza. From our discussions in class regarding H5N1 and the jump from birds to humans, could this be useful to impact the spread of avian flu within bird populations? Because of the protecting virus' ability to act as a vaccine to highly mutable viruses, could this be a tool to use against other infections?

This pioneering research was done by Nigel Dimmock at the University of Warick and continues within a startup company at the university.

Emerging viruses in transplantation

In class we have discussed several pitfalls in transplantation of organs and bone marrow. A classic case was of the boy in the bubble who died from donor derived EBV effects on immunocompromised individuals. This paper describes an increased understanding of other viral infections and their associated risks for transplant patients that would not normally have high rates of morbidity and mortality. Usually, the focus is on CMV and EBV but 12 other viral threats have been described here, some of which I have never heard even heard of. They include Adenovirus, Boca virus, corona virus, HHV-6, lymphocytic choriomeningitis virus, meta pneumovirus, mumps, measles, parainfluenza, Parvovirus B19, respiratory syncytial virus, rotavirus and west nile virus. Some of these are donor derived and some are community derived. All of these can be detected and characterized easily with advanced techniques such as PCR on easily obtained patient samples such as sputum and nasopharangeal washes. Not long ago the diagnosis was limited in specificity and was performed using primarily serology and histochemical techniques. As solid organ and stem cell/ bone marrow transplants are on the rise as effective therapies, it is important to use the techniques available to increase the longevity and quality of life for these patients. Examples of increased morbidity and mortality due to these viruses were discussed in this paper. Adenovirus can cause many types of infection including that of the respiratory tract. In healthy people, a 5-10% mortality rate can be seen with some infections. In transplant recipients, some adenovirus diseases have mortality rates of up to 80% and can occur up to 4 years after transplantation. Some manifestations are asymptomatic and affect many tissues and cell types. After detection, antivirals and intravenous Ig (IVIg) have been associated with positive outcomes.
HHV-6 is another common virus and is latent in ~90% of adults in immune, salivary and bronchial epithelial cells. Immunocompromised individuals reactivate with replication in CD4+ cells further suppressing the patient immune response ultimately leading to high mortality rates of up to 58%. Once detected as an active infection, antivirals have been seen to be effective treatments. Mumps and measles have a slightly different approach to deal with in immunocompromised patients as there are no specific antiviral treatments. It is recommended to vaccinate for example, stem cell transplant patients 2 years after the transplant. However, this leaves a small gap in time where people are susceptible with high attack rates and associated high mortality rates. The evaluation of viral infection, diagnosis and treatment continue in this paper but all remain serious threats and deserve attention as they can be major factor in increasing the longevity of transplant patients.

Emerging Viruses in Transplantation: There Is More to Infection After Transplant Than CMV and EBV.
Transplantation. 86(10):1327-1339, November 27, 2008.
Fischer, Staci A.

Chemokine microbicides

At a presentation on World AIDS day last week, anti-HIV microbicides were discussed. One microbicide, PSC-RANTES, showed considerable effectiveness but was proclaimed to be too costly and unsuitable for common use especially in developing countries. This paper therefore caught my attention as it talks about analogues to that microbicide that do have suitable characteristics for common use. The analogues are recombinant proteins making them easy and inexpensive to produce like all other recombinant proteins such as human growth factor (rHGH) or insulin. The preliminary evaluation of these analogues show stability at 40˚C for a week or longer with very little change in biological equivalence which facilitates transport and storage outside of the cold- chain required for many protein based therapeutics. They also withstood low pH conditions that resemble environments where they will be used as a prophylactic and be expected to maintain biological activity. A desired characteristic is that protection also be maintained for longer duration after a single dose. It appears that biological activity is suitable in that it is maintained for at least 24 hrs.
Both analogues tested show equivalent potency against viral replication as compared to PSC-RANTES invitro and in macaque challenge models. They achieve this in the same manner as PSC-RANTES by inhibiting the CCR5 receptor availability to the virus. One analogue causes the CCR5 receptor to sequester intracellularly but the other analogue doesn’t utilize this method and a mechanism was not described here. In the absence of a vaccine, the meaning of this very exciting discovery is enhanced due to the need of other avenues to slow the spread of virus. At the lecture, a recent study was also presented that statistically, we could treat out way out of this epidemic by affecting the spread of the disease. This is clearly a step in that direction while research to develop vaccines continue.

Cerini, Fabrice *; Landay, Alan PhD + ; Gichinga, Carolyne + ; Lederman, Michael M MD ++ ; Flyckt, Rebecca MD [S] ; Starks, David MD [S] ; Offord, Robin E PhD || ; Le Gal, Francois PhD [P]; Hartley, Oliver PhD * , Chemokine Analogues Show Suitable Stability for Development as Microbicides. J Aquir Defic Syndr. 2008;49;472-476.

TRAIL: Apoptotic pathway important in influenza clearance

We’ve discussed CD8+ CTL cells and the mechanism recognition and killing of targeted cells using FasL and perforin mediated apoptosis. This paper discusses how another apoptotic pathway, TRAIL, is important in influenza infection. TRAIL has been seen to select for tumor cells and is an important tool for immune surveillance. The immune system also relies on TRAIL to clear some viral infections. The author show that TRAIL is directly associated with increased levels of influenza virus clearance and by inhibiting TRAIL using a monoclonal antibody, longer durations of influenza infection persisted. Using mice that express TRAIL normally and TRAIL deficient mice, they were able to make some interesting observations related to influenza. TRAIL positive mice could clear flu virus significantly in 6 days where as TRAIL deficient mice had increased morbidity and increased flu viral loads. Target cells in pulmonary infection also show the receptor for TRAIL, DR5, indicating that TRAIL might be very important for controlling flu virus. Actually, influenza was shown to increase TRAIL on CD8+ T-cells and it’s DR5 receptors on infected cells. This is a very interesting mechanism we have developed to control a virus. Usually, we are talking about how a virus has out-evolved us. Influenza specific CD8+ T-cells were also shown to have TRAIL while non-influenza specific CD8+ T-cells did not. Regardless of TRAIL expression, FasL, perforin, IFN-g, degranulation and total T-cell levels did not change indicating the importance of TRAIL for clearance as well as protection from lethal doses of influenza which killed over 80% of non-TRAIL expressing mice.

Can TRAIL deficiencies or inhibited expression be cause of virulence in some influenza infections? Could this also be related to other persistent viral infections?

E. L. Brincks, A. Katewa, T. A. Kucaba, T. S. Griffith, and K. L. Legge
CD8 T cells utilize TRAIL to control influenza virus infection.
J. Immunol., Nov 2008; 181: 7428.

The Tumor Promoting Role of the Immune System?

