Inflammablog 2

Immunity From Mom

2008-12-15T11:33:00.003-07:00

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

2008-12-13T17:44:00.001-07:00

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

2008-12-12T12:07:00.002-07:00

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

2008-12-12T11:33:00.003-07:00

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

2008-12-11T14:03:00.003-07:00

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

2008-12-10T23:07:00.003-07:00

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

2008-12-10T15:36:00.002-07:00

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

2008-12-09T10:29:00.001-07:00

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

2008-12-09T10:27:00.001-07:00

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

2008-12-09T10:24:00.002-07:00

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

2008-12-09T10:23:00.001-07:00

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?

2008-12-09T08:26:00.002-07:00

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?)

2008-12-09T04:58:00.005-07:00

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

2008-12-05T13:37:00.001-07:00

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

2008-12-05T12:57:00.002-07:00

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

2008-12-03T23:16:00.001-07:00

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?

2008-12-03T22:10:00.003-07:00

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

2008-12-03T19:33:00.005-07:00

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

2008-12-02T16:51:00.002-07:00

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?

2008-12-01T20:51:00.002-07:00

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

2008-12-01T19:26:00.004-07:00

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

2008-11-30T22:56:00.001-07:00

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

2008-11-30T17:59:00.006-07:00

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

2008-11-30T17:52:00.002-07:00

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

2008-11-30T15:13:00.002-07:00

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

2008-11-30T01:43:00.005-07:00

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

2008-11-29T11:47:00.002-07:00

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

2008-11-25T15:43:00.002-07:00

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

2008-11-24T12:38:00.007-07:00

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

2008-11-24T11:47:00.004-07:00

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

2008-11-24T08:15:00.004-07:00

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.

Air Cupping: most common, no side effects, prevents and treats slight ailments
Aggressive Cupping: used for serious chronic diseases, marks may remain up to 1 year
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

2008-11-21T13:35:00.003-07:00

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

2008-11-20T12:10:00.005-07:00

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, wereunrelated to PD incidence. The relationship between caffeineand 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...

2008-11-18T11:06:00.003-07:00

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

2008-11-17T20:25:00.000-07:00

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

First Transgenic Monkey Model of Huntington's Disease

2008-11-17T13:15:00.002-07:00

Huntington's disease is a neurodegenerative disease that we haven't really discussed in class. It is caused by a defective gene that triggers certain nerve cells in the brain to die and symptoms may include uncontrolled movements, mood swings, cognitive decline, balance problems, and eventually losing the ability to walk, talk or swallow. I found an article that was published in May 2008 discussing the development of the first transgenic monkey model of Huntington's disease, which allows scientists to advance beyond the mouse model in hopes of better understanding the disease, develop more effective therapies, and even introduce using similar models for other genetic dieseases. It's a really enlightening article and illustrates the advances that are presently being achieved in medical technology and neurodegenerative diseases.

Article:
http://www.ninds.nih.gov/news_and_events/press_releases/pressrelease_HD_monkey_model.htm

Fibrin

2008-11-17T12:22:00.002-07:00

Fibrin is the subject of one of the papers for this week. I found a review through Pub Med that discusses the way fibrin activates different pathways and its receptors, the way that ancrod is able to deplete fibrinogen, and its effects on the peripheral and central nervous systems. It's a very well written and easy to read article.

"Fibrin mechanisms and functions in nervous system pathology." Adams RA, Passino M, Sachs BD, Nuriel T, Akassoglou K

Lack Of Vitamin D Linked To Parkinson's Disease

2008-11-17T10:20:00.004-07:00

Parkinson's disease affects nerve cells in many parts of the brain, particularly those that use the chemical messenger dopamine to control movement. The most common symptoms are Tremor, Rigidity, Akinesia and Postural instability, also known as TRAP. Although, patients with PD have been being treated with oral replacement of dopamine.

It is thought that an insufficiency in Vitamin D can lead to Parkinson's and other neurodegenerative diseases, or that it is an outcome of having these diseases. A study at Emory University School of Medicine showed that people with PD are more likely to be Vitamin D deficient when compared to healthy adults or people with Alzheimer's disease. Vitamin D insufficiency can be determined from a blood test. Insufficiency is defined as less than 30 nanograms per milliliter of blood of the 25-hydroxy form, while a deficiency is defined as less than 20 nanograms per milliliter. People usually get their dose of vitamin D from exposure to sunlight or by dietary supplements, but with increasing age it is harder for older individuals to absorb Vitamin D from the sun. This can also be a problem for people with PD due to lack of activity or exposure to the sun. Studies have also shown that people have lower levels of Vitamin D in the fall and winter when compared to the spring and summer. But, that is again related to the amount of sun exposure and activity during those seasons. It is known that the part of the brain most affected by Parkinson's is the substantia nigra. This area has high levels of the vitamin D receptor, which could be where the lack of vitamin D could be important for normal functions of these cells. Further research is necessary to determine at what stage the deficiency in vitamin D levels occurs in the brains of people with PD. It is still not known if taking a dietary supplement, or increased exposure to the sun could help alleviate symptoms or have an affect on the rate of the condition's progression.

Nun Study and Alzheimer's Disease

2008-11-16T23:03:00.003-07:00

Here's the video about the Nun study done by researcher David Snowdon:

http://www.liveleak.com/view?i=6c4_1226747631

These nuns have agreed to donate their brains to science to study more about how brain diseases develop. I found it amazing that 6 of the nuns were over 100 years old and still in very good shape. Their brains showed signs of Alzheimer's but they don't have any physical or mental characteristics of the disease. In addition, higher educated nuns have lived longer. This just shows the importance of keeping your mind active. As they say... "Use it or lose it.

Endogenous Anti-Inflammatory Neuropeptides and Proresolving Lipid Mediators: A New Therapeutic Approach for Immune Disorders

2008-11-14T10:39:00.002-07:00

This is a review article that I found interesting given the fact that at the Barbara Davis Center I hear a lot of talks about autoimmune disease. The paper discussed factors affecting the balance between pro-inflammatory and anti-inflammatory signals in the body, including regulatory T cells and T cell effectors. Mainly discussed were the regulatory abilities of endogenous neuropeptides (such as vasoactive intestinal peptide, α-melanocyte stimulating hormone, urocortin, adrenomedullin, cortistatin and ghrelin) and lipid mediators (omega-3 and omega-6 polyunsaturated fatty acids--PUFAs).