From our lecture on tumor immunology we focused on how components of the immune system fight tumor progression. Clearly the immune system is very important in this regard, and people with compromised immune systems have higher incidence of cancer. The immune system is not always beneficial though. There is a body of work that suggests a pro-tumorgenic role for macrophages in cancer progression.
The theory is that macrophages initially fight cancer cells but then can become subverted by the tumor to actually become tumor promoting. In many human tumors, a high number of infiltrating macrophages correlates with a poor prognosis. Tumors are actually able to attract macrophages through the release of various chemotactic agents. Molecular studies have elucidated many protumoral functions macrophages carry out once at the tumor. These are mediated through the improper release of various cytokines. One protumoral function is the expression of growth factors which increase the growth rate of cancer cells. Macrophages have also been show to release signals that promote the formation of blood vessels in the tumor which is a necessary step for tumor progression. Macrophages are also capable of suppressing adaptive immunity.
This theory initially seemed very unlikely to me since we usually associate the immune system with fighting disease but taken together with what we have learned about how macrophages work, it makes more sense. There is normally a division of labor with T cells recognizing a danger and then instructing macrophages to remove it. With this is mind, it is less of a stretch to see how a different cells type (ie. a tumor cell) could step in and instruct a macrophage to act much differently. In fact, one of the phenotypes of the macrophage protumorgenic switch is a reduction in IL-12. We have learned that this cytokine favors a Th1 T cell which in turn makes macrophages ‘angry’.
If you would like to learn more about this research, there are many reviews available. A few are listed below:

1. Ostrand Rosenberg. Immune surveillance: a balance between protumor and antitumor immunity. Current Opinions in Genetics and Development. 2008. 18:11-18.

2. Mantovani, Alberto et al. The inflammatory micro-environment in tumor progression: The role of tumor associated macrophages. Crit. Rev. Oncol./Hematol. 2007. 10:1016.

3. Eremin, O et al. Tumor-associated macrophages (TAMS):disordered function, immune suppression and progressive tumour growth. J.R Coll. Surg Edinb. 2000 Feb;45(1):1-16

To vaccinate, or not to vaccinate (really? this is still a question?)

In true procrastinator fashion, I am finally submitting a post. This topic is near and dear to my heart, as I’ve spent the last year working in vaccine formulations and prior to that, spent a year and a half working at a group home for autistic adults…

This year experienced a resurgence in the vaccine/autism debate, as Hannah Poling – the now 10-year-old daughter of Dr. Jon Poling, a neurologist, won their lawsuit against the Department of Health and Human Services. As a seemingly normal 18-month-old baby, Hannah, was taken in for her well-baby checkup and administered several routine vaccines. Two days after inoculation, Hannah developed a high fever, ceased responding to verbal stimuli, and for a short period – refused to walk. If you are interested in the case, the CNN News Report is a fairly unbiased source of general information on the case… http://www.cnn.com/2008/HEALTH/conditions/03/06/vaccines.autism/index.html however, since this IS an immunology course, I am not going to leave you thinking that Hannah’s vaccines were in fact responsible for her condition.

Dr. Paul Offit, chief of infectious disease, at Children’s Hospital of Philadelphia scientifically responded to the court’s ruling in an article in a May issue of the New England Journal of Medicine. Dr. Offit highlights that Hannah was special case. Born with a genetic mitochondrial enzyme deficiency, Hannah was succeptible to infection and while natural infection has been shown to aggrevate encephalopathy in these patients – vaccines HAVE NOT and are in fact recommended for these children.

Is it possible we can overwhelm the immune system? While I am sure there exists some case that demonstrates this, a typical child will have no problems (apart from slight discomfort) with the administration of the 14 recommended childhood vaccines which contain in total approximately 150 immunological components (vs. the 200+ immunological components of the smallpox vaccine formulation used 100 years ago).

Well, what is the harm in spreading the immunizations out over a course of time? The distribution of vaccines over a course of time provides a window for a not-yet-vaccinated-against infection to occur, which will compromise the immune system of the child and result in a higher risk of vaccine ‘injury’ (perhaps a rash, swelling, ect.).

Back to Hannah… if vaccinations for children with this genetic deficiency carry with them the risk of exacerbated encephalopathy, what should our strategy be for reducing this incidence – and when it does occur, who is to blame? As the role of genomics increases in medicine, will we find the answers?

Sadly and somewhat ignorantly, the resurgence of this heated debate has had an effect on U.S. vaccinations. This year, we have witnessed isolated outbreaks of measles resulting in the most cases we’ve seen in 12 years.

Let’s keep in mind that the incidence of autism is increasing – if vaccines were really the agent, wouldn’t we expect the incidence to decrease as our methods become more refined?

With all of this said, please speak with you pediatrician about any concerns you might have and don’t be too quick to dismiss the largest medical advance in the history of medicine (ok, so I may be a little bias – but it is with good intentions).

Offit, PA. N Engl J Med. 2008 May 15;358(20):2089-91.
http://www.immunize.org/catg.d/p2065.htm
http://www.chop.edu/consumer/jsp/division/generic.jsp?id=75807

Hot Tub Lung

Hot tubs have been shown to be associated with disease. A well documented example of this is Hot Tub Lung (Mycobacteria induced respiratory illness) as a result of hot tub use.

Hot tubs are a favorable environment for these thermophillic bacteria and their disinfectant-resistant nature can make them a potential health risk for bathers. Once established, a Mycobacteria infection can also be very difficult to treat with antibiotics. The Center for Biofilm Engineering at Montana State University has developed hot tub simulations to study the efficacy of chlorine as a disinfectant against Mycobacterium fortuitum.

Bacterial samples were taken from three locations: from the bulk water, from coupons mimicking hot tub surfaces such as walls, and from inline hot tub filters. In the control, it was determined that colonies were particularly prevalent in the bulk water and on the inline filters. The main result was that while chlorine worked fairly well in a clean system inoculated with an organism, if fouled filters were moved to a clean system (analogous to a poor cleaning or just a spray down of the filter) with no new inoculation, M. fortuitum would not just survive but would actually GROW in the presence of chlorine. This enhances the chances for a user to experience repeat exposure and eventually develop a Type III Immunopathology response, hypersensitivity pneumonitis.

Chronic hot tub use can lead to inoculation of the bacterium resulting in the development of antibodies circulating in the blood stream. At a certain threshold, an individual may enter the hot tub and develop an immune response to the bacteria, as the circulating antibodies bind to the antigen. When the antibodies bind to the antigen large immune complexes form that cannot be cleared and they are subsequently deposited in vessel walls and there is an inflammatory response.

The center at MSU suggested that hot tub filters are really tricky to effectively clean due to all of the folds and even an aggressive cleaning could result in this occurrence.

All that said and I will be hot tubbing sometime this winter season!

Cell Death

Last February there was a series of three papers in Immunity on the contraction of the T cell response and the mechanisms of the two major cell death pathways. I have always found the process of cell death fascinating. Apoptosis: the programmed cell death brought about by signals that trigger the activation of a cascade of ‘suicide’ proteins in the cells destined to die. This was the first definition of cell death I learned, but as my education continued and as the scientific literature advanced the science of the cellular death pathway the definition has become more complex.

There are two known pathways of apoptosis; extrinsic and intrinsic. Extrinsic apoptosis: death ligands (FasL) bind to associative death receptors (Fas) on the cell surface triggering recruitment of varying molecules and eventual autocatalysis and subsequent cell degradation. Intrinsic apoptosis: Bcl-2 proteins, one of which is Bim, is an apoptosis pathway occurring near or within the mitochondria. Bim is a trigger of the mitochondrial pathway of apoptosis and plays a prominent role in cell death caused by cytokine deprivation of T cells. When these mechanisms of cell death do not operate properly autoimmune disease can result and have accelerated progression.

Hughes et. al. (2008) discovered overlapping roles for Fas and Bim in T cell death. Mice lacking both Fas and Bim mediated death had enhanced and accelerated fatal lymphadenopathy (disease or swelling of the lymph nodes) and autoimmunity relative to those lacking only one of the death proteins. Hutcheson et. al. (2008) focused on the progression of systemic lupus erythematosus (SLE) as it related to the balance of the two cell death pathways. Mice with defects in the two pathways developed severe SLE-like disease. Weant et. al. (2008) came to the similar conclusion that both death pathways concurrently prevent autoimmunity and regulate T cell response.

Green (2008) in his review of these three articles poses the question; there is a redundancy in the cell-death process, but who is backing up whom? He reviews literature that suggested the process of T cell clonal contraction during an immune response was due to limited growth and survival factors rather than active ligation of death receptors. These new studies highlight the essential combination of each pathway in the T cell clonal contraction process.

Epstein-Barr Virus, Complement Receptor 2, and Immortal B Cells

In class this past Tuesday, Dr. Cohen mentioned Epstein-Barr virus (EBV) and its role in triggering Burkitt lymphoma. He mentioned briefly how EBV infects B lymphocytes; I thought I would share how our lab uses this phenomenon as part of our research.

I work in a lab dedicated to researching the pathogenesis of the autoimmune disease systemic lupus erythematosus. We are specifically focused on the role of Complement Receptor 2 (CR2), a receptor found primarily on the surface of B cells. This receptor is actually involved in both innate and adaptive immune responses due to the variety of ligands with which it interacts. Among these ligands are gp 350/220, found on EBV. Once EBV has entered the B cell, it acts as an internal mitogen and the infected cell begins to proliferate.

Our lab actually cultivates EBV from a special cell line. We periodically collect supernatant from this cell culture and then use it to “transform” human peripheral blood mononuclear cells into immortalized B cell lines. After infection with EBV, the B cells begin to proliferate and within a week form visible “clumps.” The cells will usually continue to divide as long as I add fresh “cell chow.” Once I have a sufficient number of healthy B cells, I freeze them using a special freezing media. The cells can later be thawed and grown in culture again!

Booze your way to a healthier heart?

Many people were wondering what was so great about red wine and why was it good for the heart, the answer is resveratol. Resveratrol is a chemical compound found in certain plants. It is called a phytoalexin because plants naturally produce it as an antibiotic substance to fight both bacteria and fungi. Plants containing resveratrol include the grapes and skins of grapes that produce wine, raspberries, mulberries, blueberries and cranberries. However, the amount of resveratol in red wine is minimal. Probably the best common food source if one wants to consume resveratrol in its natural state is peanuts. Peanuts have significantly higher resveratrol content than do any berries or grapes that produce the chemical. This idea of drinking moderate consumptions of red wine is called the "French paradox" because French people have low cardiovascular mortality rates even though they eat foods high in fats. I found an article from the mayo clinic website that lays out the benefits of resveratol in layman's terms. I also found an article from a study that uses resveratol to reduce infarct size and improving ventricular function after myocardial ischemia in rats. The study proves that resveratol is a cardioprotective agent. I will post both the article and the study for those of you that are interested in drinking red wine to save your ticker.

This is the article:
http://www.mayoclinic.com/health/red-wine/HB00089

This is the study:
http://zp9vv3zm2k.ssscom.ezproxy2.library.arizona.edu/OpenURL_local?sid=Entrez:PubMed&id=pmid:18639559

Omega 3 and 6 fatty acids

I wanted to shed some light on omega-3 fatty acids since they have been mentioned on and off throughout the semester. The key to getting the most benefit from polyunsaturated fatty acids is balance between omega-3 and 6. The typical American consumes approximately 20 to 25 times more omega-6 fatty acids (linoleic acid) than omega-3 fatty acids. Predominant sources of omega-6 include soy, corn, safflower, and sunflower oils. In contrast there is a relatively low amount of omega-3 fatty acids (alpha-linolenic acid) in the western diet as its predominant sources include dark leafy green vegetables and flaxseed. Linoleic acid(LA) is converted to arachidonic acid (AA) while alpha-linolenic is converted to eicosapentaenoic acid (EPA). Cold, water fatty fish such as salmon and trout are good sources of dietary EPA. Both omega-6 and 3 are considered to be essential fatty acids as they are not synthesized endogenously.
Increasing dietary omega-3 fatty acids can shift the balance of the eicosanoids produced to a less inflammatory mixture through EPA competing with AA pathway. I have included a schematic below:

There is also a good journal article on polyunsaturated fatty acids in the American Journal of Clinical Nutritoin.

Ref:

James, M et al. Dietary Polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 2000, 71(suppl):343s-8s.

Vegan and Vegetarian Diets

Vegan and vegetarian diets are both great in fighting inflammation. Eating a diet rich in vegetables and excluding meat (vegetarian) is associated with a lower risk of developing cancer, heart disease, obesity, and diabetes. Vegetarians also tend to weigh less, have lower cholesterol and lower blood pressure.

A vegan diet (vegetarian diet but excludes ALL animal products including eggs, cheese, yogurt, and milk) is also very beneficial in reducing inflammation, especially in people with rheumatoid arthritis. It decreases risk of heart attack and stroke in RA patients as well as reduces the severity of the disease. In one study, it was discovered that RA patients following a vegan diet had lower levels of C-reactive protein as well as RA factor, thus decreasing inflammatory markers.

Although both of these diets show promising anti-inflammatory effects, vegans and vegetarians must make sure they are getting proper nutrition. A don't forget about omega-3s! Look to supplement fish oils for flaxseed and other plant or nut oils.

The Wonder Herb Has A Sidekick?

In discussion today someone mentioned that they would be curious to see the effect of a combination of anti-inflammatories such as omega-3 fatty acids and curcumin. I happened to be researching some more studies on curcumin and came across a study dealing with the prevention and treatment of pancreatic cancer with the use of curcumin and omega-3 fatty acids. The study was actually very interesting and is the first study done of its kind. Pancreatic adenocarcinoma is the fourth most common cause of cancer-related deaths and occurs in both men and women. It kills very quickly, patients usually die within 6 months of being diagnosed. Pancreatic cancer has upregulation of inflammation mediators suchs as those we have already discussed including nuclear factor kappa B, inductible nitric oxide synthase (iNOS), cycloxygenase-2 (COX-2) and 5-lipoinase (5-LOX). The study was done in vitro and in vivo models. This study shows that dietary administration of omega-3 fatty acids and curcumin suppresses the pancreatic tumor bettter than either one alone. The study overall shows many different things dealing with iNOS, COX-2, 5-LOX mediators. If you care to check out the study more I have provided the link to the article. I figured this article would tie in great with the omega-3 exercise article we discussed today in class.