Endogenous neuropeptides have been observed to do the following:
1. Counterbalance inflammatory response
2. Downregulate Th1 response
3. Generate regulatory T cells (Tregs)

What especially caught my eye during my reading about the neuropeptides is that they induce the peripheral expansion of antigen-specific Tregs, which have a suppressive activity on self-reactive T cells. The suppressive mechanism of Tregs is mainly dependent on cytotoxic T-lymphocyte-associated protein 4 (CTLA4), or through production of immunosuppressive cytokines. Trialnet, the large diabetes prevention/amelioration study which I participate in (doing HLA typing) has a CTLA4 study going on using the drug Abatacept, which is a fusion protein of the extracellular domain of CTLA4 bound to immunoglobulin. Abatacept prevents T cells from getting activated when the CTLA4 domain binds to B7 on the antigen presenting cell. If the B7 is bound by the CTLA4 domain, then CD28 on the T cell cannot bind B7 and receive the costimulation necessary to activate the T cell. The drug Abatacept is currently approved for the treatment of Rheumatoid Arthritis.

Omega-3 and Omega-6 PUFAs are precursors for tons of different molecules, both pro-and anti-inflammatory. Some of the molecules Omega-6 PUFAs make are prostaglandins and leukotrienes, which are strongly pro-inflammatory molecules. I had been under the impression that Omega-6 PUFAs were exclusively pro-inflammatory, but according to this review, they can also stimulate pathways that lead to inflammation resolution. I have read some material that indicates the American diet has a too high Omega-6 to Omega-3 PUFA ratio which ruins our health (heart disease, cancer, etc.) So I was surprised to find that it is possible for them to aid inflammation resolution as well. I wonder if there is a way to make Omega-6 PUFAs be anti- rather than pro-inflammatory?

The article concluded with some analysis on how these molecules could be developed into novel therapeutics. Some have been successfully tested in animal models. Advantages of these molecules include that fact that they have a wide spectrum of action in vivo. However, neuropeptides are extremely unstable and side effects of most of the molecules are unknown. For example, I recently found out that ghrelin is involved in hunger and satiety, so would use of this neuropeptide therapeutically affect patient weight? I’m sure there are many such questions that could only be answered with animal experiments and clinical trials. In view of other natural human compounds that have been found to be therapeutic such as insulin and cortisone, these substances may present an attractive therapeutic option, but as usual, much work needs to be done.

Resource: Anderson, P., Delgado, M. ENDOGENOUS ANTI-INFLAMMATORY NEUROPEPTIDES AND PRORESOLVING LIPID MEDIATORS: A NEW THERAPEUTIC APPROACH FOR IMMUNE DISORDERS.
J Cell Mol Med. 2008 Jun 12. [Epub ahead of print]

High Times with Alzheimer"s

2008-11-12T19:05:00.002-07:00

As we all know there is no cure for the degenerative Alzheimer's. But there is evidence according to Spanish studies that marijuana helps. The drug's active ingredients, cannabinoids have been shown to help prevent inflammation and protect the brain. No tests have been performed on people living with the disease, but researchers have studied human brain tissue, of normal and Alzheimer's, and conducted cannibinoid experiments on rats.

The rats were injected with beta-amyloid, a protein which simulated Alzheimer-like effects on their brain. They were also injected with the marijuana ingredient--cannibinoid. For comparison, other rats were injected with another protein along with the cannibinoid. Then they were tested for memory, learning, and mental function. The cannibinoid was shown to prevent the trigger of inflammation in the cells around the Alzheimer "plaque" which is believed to be involved in development. "Our results indicate that cannabinoid receptors are important in the pathology of Alzheimer's disease and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease," write the researchers in the journal.

SOURCES: Ramirez, B. The Journal of Neuroscience, Feb. 23, 2005; vol 25: pp 1904-1913. WebMD Medical Reference from Healthwise: "Alzheimer's Disease: Topic Overview." News release, Society for Neuroscience.

Alzheimer's Disease

2008-11-10T13:15:00.002-07:00

Alzheimer's Disease was first discovered in 1906 by Alois Alzheimer's. This disease is the 6th leading cause of death in the United States. It effects individuals by killing brain cells which leads to memory loss, thinking, and behavioral processes. Alzheimer's is just one of a number of forms of dementia, which is the general term used for memory loss and the loss of other abilities that effects everyday life. Alzheimer's can occur in conjunction with another form of dementia known as vascular dementia. Vascular dementia destroys the brain by constricting blood flow ultimately leading to cell death. There is sadly no cure for dementia but there are numberous treatments available to alleviate the symptoms and improve the quality of life for those effected with this disease.

For more information on Alzheimer's Disease please visit www.alz.org
(all information provided above was from this website as well)

Neurodegenerative Disease: Parkinson's Disease

2008-11-10T12:53:00.003-07:00

Parkinson's Disease is a neurodegenerative disorder that affects nerve cells in the brain that control muscle movement. The disease results from the lack of the chemical messenger dopamine in the brain. Dopamine is produced in the substantia nigra of the brain. Parkinson

s Disease causes the cells that produce dopamine to either become impaired or die. What sets this in motion is yet to be determined.

Signs and Symptoms

The symptoms of PD are often described using the acronym: TRAP.

T = Tremor: The characteristic tremor of PD often begins in a hand.

R = Rigidity: Muscle stiffness often occurs in the limbs or neck. This stiffness can be so severe that range of motion and/or pain can result

A = Akinseia: this is the lack of movement or slowness in initiating/maintaining movement.

P = Posture Instability: Characteristic bending or flexion of the body. It is associated with difficulty in balance and disturbances when walking.

Other symptoms that can appear with the progression of the disease include the loss of automatic movements, speech changes, and dementia.