Here is the link to the article:
http://www.informaworld.com.ezproxy1.library.arizona.edu/smpp/section?content=a905311628&fulltext=713240928

Follow-up to last week's lay article on cognitive function and anti-inflammatories

After last week's lay article and discussion on cognitive function and the use of anti-inflammatories I wanted to follow-up with more specifics on the research study and the complete reference for the paper if you wanted to read further.

Study Design:
2528 participants randomized in 1:1:1.5 fashion to either 200mg of celecoxib twice daily, 220mg naproxen sodium twice daily or placebo (n= 726, 719, 1083) respectively.

Participant eligibility:
Participants were recruited from 6 sites around the country (Boston,MA, Rochester, NY, Balitmore, MD, Seattle, WA, Tampa, FL, Suncity, AZ) through mailers to medicare beneficiaries in targeted age and zip code ranges. Paticipants were then sub-divided into age groups (70-74, 75-79 and >80 years)and also had to have a first degree relative with Alzheimer's disease type dementia, score satisfactorily on cognitive battery test, and did not regularly take NSAIDs (with the exception of 81mg aspirin).


Data collection:
Participants completed a series of cognitive tests prior to randomization, including modified mini-mental state examination, the Hopkins learning verbal test revised and the informant rated dementia severity rating scale. After randomization the following tests were also administered the Digit Span Test, a generative verbal fluency of naming as many supermarket items as possible in 1 minute, narratives
from the Rivermead Behavioral Memory Test, the Brief Visuospatial Memory Test–Revised, self-rating of memory functions, and the Geriatric Depression Scale. The cognitive battery was then administered annually there after.

Study results:
The study was designed to last for 7 years, however was stopped after 4 years due to the fear of increased risk of cardiovascular events in participants taking celecoxib after observations from another trial reported increases in cardiovascular events for participants on celecoxib. In these 4 years study investigators saw no difference in cognitive function between the 3 study groups.

Reference:
ADAPT Research Group, Cognitive function over time in the Alzheimer's disease anti-inflammatory prevention trial (ADAPT), Arch Neurol, 2008;65(7):896-905.

NSAIDs, Your Bones, and Surgery

Fractures and Surgery:
Non-steroidal anti-inflammatory drugs are a large class of compounds that inhibit cyclo-oxygenase and thus the formation of prostaglandins, which are involved in bone metabolism. However, the effect of these drugs on bone metabolism is often overlooked. They inhibit osteoblasts at the endosteal bone surface and also reduce both the immune response and the inflammatory response. PGs have been shown to elicit and participate in inflammatory responses, increase osteoclast activity and subsequent bone resorption, and increase osteoblast activity and new bone formation. This apparent integral role for PGs in the process of bone healing, coupled with the knowledge that NSAIDs act by inhibiting the production of PGs, results in an understanding of the likely mechanism through which NSAIDs impart their deleterious effects on bone healing. By inhibiting the COX enzymes and the subsequent production of PGs, NSAIDs not only achieve their desired anti-inflammatory effects but also inhibit the increased production of PGs that is necessary for bone healing to occur.
On studies strong argues, the harmful effects of NSAIDs on bone: 'Despite animal studies which have highlighted the harmful effects of these drugs on the healing of fractures and spinal fusion, they continue to be used commonly for the relief of postoperative pain in the absence of well designed human trials. A random survey of the type of analgesia received by patients undergoing hip arthroplasties on our elective orthopaedic ward showed that 95% (18/19) were being treated with these drugs.' Based on this site ibuprofen has been shown to have an irreversible effect on the healing of fractures. Also the inhibitory effect of these drugs on fracture healing is greater the longer the duration of use.

Hip Surgery:
Another site argues that NSAIDs are good after hip surgery due to prevention of abnormal bone formation. 'Abnormal bone formation in the muscles around the hip occurs after about one third of all hip replacements. Use of an NSAID (apart from low dose aspirin) around the time of surgery reduces the risk of such bone developing by between one half and two thirds with little risk of side effects from treatment. Prevention of abnormal bone formation is likely to reduce the risk of long-term pain, stiffness and disability after hip replacement. However, the effects of treatment on these outcomes needs to be proved in a large-scale trial.'
It seems that NSAIDs have the ability to inhibit bone formation. This could be a good thing after hip surgery or a bad thing after a fracture or spinal fusion. However, more studies are needed.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1113091
http://www.cochrane.org/reviews/en/ab001160.html

Exercise: Anti-inflammatory

We have discussed in almost every class the importance of a balanced diet and exercise. It seems fit to discuss how exercise acts as an anti-inflammatory. Regular exercise offers protection against chronic, low-grade systemic inflammation. We have talked about many different types of chronic inflammatory diseases; obesity/type II diabetes, stroke, inflammatory bowel diseases, arthritis, and neurodegenerative diseases.

Chronic, low-grade systemic inflammation has been introduced as a term for conditions in which there is typically a two to threefold increase in the systemic concentrations of TNF-α, IL-1, IL-6, IL-1ra, sTNF-R, and CRP is reflected.

Typically, IL-6 is the first cytokine present in the circulation during exercise. Plasma-IL-6 increases in an exponential fashion with exercise and is related to exercise intensity, duration, the mass of muscle recruited, and endurance. It has been demonstrated that the IL-6 protein is expressed in contracting muscle fibers, and that IL-6 is released from skeletal muscle during exercise.

The anti-inflammatory effects of IL-6 are demonstrated by stimulating the production of anti-inflammatory cytokines and cytokine inhibitors such as IL-1ra and IL-10 and
TNF-R. Furthermore, IL-6 stimulates the release of soluble TNF-α receptors, but not IL-1β or TNF-α.

Figure 1: A marked increase in IL-6, which is followed by IL-1ra, TNF-R, and IL-10.

IL-10 acts as an anti-inflammatory by inhibiting the synthesis of pro-inflammatory cytokines like IL-1β, IL-1-α, and TNF-α along with the production of chemokines, all of which play a critical role in the activation of granulocytes, monocytes/macrophages, natural killer cells, and T and B cells and, in their recruitment to the sites of inflammation.

http://jap.physiology.org/cgi/reprint/98/4/1154

As I researched, I found many different websites that demonstrated how exercise can prove beneficial to those suffering from inflammatory diseases.

Heart Disease/Stroke:

• increase strength of heart muscle
• decrease blood pressure
• increase HDL
• decrease LDL
• improve blood flow

Obesity/Type II Diabetes:

• decrease body fat
• increase muscle mass
• increase body’s ability to use calories

Rheumatoid Arthritis/Osteoarthritis:

• increase muscle strength
• decrease pain and fatigue
• increase grip strength
• replenishment of lubrication to joint
• promotion of bone formation
• prevention of bone loss with aging

Crohn’s Disease (mild only)

• improved symptoms
• increased ratings of quality of life

Multiple Sclerosis:

• improved bowel and bladder function
• increased coordination
• increased ratings of quality of life
• decreased risk of CAD
• increased endurance

Parkinson’s Disease:

• decreased incidence of muscle cramps, rigidity of joints
• decreased aches/pains associated with staying still
• maintained control of gross movement (not tremors)
• heighten sense of achievement kept stress and anxiety levels low

In conclusion, regular exercise protects against diseases associated with chronic low-grade systemic inflammation.

http://www.medicinenet.com/benefits_of_exercise/article.htm
http://www.heuga.org/articles/benefits_of_exercise_for_people_with_ms
http://www.ccfa.org/reuters/excercise
http://www.worldwidehealth.com/health-article-The-Benefits-of-Exercise-for-People-Who-Suffer-From-Parkinsons-Disease.html
http://www.nutristrategy.com/health.htm
http://www.hopkins-arthritis.org/patient-corner/disease-management/exercise.html

Top 10 Anti-Inflammatory Foods

Hope everyone's Thanksgiving was wonderful!! Now that everyone ate a bunch of food, let's see if anyone got in their anti-inflammatories. Here are the Top 10 Anti-inflammatory Foods in no particular order...according to dlife.com.

Cold Water Fish and Grass Fed Animals.
This includes Salmon, Free-Range Chicken, and Grass Fed Beef. The thing that all three have in common is the super healthy fats, omega-3s. Although your cold water fish like salmon is going to give the most omega-3s, Grass Fed Cows and Chickens are going to have way more than grain fed, which have next to none. Grass fed beef may be a little tougher though so cook it ground or slow!!

Olive Oil
Olive oil is another great source of an anti-inflammatory fat. This one is called oleic acid. According to the American College of Nutrition, those who consume more oleic acid have better insulin function and lower blood sugar. Extra Virgin is the least processed so it is better for you. Other "cold-pressed" or "expeller-pressed" can be good for you too!

Salads
Dark green lettuce, spinach, tomatoes, and other salad veggies that are rich in vitamin C are anti-inflammatories. They are also rich in anti-oxidants and nutrients that also dampen inflammation. Use olive oil and vinegar for the dressing for even more anti-inflammatory action!!

Cruciferous Vegetables
What are they? Vegetables like broccoli, cauliflower, brussel sprouts, and kale. These veggies contain anti-oxidants as well as sulfur which which allows the body to make another much needed, high powered anti-oxidant, glutathione.

Cherries
According to the Journal of Nutrition, cherries are once again packed with anti-oxidants and if eaten daily, significantly reduce inflammation. Not in season? Frozen are just as good.

Blueberries
Not only do they have natural compound that reduce inflammation, they may also protect the brain from the effects of aging (Alzheimer's?). Again, frozen are just as good as fresh, and maybe a little cheaper.

Tumeric
A revisited spice. According to Biochemical Pharmacology, it is a powerful, natural anti-inflammatory. Pan fry curry seasoned, free range chicken in some extra virgin olive oil...very anti-inflammatory!!

Ginger
Here is another East Asian flavor that has anti-inflammatory benefits. Studies have shown that ginger can be used to help control blood sugar.

Garlic
The jury is still out on this one, there has been inconsistent research. But garlic might have anti-inflammatory effects and glucose-regulating benefits. Also, it might help the body fight off infections.

Green Tea
Green Tea is like fruits and vegetables where it contains natural, anti-inflammatory compounds. Also, it may reduce the risk of heart disease and cancer. It is suggested to drink a cup a day.

So did you have a Free-Range turkey on Turkey Day?

Turmeric and Inflammation

Is there a correlation between the Eastern Indian diet and cancer?

Compared to the United States, India has a significantly lower incidence of reported cancer cases. This is true for both men and women. There have been many studies performed in this area, all of which report that an Indian diet plays a major role in the health.

Turmeric is a spice used in Indian dishes, such as curry, that acts as an anti-inflammatory and an antioxidant. Turmeric is one of the 700 Ayurvic medications prescribed to promote good health and well-being. Ayurveda is traditional medicine native to India, which is practiced as a form of alternative medicine. Turmeric has been used for centuries in India to treat various diseases including cancer. The spice has been found to suppress and destroy blood cancer cell lines in humans.

Lastly, Indians may also have a decreased risk of cancer due to their vegetarian diets, which rely on legumes (beans, chickpeas, and lentils) as protein. Studies have shown that legumes are associated with a reduction in cancer.

Bottom line: Eat your veggies and curry!

Dealcoholized Red and White Wines Decrease Oxidative Stress Associated with Inflammation in Rats

When I read this article the first time (I ended up reading it 3 times!) I was very lost and so I thought it would be a good idea to do my blog this week on the article itself. Hopefully this sum up of the information will help you better understand the article.


This article looked at the antioxidant and anti-inflammatory affects of dealcoholized red and white wine. Both of theses affects are due to the polyphenols that are present in wine.


In the study they had three groups of rats, a control group that was fed standard food, a group that was fed food containing dealcoholized red wine (DRW), and a group that was fed food containing dealcoholized white wine (DWW). After 15 days the authors induced a granuloma with carrageenan (a component of red seaweed) in all the rats from all three groups. After 24 hours blood from the heart and exudate from the granuloma was taken from all the rats.

In the blood and exudate total phenols was measured. TBARS, or thiobarbituric acid-reactive substances were measured. This shows the amount of malondialdehyde in the blood plasma and the exudate which demonstrates the amount of lipid peroxidation. Lipid peroxidation is the break down of lipids via free radicals (see figure below courtesy of Wikipedia). They also measured the amount of NO in the plasma and exudate and the ratio of L-citrulline vs L-arginine. This ratio can be used as an indication of iNOS activity.



The authors also removed polymorphonuclear (PMN) leukocytes from each of the three groups of rats. When these cells are activated they cause the release of superoxide anion (O2-) which is generated by NADPH oxidase and xanthine oxidase. PMN cells also release NO, which is generated by iNOS activity. Once released O2- will cause damage while the effects of NO release depends on the amount released, the location of their release, and what other reactive species are present. With these removed cells, the authors could then measure O2- and NO production by the cells and the level of COX-2 activation. For the amount of NO they looked at both nitrites and nitrates, as well as the amount of L-citrulline formed from L-arginine which shows the iNOS activity as previously stated. To measure the amount of COX-2 activation the authors looked at the amount of PGE2 produced, which is a prostaglandin released due to COX-2 activation.


From all of these measurements the authors found that DRW had more polyphenolic compounds than DWW, which explained the slightly increased antioxidant abilities of DRW in comparison to DWW. They also found that with both DRW and DWW there was a decrease in the number of cells in the exudate, which they said was due to the fact that O2- will recruit leukocytes while NO inhibits this. Since there was a decrease in O2- and an increase in NO in the exudate for both of the wine groups then a decrease in cell number in the exudate was expected. One unexpected finding was that there was actually an increase in PGE2 in the DRW. The authors said that this might be due to something else in the wine that is interacting with the polyphenolic compounds. This was an important point in the paper, that though they see that polyphenolic compounds are the substances that are the most important in their rat model, in the human body the interactions of all the substances within metabolism make it hard to directly apply the results of the study to humans.

Hopefully this helps you with the reading the article, it sure helped me!

Inflammation, Alzheimer's and polypharmacy

Hi everyone:

The last couple of topics have covered some areas of research that I help with at UA, so I thought it would be interesting to blog about them. 