Risk Factors

There are a few known risk factors for the development of PD. First and foremost, it is very uncommon for young adults to experience the disease and risk of development increases with the progression of age. Also, men are more likely to develop Parkinson's Disease than women. Finally, if you have one or more close relatives have PD your chances of developing it increase. However, your risk is still less than 5%. Again, what sets off the initial events towards the development of PD is still unknown.

Diagnosis

Currently there are no definitive tests towards the diagnosis of PD. This makes it incredibly difficult to diagnosis, especially in the early stages of disease progression. Often, a diagnosis is made based on your medical history and neurological exam. This exam includes an evaluation of walking and coordination. Finally, with a diagnosis, a patient will normally have 2 out of the 3 cardinal Parkinson's Symptoms as mentioned earlier: either tremor, akinesia, or rigidity.

Treatment Options

Currently there are two major drugs on the market to treat PD. First, there is Levodopa. This is a natural substance that everyone has in their bodies. When it is taken in a pill form, it passes into the brain and is converted into dopamine. As PD progresses, medication adjustments will have to occur due to the tendency of the drug to wear off. Dopamine antagonists are also used to treat PD. Unlike levodopa, these are not converted into dopamine. Instead, they mimic the effects of dopamine causing neurons to react as if dopamine were present. However, they are not nearly as effective in treating the symptoms of PD and are often used to smooth the on-off effect of levodopa. Other forms of drugs are: MAO B Inhibitors, COMT Inhibitors, Anticholinergics, and Antivirals. Accompanying drug treatment is physical therapy. This helps to improve range of motion and muscle tone. Finally, the most common surgical procedure to treat PD is deep brain stimulation in which an electrode is place in the area of the brain that controls movement. Stimulation is controlled by a pacemaker-like device placed under the skin in the upper chest. This form of treatment is often used with patients in advanced stages of the disease. Although the above treatment options have proven to be beneficial in helping with the symptoms of PD, there still is no cure for the condition.

References: www.mayoclinic.com

Stress and Neurodegenerative Disease

2008-11-10T10:41:00.002-07:00

Just like most diseases and disorders we have discussed thus far in class, stress presents itself once again as an agent for distruction. Chronic stress will intensify inflammation and increase the risk for developing neurodegenerative diseases, such as Multiple Sclerosis. Researchers presenting at the 115th Annual Convention of the American Psychological Association (APA) have revealed that stress-related increases in the central nervous system inflammation are prevalent in animal models with multiple sclerosis. Researchers have found that stress-induced increases of proinflammatory cytokines will inhibit the clearing of a virus and allow the inflammatory process to run amok, ultimately increasing the vulnerability of the body to be overrun with a neurodegenerative diseases, like MS. Studies have also revealed that patients already presenting with MS will have severly worsened symptoms in reasponse to stressful events. The specific cytokine found guilty for this vulnerability to nuerodegenerative diseases is interleukin-6 (IL-6). Researchers used a social disruption model to simulate stress for mice and what they found is stress appears to elevate levels of IL-6 which subsequently increases the severity of MS symptoms. On a lighter note, they have also found that this worsening can be prevented through neutralizing antibody treatments. Furthermore, interventions that prevented or reversed the stress-induced increases in IL-6 in the mouse model may have implications for humans and recent evidence suggests that some potential interventions include certain anti-inflammatory drugs, exercise, antidepressant medication, omega-3 fatty acids, and mindfulness relaxation training.

Resources:
Exam Health-http://www.emaxhealth.com/32/15106.html

Neurodegenerative disease: Multiple Sclerosis

2008-11-10T02:33:00.010-07:00

MS is an autoimmune disease in which antibodies attack the white matter in the brain. The white matter is made up of oligodendrocytes that wrap around the axons in the central nervous system (brain and spinal cord) and form a fatty layer called the myelin sheath which helps in signal transduction. When demyelination occurs, the axons of neurons can't effectively conduct action potentials. If you have multiple sclerosis, you’re not alone. MS affects over 400,000 people in the United States and may affect 2.5 million people worldwide. Multiple sclerosis affects 2-3 times as many women as men. No two people get MS in the exact same way as in it differs in timing, location, and severity. In general, people with MS can experience partial or complete loss of any function that is controlled by, or passes through, the brain or spinal cord.

There are 4 different types of MS:

1. Relapsing/Remitting (RRMS):
This is characterized by relapses (also known as exacerbations) during which time new symptoms can appear and old ones resurface or worsen. The relapses are followed by periods of remission, during which time the person fully or partially recovers from the deficits acquired during the relapse. Relapses can last for days, weeks or months and recovery can be slow and gradual or almost instantaneous. The vast majority of people presenting with Multiple Sclerosis are first diagnosed with relapsing/remitting. This is typically when they are in their twenties or thirties, though diagnoses much earlier or later are known. Around twice as many women as men present with this variety.

2. Secondary Progressive (SPMS):
After a number of years many people who have had relapsing/remitting MS will pass into a secondary progressive phase of the disease. This is characterised by a gradual worsening of the disease between relapses. In the early phases of Secondary Progressive, the person may still experience a few relapses but after a while these merge into a general progression. People with secondary progressive may experience good and bad days or weeks, but, apart from some remission following relapsing episodes, no real recovery. After 10 years, 50% of people with relapsing/remitting MS will have developed secondary progressive

3. Progressive Relapsing Multiple Sclerosis (PRMS):
This form of MS follows a progressive course from onset, punctuated by relapses. There is significant recovery immediately following a relapse but between relapses there is a gradual worsening of symptoms.

4.Primary Progressive (PPMS):
This type of MS is characterised by a gradual progression of the disease from its onset with no remissions at all. There may be periods of a leveling off of disease activity and, as with secondary progressive, there may be good and bad days or weeks. PPMS differs from Relapsing/Remitting and Secondary Progressive in that onset is typically in the late thirties or early forties, men are as likely women to develop it and initial disease activity is in the spinal cord and not in the brain. Primary Progressive MS often migrates into the brain, but is less likely to damage brain areas than relapsing/remitting or secondary progressive - for example, people with Primary Progressive are less likely to develop cognitive problems.

There is no known cause for MS, however, factors such as heredity, the immune system, geography and climate, and viruses are being studied.