 We study the neurological control of upper respiratory muscles in healthy individuals as well as certain disease states. As a primary clinical interest we want to investigate the pathophysiology of obstructive sleep apnea (OSA), since there are several other severe, multi-system complications that can arise from OSA including metabolic issues, cardiovascular problems and neurological dysfunction, either arising from a lack of proper sleep architecture or improper oxygenation. OSA is more common in obese individuals, but not exclusively. People with underlying neurological or psychological conditions are at a greater risk, as well as menopausal women.

For awhile we were studying the respiratory muscle functions of a man with Parkinson's Disease (PD) that was being treated for it using a deep-brain stimulator. We were able to turn off his stimulator for the trials, and the difference in symptom manifestation was remarkable. His tremors literally would start and stop like a switch was being flipped. He said that the therapy had changed his life, though it wasn’t perfect. He was willing to trade infrequent nausea for the ability to eat a bowl of cereal on his own or to tie his shoes without help.

 Deep brain stimulation, also known as a "brain pacemaker," has been used for quite some time, though the underlying mechanisms of function are unclear. Anytime we hear that kind of description for a therapy, we want to try and investigate possible side effects, particularly respiratory side effects. We were getting inconclusive and inconsistent recordings from our PD patient, and eventually noticed that he was dozing in and out while we were taking muscle recordings. This is a very common sign of poor sleep, and because of the patient's age we figured he hadn't been pulling any all-nighters or drinking huge amounts of caffeine like a college student, so we started trying to get some background information on his sleep history.

 He claimed that he actually slept fairly well, but that his wife complained about his snoring. Snoring is generally an indicator of OSA, so we got some more information. He had been taking Requip, which is a drug used to treat Restless Leg Syndrome. RLS is a condition commonly associated with PD, though some researchers question whether or not it is actually a unique condition or a manifestation of other disease conditions. Some ongoing research suggests that pharmacological treatment of RLS can exacerbate the condition for people with PD, and other research has demonstrated a potential link between RLS and sleep apnea. He also was taking preventative Aspirin therapy, and occasionally took sleep aids because he felt tired during the day. At this point we realized that we weren't going to be able to use this guy as a subject, because there were so many things potentially interfering with his respiratory cycle.

 I found it very interesting that “polypharmacy” had been associated with other inflammation state treatments, since we potentially ran into this problem doing neurophysiology research. Consideration of these neurologic conditions as inflammation states is a promising step towards furthering our neurophysiological research.

 http://www.mayoclinic.com/health/restless-legs-syndrome/DS00191

http://restless-legs-syndrome.emedtv.com/requip/requip-side-effects.html

http://www.ninds.nih.gov/disorders/deep_brain_stimulation/deep_brain_stimulation.htm

Probiotics and Clinical Disease

A few weeks ago, I went to an interesting lecture entitled, “Bacterial Colonization, Probiotics, and Clinical Disease” given by Allan Walker. The lecture focused on the hygiene hypothesis and the colonization of gut bacteria in children. Dr. Walker pointed that the colonization of bacteria in a person’s body occurs in four steps after leaving the germ-free in utero environment. The first exposure to bacteria is from a person’s mother while leaving the birth canal, the second round of exposure arises from oral feeding, the third from weaning, and the fourth phase is complete around the age of 2 years when the baby has complete adult colonization. Breast feeding and normal vaginal birth both help promote this bacterial colonization and can help against abnormal colonization that may lead to increased susceptibility to pathogens and immune mediated disease. It is apparent that a disruption in any of these steps may lead to a disruption in bacterial exposure during childhood development.

He highlighted many previous studies that have demonstrated the relationship between bacterial colonization and clinical disease. For example a study in Japan demonstrated that antibiotic use during infancy promotes a shift in the Th1/Th2 balance towards a Th2 dominant immunity in mice[1]. He also highlighted the importance of breast milk in promoting a normal pH and presence of normal intestinal flora. He argued that bacterial colonization helps promote a health host defense and that imbalances in T helper cells may lead to disease.

Through his description of countless studies that have examined the relationship of innate immunity and the presence of old friends, I was most interested in his research in probiotic treatment for clinical disease. He discussed that it may be possible to address the hygiene hypothesis by using probiotics as a surrogate for initial colonization and therapy for prevention and treatment of microbial-induced disease. I did not have much knowledge about probiotics but a simple google search yielded over two million matches, so it seems that they are certainly a hot topic. Probiotics are viable microbial dietary supplements used in fermented foods like yogurt and they claim to enhance natural defenses and prevent disease. You can by these in capsules in the supplement aisle and there are many dairy products that tout their probiotic qualities (such as Activia). Studies have shown that oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants[2]. However, clinical recommendations for probiotics are very much in the early stages, and Walker’s final conclusions stated that although probiotics may be a useful tool, many additional studies should be conducted to understand the specific function in clinical treatment.

[1] J Allergy Clin Immunol. 2001; 107(1):153-9
[2] Pediatrics 2005; 115; 1-4

For those of you interested in background of Probiotics
http://www.mayoclinic.com/health/probiotics/AN00389
http://www.msnbc.msn.com/id/27454348/ (mainstream article on MSNBC on probiotics in the news)
http://en.wikipedia.org/wiki/Probiotic (I know this is wiki, but it had an interesting history of their use, take it as a wiki source)

I addition I have the biliography from the lecture. If you are interested, let me know and I can scan/e-mail to you.

Acupuncture

I read the article titled The Neuroimmune Basis of Anti-inflammatory Acupuncture. I thought it would be helpful to blog about acupuncture and some of the theories behind its effects on the body.

HISTORY

Acupuncture originated in China and can be traced back to the Stone Age. At this time instead of needles sharp stones were used. As mentioned in the article the 5000-year-old mummy, Otzi, found in the Alps is thought to be further evidence of the use of acupuncture in ancient times. On his body there are over 50 tattoos that mark the locations of acupuncture points on his body.

Despite these ancient roots in Chinese history, acupuncture and other folk medicine declined during the Revolution of China in 1911. Yet during the Long March many of the soldiers used acupuncture to maintain the health of the People's Liberation Army. With the success of acupuncture in this situation, Mao Zedong, the leader of the Chinese Communist Party, became an advocate for the use of acupuncture on a larger scale. This seems very opposite of the rest of the party who criticized the use of folk medicine as a step backwards.

From this support, Traditional Chinese Medicine was born. Traditional Chinese Medicine is the formalized system of folk medicine that was taught in medical schools throughout China. It is still an important part of Chinese medical curriculum today.

Acupuncture was first brought over to the US in the 1970s. Travelers to China were fascinated by the use of acupuncture as the only anesthesia for patients during surgery. The National Acupuncture Association (NAA) was started during this time. The NAA hosted a number of seminars and research presentations around the US in order to increase acupuncture's popularity. It succeeded and in 1972 the first acupuncture clinic was opened in Washington, D.C.

METHODS

The basis of acupuncture is rooted in the belief that there is a substance within our bodies called Qi. This vital energy runs freely through our body along meridians. When an imbalance, or blockage of our Qi occurs, that is when acupuncture needs to be done. Acupuncture allows for drainage of excess Qi from certain areas, clearing of blockages, and promoting flow where stagnation has occurred.

When acupuncture is done, it is done along the meridians in the body. The twelve primary meridians in the body, or mai, correspond to the systems of function. These primary meridians are: Lung, Large Intestine, Stomach, Spleen, Heart, Small Intestine, Bladder, Kidney, Pericardium, San Jiao (not really associated with a specific body part, it is for the control of temperature), Gall Bladder, and Liver. There are also Eight Extraordinary Pathways, the Luo Vessels, the Divergents, and the Sinew Channels that are also used, just not as commonly.

In clinical practice a disposable stainless steel needle is usually used. The needle has a diameter between .18mm to .51 mm depending on the location. The ends of the needle is wrapped with wire or covered in plastic to stiffen the needle and allow it to be easily grasped by the acupuncturist. The length of the needle, and the depth it is inserted, depends on the style that the acupuncturist is using as well as what he is trying to alleviate.

With acupuncture heat or electricity can be applied to the area in order to further the affects of the needle. When heat is applied is usually done via moxibustion, which is the burning of herbs (usually mugwort). Moxibustion can be done several different ways. One way involves attaching the herbs to the exposed end of the needle and lighting it on fire. Another technique is holding a light stick of mugwort near the acupuncture needle. Another is applying an ointment to the area of the skin and then lighting the mugwort directly on the skin before inserting the acupuncture needle.

THEORIES


The two theories that are mentioned in the article that I felt weren't really explained clearly are the Gate-Control Theory and the DNIC theory. I wanted to share the information I found when I looked them up. This helped me out so I thought it might be helpful to others.

Gate-Control Theory

The Gate-Control Theory of Pain was proposed by Ronald Melzack and Patrick Wall in 1962 and in 1965. The theory states that pain is not just determined by the action of nociceptors. Nociceptors are receptors that take in a stimulus and cause us to perceive pain due to this stimulus. Yet Melzack and Wall state that there are other fibers that can affect this transmission of stimulus into pain. They state there are other nonnociceptive fibers that interact with the nociceptor fibers. Thus if these other fibers are stimulated they can actually counter the pain signal of the nociceptors.

This can be applied to acupuncture very easily. When applied to acupuncture this theory is saying that the insertion of the needle is actually activating nonnociceptive fibers in that area. This activation then causes a signal to be sent, which interferes with the nociceptors and the pain that is perceived is lessened.



DNIC

This stands for Diffuse Noxious Inhibitory Control. This theory seemed pretty complicated to me, so my explanation is only what I got from the information I found. I kind of simplified it down so I could easily understand it.

This idea is very similar to that of the Gate-Control Theory of Pain. It states that if you have a stimulus that is perceived as pain in a certain area, you can inhibit this by administering a painful stimulus in a distal area. This is like the general idea that if your head hurts and someone stands on your foot you won't head won't hurt anymore.


LINKS
Here is a link to an interactive map of the acupuncture points and meridians:
http://www.yinyanghouse.com/acupuncturepoints/locations_theory_and_clinical_applications


Here is a link to the NIH Conference statement that is mentioned in the article:
http://consensus.nih.gov/1997/1997Acupuncture107html.htm


Here is where I got some of the information about DNIC:
http://www.clas.ufl.edu/jur/200611/papers/paper_lovell.html

Aspirin and Myocardial Infarctions

Everyone has seen the commerical where the man takes apsirin to stop his heart attack...well that got me thinking...is it true? How does it work?

In October 1997, the AHA reported in its journal, Circulation, that up to 10,000 more people would survive heart attacks if they would chew one 325 milligram aspirin tablet when they first had chest pain or other sign of a heart attack. Other studies have come to similar conclusions. One found that heart attack patients who took aspirin when their symptoms began, and then daily for one month, significantly lowered their risk of dying and of having another heart attack or stroke over the people in the study who were given the placebo. Now, just about all researchers agree that patients should be given aspirin during the first hour -- during pre-hospital transport or in the Emergency Room -- if a heart attack is suspected.

How it works: The Basics:

Basically, it interferes with the production of a series of chemicals in the body -- called prostaglandins -- that regulate many of the body’s vital functions. By blocking certain prostaglandins, aspirin lowers body temperature, relieves minor aches and pains, relieves inflammation and interferes with the role of blood platelets in forming clots. It is this last effect that appears to impact on risk for heart disease. Blood clots are formed by platelets grouping together. Aspirin interferes with this process by making the platelets less “sticky” -- and therefore less successful in grouping together -- by inhibiting the manufacture of prostaglandins. This same blood “thinning” action that makes aspirin effective in reducing a person’s risk for heart disease, but “you have to chew the aspirin, especially if you only have enteric-coated aspirin, because if you just pop one of those, you won’t see any action for hours.” Always call 911 first. Then, after chewing the aspirin, you can wash it down with water and get immediate medical attention.

Interesting Facts:

Aspirin was officially introduced 100 years ago and has been marketed in its current form for more than 80 years.
The origin of the drug can be traced back to Hippocrates. he advised his followers to chew the leaves of the willow tree to alleviate pain.
The Chinese have been using the bark of the same trees -- which contain salicin -- to control fever.
In the early 1800’s different derivatives of this bark were tested and one -- acetylsalicylic acid, the chemical name for aspirin -- was found to be tolerated better than the others.

http://www.yourfamilyshealth.com/cardiology/aspirin/

Alternative Medicine: Cupping

The review article, The Neuroimmune Basis of Anti–inflammatory Acupuncture, mentions the term “cupping”. As I had mentioned before in class, I grew up with Russian gymnastic coaches who brought their knowledge of Eastern Medicine to the West. I was lucky enough not to get stung by bees but had the enjoyment of having cupping done. Hope you find it as interesting as I did.

Illness is caused by an imbalanced, stagnated or weak Qi. Acupuncturists are trained to use cupping when Qi needs to be drawn to the surface of the body from deep within. The cups are applied to acupuncture points. Cupping is a technique in which glass cups are heated from the inside with fire to create a vacuum and then placed on the afflicted area of the body. The cup's suction pulls at the skin and is said to "suck out" the body's toxins.

Sources of these toxins include: air pollution, drugs, junk food, and smoking, waste products of metabolism, trauma/accidents, stress, anger, anxiety and depression. Toxins can slow down or block supply of blood that delivers much needed oxygen, nutrients, water, mineral electrolyte, vitamins, enzymes, hormones and immune system cells to cells, tissues and organs. This also prevents the removal of metabolic waste products and toxic substances which are excreted through our lungs, skin and urine. As a result, our cells, tissues, and organs become progressively weak, inefficient, and easily overcome. This can cause tissue/organ malfunction and infection to take place. This will cause symptoms of diseases such as aches and pain, numbness, fever, cough, stomach ache, constipation, diarrhea and headaches. If left untreated, further accumulation of toxic waste may lead to serious chronic diseases including hypertension, ulcers, diabetes, arthritis, Alzheimer disease, migraine, heart disease, stroke and cancer.

There are 3 different cupping techniques.