There is no cure for MS. The current treatment for MS is either injectable or infusion therapy.

Resources:
http://www.mult-sclerosis.org/whatisms.html
http://www.msactivesource.com/msavProject/msas.portal/_baseurl/twoColLayout/SCSRepository/en_US/msas/home/What-Is-Multiple-Sclerosis/index.xml

Obesity and RA

2008-11-07T13:16:00.003-07:00

In response to the question posed in class, "Is there an association between obesity and rheumatoid arthritis?", the answer is yes. A number of studies have been performed on this subject and many of them reveal interesting findings.

First, a couple of studies have been conducted in regards to RA and obesity. Researchers have found that obese patients with RA not only had a decreased quality of life (when compared to normal weight RA patients) but also had increased joint pain, fatigue, and loss of physical function in affected joints. On the flip side, obesity may result from RA because of inactivity due to joint pain.

Next, a study performed at the Fred Hutchinson Cancer Research Center in Seattle, Washington found some evidence that sex hormones may influence the incidence of RA. Obesity has been found to increase endogenous estrogens and thus may increase the risk for developing RA.

Because both obesity and RA are inflammatory diseases, it makes sense that the two may be associated. Even though it may seem obvious that there is a correlation between the two diseases, more research is required to determine the exact mechanism in how both are related.

Spread of Polio - Nigeria

2008-11-06T09:57:00.002-07:00

In class on October 28th, Dr. Cohen mentioned an article he recently read in the New York Times about the spread of Polio. The article, “Polio Spreads to New Countries And Increases Where It’s Endemic” does not have a hopeful tone for Nigeria. It states that, “Nigeria, whose northern provinces are the epicenter of Africa’s epidemic, recently dismissed the head of its national vaccination program.” Nigeria has been reluctant to administer the polio vaccine because of fears it may not be safe. “Many Muslims in the north believe that polio vaccination is being used as a ploy by Western countries to inject people with certain chemicals to reduce their fertility or infect them with HIV/AIDS in order to reduce the population of Muslims.” According to the World Health Organization, the number of 2008 year-to-date (Oct. 28, 2008) cases is 736 compared to the 2007 year-to-date cases of 220. The WPV1 cases, however, are very localized and reported in only 6 of Nigeria’s 37 states. The Expert Review Committee (ERC) on Polio Eradication and Routine Immunization (ERC) met on October 27-28, in Abuja. Plans have been finalized for immunizations in November and December. “The group also finalized the SIA dates for the coming months, with mOPV1 to be added to an integrated measles campaign at end-November (in the north) and December (in the south), with separate Immunization Plus Days (IPDs) to be held in high-risk areas in the north in December.”

Polio History (Past 15 Years):
200 countries, 20 million volunteers, US $3 Billion, Largest Public Health Campain

FACTS:
In 1988, the World Health Assembly (WHA) the annual meeting of the ministers of health of all Member States of the World Health Organization, voted to launch a global goal to eradicate polio. As a result of the Global Polio Eradication Initiative - the single largest, internationally-coordinated public health project to date - by the end of 2006, only four countries remained which had never interrupted endemic transmission of wild poliovirus (Nigeria, India, Pakistan and Afghanistan). In 2006, fewer than 2000 cases were reported. Back when the Global Polio Eradication Initiative was launched, wild poliovirus was endemic in more than 125 countries on five continents, paralyzing more than 1000 children every day.

Eight new cases were reported last week in Nigeria (1st week of November 08).

http://www.who.int/features/2004/polio/en/
http://www.polioeradication.org/casecount.asp
http://www.polioeradication.org/content/general/casemap.shtml
http://www.polioeradication.org/content/polionews/PolioNews31.pdf
http://www.scienceinafrica.co.za/2004/march/polio.htm
http://news.bbc.co.uk/2/hi/health/7671070.stm

Genetics and Arthritis

2008-11-04T12:01:00.001-07:00

In class someone mentioned if there were genetic predispositions involved in arthritis, and I was curious to find more information about that. I found an article that did a study about this topic. They found that genetic susceptibility is caused by many factors. The article said, “it involves several polymorphic genes, perhaps each contributing with a small increment.” Since we also looked at NOS, it was interested that part of their results was that they found out the NOS2 gene promoter polymorphisms don’t have a huge effect on RA predisposition. It also mentioned that there should be more research done to look into the CTTT alleles. The articles also said, “In addition, the reported genetic heterogeneity within and between ethnic groups in the highly polymorphic promoter (CCTTT)n repeat13 raises the possibility that a (CCTTT)n allele might be associated with the disease in a different population.” This goes along with the issue brought about in class about the disease being associated in different populations or ethnic groups like Italians. (http://www.nature.com/gene/journal/v3/n5/full/6363856a.html) I also found a general website that had information about arthritis and I found a section entitled, “Issues of Genetics and Arthritis”. It mentioned that there are more studies that are looking at the genetics involved in arthritis. It mentioned that in Britain there has been a discovery of knee osteoarthritis that is now added to the group, genetically caused arthritis. They found that brothers are more likely to get the disease than sisters, which is surprising since females are more susceptible than males. Once again, there still needs to be more research and the article mentioned that another group in California is looking into this study in order to find out more information about genetics and arthritis. (http://www.creakyjoints.com/go/article0062.shtml)Therefore, there are genetic predispositions involved, but to determine more information about it and find more types of arthritis that have a genetic predisposition there has to be more research conducted.

Italian Arthritis

2008-11-03T21:55:00.002-07:00

In class we discussed multiple articles that had come out of Italy to the 1990’s; so I wanted to know if their were any reasons for this. I searched for evidence of this trend and could only find one that discussed the subject and it claims “prevalence of RA is low in Italy”. Low prevalence of RA does make sense in a country whose traditional food staples are whole grains, fresh fruit and vegetables, and fish. All of which are included in a good anti-arthritis diet according to the article we read last week in Environmental Nutrition.

I could not find any special reason why arthritis was of such interest to Italian researchers in the 1990’s.