1. Air Cupping: most common, no side effects, prevents and treats slight ailments
2. Aggressive Cupping: used for serious chronic diseases, marks may remain up to 1 year
3. Blood Cupping: cups applied to scratched skin, toxic blood is removed

Some diseases treated by Cupping Therapy

• cold/cough
• headaches/migraine
• asthma
• allergies
• hypertension/hypotension
• osteoarthritis
• rheumatoid arthritis
• diabetes
• kidney/liver problems
• Alzheimer’s disease
• stroke
• cancer

Interestingly, if the person is really healthy, the redness will dissipate very quickly with the skin returning to its normal color, usually within minutes or hours. However, if the person is in poor health, injured or experiencing Qi blockages, there will be some bruising and skin will not return to normal color for a couple of days rather than hours.

http://www.bestcuppingtreatment.com/page/1069270

Stem Cell Research

I was looking on YouTube and saw quite a few videos about Michael J. Fox. One of them was an ad he had about his support for stem cell research and Parkinson's. So I looked up any studies with the use of stem cells and came across xcell-center.com. They specialize in regenerative medicine.

There was a specific stem cell study which involved collecting stem cells from a patient's bone marrow, specifically the iliac crest, then re-implanting the cells in the body days later. Stem cells are used as a type of self-healing for they have the potential to change into many different types of cells and regenerate damaged tissue.

Results:

• Two out of 11 patients reported an overall improvement, with improved mobility (legs, arms) and/or improved strength. Some patients reported a regaining of muscle strength and/or an improvement of balance. There was some improvement of speech and/or a reduction of pain and spasms.
• Eight out of 11 patients reported a strong improvement, with a marked improvement of mobility, speech and significantly reduced pain and spasms.

**Stem cell treatment studies were also used for Alzheimer's, Diabetes, Multiple Sclerosis, Osteoarthritis, and Stroke patients.

Parkinson's Disease and Caffeine

I found some other interesting info on Parkinson’s Disease. I remember hearing about this in PSIO 480 and wanted to learn more about it. There was a study done about the effects of caffeine on PD. It was a longitudinal study over a period of 30 years where 8,004 Japanese-American men (aged 45-68) drank different amounts of coffee each day. It turns out that only 102 of these men developed PD. The ones who drank the most coffee (more than 28oz/day) were least likely to develop PD and the ones who did not drink any coffee were five time more likely to get PD than those who drank more than 28oz/day. Drinking other caffeine sources such as black tea, green tea, chocolate, and soda were also associated with a lower risk of PD. Other nutrients in coffee, including niacin, were unrelated to PD incidence. The relationship between caffeine and PD was not affected by sugar or milk that was added in the coffee.

Caffeine belongs to the xanthine chemical group. A naturally occurring xanthine in the brain called adenosine is used as a neurotransmitter at some synapses. When adenosine receptors are blocked, levels of the neurotransmitter dopamine increase. Caffeine may protect against Parkinson's disease by blocking adenosine receptors, thus increasing the amount of dopamine in the brain.

Although the new research is suggestive of a link between caffeine and Parkinson's disease, it is too early to say that caffeine will prevent Parkinson's disease. Perhaps the brains of people who like and dislike coffee are different. It may be that this difference results in the different incidence of Parkinson's disease and in the consumption of coffee. Also, the study included older, Japanese-American men. It is unknown if the caffeine/Parkinson disease relationship holds for other ethnic groups, women and younger people. As with many preliminary studies, this research requires further experiments to establish a causal link between caffeine and reduced incidence of Parkinson's disease. Overall, caffeine can be thought of as a preventative for PD, but not necessarily a treatment or cure. Now don't go drinking high amounts of caffeine to prevent PD because too much caffeine has been linked to developing schizophrenia.

Resources:

http://jama.ama-assn.org/cgi/content/abstract/283/20/2674?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=coffee&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

http://www.webmd.com/news/20000523/caffeine-protect-against-parkinsons-disease

http://faculty.washington.edu/chudler/parkinc.html

AD and Nuns...

I know there were a couple more questions about the Nun Study that came up in class on Monday.  I haven't been able to find anything about the differences in lesions but something I found was interesting...

In my other research of the Nun Study I didn't see the references to early cognitive ability that this review talks about.  It basically says that early linguistic skills can be markers for later cognitive issues.  The Nuns with lower linguistic skills earlier in life showed more cognitive issues later in life.  Here is the article:

http://www.alzheimers.org/nianews/nianews6.html

Helmith (worm) therapy in intestinal inflammation

The last few lectures Dr. Cohen had talked about the use of helmith (worms) to treat certain inflammatory diseases such as Crohn’s disease. I thought this was very interesting and decided to do a little more research and expand on it.

There’s a vast amount of literature of the use of helminth as a therapeutic approach to autoimmune diseases causing chronic inflammation and allergies. Helminths are multicellular parasites that have typically co-existed with humans. Most are infectious and are found to be in two phyla, Platyhelminths (includes tapeworms and digenean flukes) and Nemotoda (roundworms). In well established populations with modern care helminthes infection is rare; however, about one million people worldwide are infected with most victims living in sub-Africa, Asia, and Latin America.

Recent studies have found a correlation in the decrease of infectious diseases and an increase incidence of other diseases such as allergies and autoimmune diseases in westernized countries. It is thought that because we have naturally co-evolved with helminthes humans have adapted and relied on helminthes to regulate our immune system.

Helminth infection is characterized by its ability to induce a regulatory T cell response and a strong Th2 response (driving the immune system to produce antibodies). In order for helminth to survive, it must escape its host immune system by secreting chemokines to block neutrophil migration and down regulate T and B cell response by activating Treg or induce anti-inflammatory cytokines. Therefore, one hypothesis is that with improved hygiene the rate of helminthes infection decreases increasing the rate of allergies and autoimmune diseases, and is thought to be due to an over production of Th1 immune response. It can be concluded that having some sort of helminth infection at one point in life helps to teach the immune system to balance its immune response.

Interestingly, helminth Trichuris suis (pig whipworm) therapy has been found to decrease disease activity in people with Chrohn’s disease and ulcerative colitis. Because T. suis does not infect humans, its eggs are eliminated after several weeks of colonizing. Other helminth may have therapeutic benefits, but are found to infect humans and cause mild to severe infection or raise public health concerns. Patients who were given T. suis found either temporary relief or decreased disease activity. The skewing of a Th2 response reduces Th1 (the inflammation and cytoxtic killer T cell response). Treating patients with chronic intestinal inflammation with helminth may be beneficial; however, the disadvantage of helminth infection is the difficulty in not only treating or fighting diseases that require Th1 response (example: HIV, tuberculosis, or malaria), but stimulating vaccines requiring an efficient Th1 response.

There are still debates and studies conducted to see if there is a relationship between helminthes and allergies. Some state that infection reduces allergies while others find the opposite. It is possible that age, genetics, and helminth species is the cause to the inconsistencies. Therapy with helminth in gastric autoimmune diseases by far seem to be consistent; however, further studies are being conducted to test whether other autoimmune diseases such as lupus and arthritis can also be treated.

Source:
World J Gastroenterol (2008) 14(33): 5125-5132
Parasitol Res (2007) 100:921–927
Immunobiology (2007) 212:475-490