Arthritis and Toads

2008-11-03T19:15:00.002-07:00

I know we had discussed this in class so I want to look it up. In an article in the New York Times, The cane toad has been conquering northern Australia, but now they are paying for it. They have been growing too big and hopping into new territories, because of this the toads are developing severe arthritis.
In 1930s the cane toads were brought to Australia in order to control the insect problem in the sugar cane fields. The toads did solve the insect problem, but also, are very toxic to the animals that try to eat them. This has allowed them to expand their territory. Researchers have also seen that the toads have evolved with larger bodies and longer legs and now are able to move faster. Furthermore, researchers found that some of the cane toads had fused vertebrae caused by bony growths with spinal abnormalities. With each hop, it puts more stress on their skeleton.

Resources:
Fountain, Henry. "Arthritis Fails to Slow Invading Toads in Australian Fields." New York Times. 2007.
http://www.nytimes.com/2007/10/16/science/16obtoad.html?_r=1&oref=slogin

Stem Cells

2008-11-03T15:49:00.005-07:00

Stem cells are undifferentiated cells waiting on the signal in which it can eventually differentiate into whatever cell is needed by the body. Embryonic stem cells which are found in the blastocysts, and adult stem cells found in adult tissue have the potential of becoming many different cell types. In essence, they can replenish our worn out cells that keep us functioning properly.

Since stem cells can be manipulated to become specialized cells, stem cell therapies have already been use in the treatment of some conditions such as leukemia. Medical science will eventually try to use this advantage in treating other diseases such as cancer, spinal cord injuries, Parkinson's disease and much more. With such potential, many thought stem cells would be the next great discovery in disease treatment.

In an article released by Health Day News, Immune Response May Hinder Stem Cell Treatments, released in August of this year, researchers have found that human stem cells can trigger an immune response in mice. It was thought/suggested by researchers that the immune system must ignore stem cells since it is in the early stages of development and both the mother and father's genetic material are present at that stage. Injections of human embryonic stem cells into mice with a normal immune system showed that cells would die off over a period of time, whereas embryonic cells that are injected into mice with an impaired immune system would go on and multiply. Further injections into mice with the normal immune system showed cells dying off more quickly suggests that the immune system is recognizing the cells as foreign and destroying them more rapidly. The results in this experiment lead researchers to believe that this rejection can also occur in human transplation of embryonic stem cells. In addition, anti-rejection compounds injected into the mouse with the normal immune system show that the embryonic cells are able to survive for 28 days.

I too thought stem cells was an amazing application to medical treatments, but with these new findings, will it be much more complicated than what was though of stem cell use? Is the immunse system all that will need to be overcome for stem cells treatments to work effeciently?

References
http://en.wikipedia.org/wiki/Stem_cell
http://www.forbes.com/health/feeds/hscout/2008/08/18/hscout618460.html
http://www.nlm.nih.gov/medlineplus/news/fullstory_68274.html

2008-11-03T00:00:00.000-07:00

Knee OA has become a growing problem among elderly people. It causes pain and functional limitations due to articular inflammation and collagen degradation. And currently there are neither preventive intervention strategies nor effective medical remedies for the management of knee OA. Ergo…..

Tai chi is an ancient Chinese exercise that uses a mind-body approach to improve muscle function, balance, and flexibility. Studies indicating significant improvements in reduction of pain and other arthritic symptoms, have made tai chi a possible effective way for treating knee osteoarthritis. The physical components of tai chi include a range of motion, flexibility, muscle conditioning, and aerobic cardiovascular exercise. The essence of the mind component of tai chi increases psychological well-being, life satisfaction, and perceptions of health.

Because current evidence is still inconclusive about the favorable outcomes of tai chi, a group of researchers have formulated the single-blind study. This study was designed to further test the effectiveness of tai chi using 40 patients with knee OA, of 55+ years of age, and with a body mass index of less than 40 kg/m2. These patients participated in two hour long tai chi sessions that were conducted weekly for 12 weeks, which also involved a 24 and 48 week follow-up. The results were to compare changes in knee pain, stiffness, and physical function.

This study, which was recently conducted this year, was designed with long term follow-ups to truly test the effectiveness of tai chi on patients with knee OA. Therefore, any conclusive results have yet to be published.

Its indicative to note that the researchers took into consideration the significant gaps in research participation that exist among ethnic minorities, something that tends to limit the generalization of findings to a particular ethnic group. As a result, the researchers did some extensive advertisement of the single-blind study for five months to ensure the adequate enrollment of underrepresented groups.

Sources:
Tai Chi for treating knee osteoarthritis: Designing a long-term follow up randomized controlled trial. BioMed Central. Vol 9, 2008.

Some additional info and questions

2008-11-02T19:40:00.002-07:00

I was curious if anyone has com across information stating if RA or OA affects a certain ethnic group more than another such as IBD and Jewish people? I was also surfing the net and found some forms of alternative medicine on the Mayo Clinic website for RA. They suggest discussing them with your doctor first but the three that gave were plant oils containing gamma linolenic acid (GLA) a type of omega-6 fatty acid that comes from plant oils, such as evening primrose, borage and black currant, fish oil that contains eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) which are omegea-3 fatty acids commonly found in fish oil, and surprisingly enough Tai Chi which is movement therapy that involves gentle exercises and stretches combined with deep breathing.

Juvenile Rheumatoid Arthritis

2008-11-02T17:46:00.002-07:00

Hi all! I know there were quite a few inquiries about Arthritis in kids, so I did a little research. According to kidshealth.org nearly 300,000 children in the United States suffer from some sort of arthritis. The most prevalent form is Juvenile Rheumatoid Arthritis (JRA), also referred to as Juvenile Idiopathic Arthritis, since it is different than the adult form. One reason it is referred to as idiopathic is that it is unknown what causes it. It usually affects children as young as 6 months to 16 years old. The initial signs are pain, swelling, and reddened joints. It is also said that the more joints that are affected, the more severe the condition. There are 3 major types of JRA.

Oligoarticular JRA affects four or fewer joints. Along with pain, stiffness, and swelling of the joints, knees, and wrists, inflammation of the iris can occur. It can be detected early by an ophthalmologist.

Polyarticular Arthritis is a type that affects more girls than boys. It involves five or more joints. The pain and swelling occurs at small joints of the hands as well as the weight bearing joints like knees, hips, ankles, feet and neck. Usually a fever as well as bumps at pressure areas accompany.

Systemic JRA is the most severe of the three. It involves the whole body. A high fever appears, increases in the evening, and then may drop back to normal. A rash may appear as well as feeling very ill and looking very pale. The spleen and lymph nodes swell, followed by the stiffness, pain, and swelling of the joints.

Diagnosis occurs through tests like X-Rays, blood culture, bone marrow exam, as well as a bone scan. Lyme disease is also checked. Nonsteroidal Anti-inflammatory Drugs, such as Advil and Ibuprofen as well as physical therapy are used to treat the conditions.

Bee Venom Therapy and Rheumatoid Arthritis

2008-11-02T17:00:00.001-07:00

Apitherapy is the use of bee venom or honey in the prevention or treatment of various diseases and conditions, including rheumatoid arthritis (RA). Utilizing bee venom for therapy has been reported from ancient Chinese medicine. Bee venom therapy (BVT) is so widely used because if its anti-inflammatory properties but there are only a hand-full of studies to prove this. Honeybee venom contains mellitin, a powerful anti-inflammatory, which is said to be 100 times stronger then hydrocortisone. Mellitin stimulates the adrenal cortex to produce cortisol, thus reducing the immune response. Interestingly enough, cortisol is sometimes used in the treatment of RA.
Looking at blogs and various websites, I found testimonies from RA sufferers regarding BVT. Many patients turn to this naturopathic remedy after drug therapies proved not to work. To determine if bee venom works, one must visit a naturopathic doctor or an apitherapist. First, it must be determined if the patient is allergic to bee venom. If they aren’t allergic, the bee venom is administered as a shot or a sting from a live bee into trigger points. The therapy is continued daily for four to six weeks, depending on the severity of the disease.
Not only does bee venom have healing properties but honey does as well. It turns out that honey has anti-fungal and anti-microbial effects. It has been used in wound therapy, treatment of infection and treatment for serious skin conditions such as eczema and psoriasis. Scientists are unsure as to why honey has such beneficial outcomes.
The only concern regarding Apitherapy is allergic reaction. Administration of bee venom could possibly result in anaphylactic shock if one is not careful. Thus, speak with your doctor or a health professional before you go out and catch bees to use on areas of inflammation or infection!

Rheumatoid Arthritis(RA) and Psoriatic Arthritis(PsA)

2008-11-02T15:56:00.001-07:00

The two conditions are very similar. They both cause progressive joints damage, as a result of over active inflammation. The major difference is PsA causes psoriatic skin lesions. The experts are not sure why or where the connection is between the inflammatory responses that are responsible for joint pain and skin lesions. However, many individuals with PsA notice that when there psoriasis is worse there arthritis is worse. A stronger connection between the two diseases comes from one of this weeks articles entitled “ENHANCED AND COORDINATED IN VIVO EXPRESSION OF INFLAMMATORY CYTOKINES AND NITRIC OXIDE SYNTHASE BY CHONDROCYTES FROM PATIENTS WITH OSTEOARTHRITIS” which examined tissue from knee biopsies in patients with osteoarthritis, traumatic knee arthritis, RA, and PsA for the presents of certain inflammatory mediators. Their results showed “No significant difference was noted between RA and PsA in synovial and cartilage staining, suggesting that the final pathogenic mechanism is similar in the two inflammatory arthritides”

HIV and Hemophilia

2008-10-30T08:44:00.003-06:00

Since we talked about HIV/AIDS a couple weeks ago in class, I wanted to remind everyone about HIV infection of hemophilia patients in the 80's. Patients with hemophilia often require frequent transfusions of clotting factors to control bleeding. This plasma-derived factor is made from pooled factor from many blood donors, which greatly increased the risk of HIV contamination in the 80s, when HIV screening of blood donors was not in place (and for some time they didn't even know about HIV). HIV transmission has not occurred from factor products since 1986, when they started viral inactivating blood products.

Unfortunately, about half of the hemophilia patients in the late 1970s and early 1980s in the United States were infected with HIV via blood products, and many have developed AIDS. Currently, 10-15% of the hemophilia population is HIV positive.

I think there is an important lesson from this story-even though we believe the blood supply is safe, it is only safe with respect to the infections we know about and can/do test for.

Rheumatoid Arthritis

2008-10-27T15:03:00.000-06:00

Rheumatoid arthritis is an autoimmune disease that causes inflammation in the joints and it’s a type III response. There are many pain medications available for arthritis, because it is very painful and gets in the way of everyday life, since joints are used everyday in mobility. The way to determine if a patient has rheumatoid arthritis is by doing a blood test or x-rays, in which they search for rheumatoid factor. The treatments involve anti-inflammatory drugs. Based on the review articles it seems as though there are many factors that are involved, so there is a lot of research going into the causes of inflammation in the synovial area. There are also reactive oxygen species that play a part in the cause for inflammation, including O2¬¬-. Also, over expression of TNF-α reduces the activity of SOD, which is important in converting O2- into H2O2. Thus, as a treatment SOD mimetics are used to decrease peroxynitrite activity, influx of neutrophils at inflammatory site, and the release of proinflammatory cytokines. Researchers are also studies looking into supplements that can alleviate pain. However, it’s important to study the relationship between treatments and supplements, because they can affect each other.

When the immune system causes harm

2008-10-27T10:53:00.005-06:00

As I have mentioned in my previous posts I am interested in Hepatitis C. There are currently over 170 million people infected with this virus worldwide. The long-term complication of Hepatitis C are cirrhosis and hepatocellular carcinoma. These complications often lead to liver transplant in the Hepatitis C patient.

As we learn more about HepatitisC and the immune response that is raised in attempts to clear the infection it becomes more clear that the inflammation intended to wipe out the virus is harming the liver and leading to cirrhosis and likely hepatocellular carcinoma.

Following viral infection there is activation of several pre-inflammatory mediators (chemokines -cytokines) that recruit immune cells into the liver. Once in the liver the immune cells are induced to generate an anti-viral immune response (T helper 1 cells secrete IFN-gamma and IL-2). If in the short-term the infection is not cleared the liver is set-up for a chronic inflammatory response (inflammation, regeneration and fibrosis). There is increasing evidence that different chemokines and receptors play roles at different stages in the infection.

Identification of serum markers for this inflammatory chemokine activity could help stage the chronic Hepatitis C viral process. Staging would assist with treatment options. Additionally, identification of an antagonist for this interaction would provide a treatment for liver inflammation, but would allow the virus to persist. Decreasing inflammation would potentially decrease cirrhosis and carcinoma. The concern is the cost of chronic Hepatitis C infection without the inflammation to hold it at bay.

There continue to be many unanswered questions for Hepatitis C, however the pieces of the puzzle continue to grow and fit into an explanation.

Reference -

Zeremski M, et al. The role of chemokines as inflammatory mediators in chronic hepatitis C virus infection. J Viral Hepat. 2007; 14(10): 675-87

Wald, O., et al. Chemokines in hepatitis C virus infection: pathogenesis, prognosis and therapeutics. Cytokine. 2007; 39(1): 50-62

DMARDS

2008-10-27T09:53:00.004-06:00

Hi everyone! As you may have seen after reading the articles this week on arthritis there is no cure. But there are treatments that help with the symptoms. There was one that was mentioned but not really discussed and that was DMARD. The acronym was thrown out there, but not really explained. So DMARD stands for Disease-modifying antirheumatic drug. This is a family of drugs that are used to slow the progression of rheumatoid arthritis. Although RA was the disease it was propagated for, many other diseases have had a response to them. Interestingly enough, Crohn's Disease is included in this list along with lupus. Ulcerative Colitis was not included though.

DMARDS include a vast array of drugs used for different purposes. There are thirteen drugs, which are used by different mechanisms. There were three that really caught my eye and they were adalimumab, etanercept, and infliximab. The three of these drugs treat RA by TNF inhibitor. Tumor Necrosis Factor (TNF) is thought to be a major contributor to RA for TNF alpha causes both cell damage and inhibits superoxide dismutases in the cell (SOD1). TNF inhibitors eliminate abnormal B cell activity which cause the apoptosis trigger by TNF alpha.
For more information on DMARDs:

http://www.webmd.com/rheumatoid-arthritis/guide/dmard-rheumatoid-arthritis-treatment

SOD memetics showing promise as future treatment for inflammatory joint disease

2008-10-26T22:20:00.003-06:00

In a disease such as RA where proinflamitory cytokines like TNF-a are being over produced and reactive oxygen species are overwhelming the bodies natural enzymatic defenses. The use of superoxide dismutase mimetic to supplement the bodies natural defense is showing promises as a possible addition to future therapeutic strategies for fighting inflammatory joint disease. Along with the article entitled “reactive oxygen species and superoxide dismutase: Role in joint diseases” I also learned of a study by a Italian pharmaceutical company which reported 56% reduction in inflammation and 70% decrease in joint erosion in arthritic rats. Both studies used the same SOD mimetic M40403. These reports appear very promising but there still needs to be more testing before human trials can start.

Optimal Timing for Surgery

2008-10-26T15:04:00.002-06:00

Within the article titled, "Optimal Timing of Surgery for Inflammatory Bowel Disease," it discusses how necessary surgery is when compared to having ulcerative colitis and Crohn's disease. Only 20% of people diagnosed with ulcerative colitis are required to have surgery at one point of their illness, while 80% of the patients with Crohn's disease are obliged to have surgery. For patients with ulcerative colitis, after surgery they are permanently cured. The surgery many surgeons suggest their patients get is total proctocolectomy because other surgeries such as partial proctocolectomy, ileoanal pouch anastomosis, and permanent stoma will not permanently cure them from UC. Thus, many surgeons it is better to perform surgery at an early stage of UC. As of today, there is no surgery that can sure Crohn's disease, but it can be to treat symptoms when the patient is not responding to medical treatment. Even then, about 20% of the patients have reoccurring symptoms after 2 years and 80% of them will show signs of symptoms again after 20 years. The surgeons have seen that if the surgery is for lessening the effects of fibrostenotic disease and not perforating or fistulizing disease there will be less frequency in how many times the symptoms reoccur. Overall, deciding when to have surgery must be a thoroughly thought-out decision for both the surgeon and the patient. Most of the time, by delaying the time of surgery can tremendously increase the suffering and pain the patient experiences and reduce the chances of having a good outcome. In contrast, while delaying other medications could continue to improve the situation and eventually eliminate the need for surgery. In addition, if during the delay time the symptoms such as infections could be reduced and as a result lessening the risk of morbidity.
In a study done in England, it showed that the rate of mortality for patients who received surgery compared to ones who had not elected for surgery in either ulcerative colitis or Crohn's disease patients lived longer. Three years after surgery only 3.7% of patients with UC died after having surgery while the mortality for patients without surgery was 13.6%. Same with Crohn's disease patients, it increased significantly from patients that had surgery to patients who had not, 3.3% and 10.1% respectively. On the other hand, patients who had a emergency colectomy versus patients who elected themselves for the surgery had higher mortality rates. The study was done in the Oxford region with 23,464 patients from 1968 until 1996.

Sources:

"Threshold for Elective Colectomy Called Too High." Medical News.

Hodin R.S. "Optimal Timing of Surgery for Inflammatory Bowel Disease." SpringerLink.

Helminths and IBD

2008-10-25T13:11:00.003-06:00

While we had a short ley article dealing with the use of helminths as a treatment for IBD, I thought it would be interesting to investigate their use further. Although usually the ingestion of worms would seem counterintuitive to treating disease, the helminth Trichuis suis has been found to be effective in relieving the symptoms of both Crohn's Disease and Ulcerative Colitis.

Unraveling the mechanism of disease for IBD has been difficult, however many studies have come to show the various biological systems which manifest these diseases. It has been found that CD is mostly a Th1 dominated immune response compared to UC. The idea behind the use of helminths is to steer the immune system from a Th1 to a Th2 mediated response. By doing this, it is possible to down regulate the Th1 response which is causing damage to the intestinal walls.

The study Trichuris suis Seems to Be Safe and Possibly Effective in the Treatment of Inflammatory Bowel Disease found the use of helminths to be beneficial in both CD and UC patients. In the study, after one treatment participants were found to have gone in to remission or had drastically lowered their CDAI or SCCAI scores. The study did show that with only one treatment, many experienced a flare up after 12 weeks, however if the treatment is repeated every 3 weeks the beneficial effects may be more lasting. One patient managed to remain in remission for over a year when treated regularly.

It seems that helminths may end up being an effective treatment for IBD, and some suggest that it may even provide a method for immunization. The link between sanitation and IBD prevalance may have to do with helminth contamination in water. Using this link, it may be possible to treat children with helminths in order to "teach" the body an appropriate immune response in order to prevent the autoimmune issues that are found in IBD.

Sources:
Trichuris suis Seems to Be Safe and Possibly Effective in the Treatment of Inflammatory Bowel Disease
Robert W. Summers, M.D., David E. Elliott, M.D., Ph.D., Khurram Qadir, M.D., Joseph F. Urban, Jr., Ph.D., Robin Thompson, M.H.A., and Joel V. Weinstock, M.D.
Department of Internal Medicine, James A. Clifton Center for Digestive Diseases, University of Iowa Health Care, Iowa City, Iowa; and The Immunology & Disease Resistance Laboratory, United States Department of Agriculture, Beltsville, Maryland

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 98, No. 9, 2003
© 2003 by Am. Coll. of Gastroenterology ISSN 0002-9270/03/$30.00
Published by Elsevier Inc. doi:10.1016/S0002-9270(03)00623-3

Diminished HIV awareness

2008-10-24T10:57:00.003-06:00

After our discussion of HIV in Tuesdays class and Dr. Cohen's comment about the younger generations lack of HIV awareness I found an article that proves his point. Recently a high school in suburban Missouri had a HIV scare. Accourding to health officals 50 out of the 1300 student population were potentially exposed to HIV. One student came forward to health officals saying he had HIV and other students may have been exposed. Students may have been exposed through sexual activity, intravenous drug use, tattoos and piercings.

One has to wonder if this would have occured if awareness of risky behaviors and HIV tranmission was higher. As Dr. Cohen stated, it seems as though the younger generation has less knowledge about HIV then in the 90's. This article also shows how little the general population knows about HIV. For example, a rival football team was concerned about playing the high school where the exposures occured and many students want to transfer out of the district.

This article shows how important education about HIV and risky behaviors is still needed.

http://www.comcast.net/articles/news-national/20081024/High.School.HIV/

Diagnosing IBD

2008-10-21T20:01:00.004-06:00

I know it was a mentioned a couple times that Crohn's disease and ulcerative colitis have very similar symptoms, and that some doctors actually think they are the same disease. So it occurred to me that it might be difficult to differentiate the two during diagnosis. As everyone knows now from the papers we read the past two weeks, it is important to tell the difference between the two. Treatments for each of the diseases is different and the treatment for one can actually cause the other to flare up. So I did some research on how IBD is diagnosed in patients.

I found out that it isn't easy to definitively diagnose CD or UC. Sometimes they have to eliminate everything else including irritable bowel syndrome (IBS), bacterial, and viral infection. Physician's usually use a complete blood count (CBC), liver function tests, stool samples and an endoscopy or colonoscopy. The colonoscopy or endoscopy is usually the most diagnostic of all the tests. The infected areas of a Crohn's disease is patchy and can have a cobble stone appearance. The lesions can also be go deep into the intestinal lining. In ulcerative colitis the mucosa and sub mucosa layers of the intestinal wall.

References:

http://health.ucsd.edu/specialties/gastro/inflammatory-bowel-disease/diagnosis.htm

http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/gastro/inflammatory_bowel/inflammatory_bowel.htm

A short interview with a patient suffering from Crohn's disease

2008-10-20T14:41:00.001-06:00

So one of the guys I work with was diagnosed with Crohn's disease and after the articles last Monday I was curious about how his smoking affected him before and after being diagnosed. I asked him a series of questions ranging from smoking to symptoms to his treatment. This is what he told me.
During the hardest times of my disease i.e. during the large flare-up, my liver decreased about 40-50 percent functionality (lack of retaining vitamins, minerals, and nutrients). I did not have surgery; surgery is for the people that cannot control their flare-ups. I quit smoking, but the cessation of my smoking is what caused my Crohn's to flare-up out of nowhere. Since I smoked for quite a long time, they say that the reason the disease was dormant was because i smoked; that created a protective jelly film around my colon, which made it impossible for the white blood cells to attack. My symptoms during flare ups are: Blood in my feces, dizziness, lots of sweating, and many terrible cramp-like stomach aches. During remission, I have a few stomach aches, but nothing more.. maybe a bad poop every once in a while. Right now, I am taking immunosupressive drugs, i.e. 150mg azathioprine daily and a drug infusion called Remicade once every six weeks.

I plan on asking him a few further questions in regards to his diet and other things.

Diet Therapy in Crohn's Disease

2008-10-19T19:46:00.006-06:00

When discussing general nutritional therapy, there are two primary forms used in medical practice, enteral and parenteral nutrition. Enteral nutrition, often referred to as tube feeding, allows for feeding into the GIT through a tube inserted nasally and fed into the stomach or small intestine. For long term usage, tubes can be surgically inserted into the stomach or small intestine through an opening made in the abdomen. Parenteral nutrition is the practice of feeding a person intravenously, and it completely bypasses the use of the stomach or intestines.

In terms of Crohn's disease, enteral nutrition is more often used as primary nutritional therapy. Parenteral nutrition is used in special cases or those of a higher severity. The overall goal for the use of diet therapy in Crohns is to correct any nutritional disturbances present and to help control the inflammatory response occurring. Remission rates of patients placed on enteral nutrition range from 53% to 80%; therefore, a direct anti-inflammatory effect of enteral nutrition in Crohn's disease is generally accepted. In one particular study, a decrease in the level of proinflammatory cytokines IL-1, IL-8, and IFN-gamma was observed in patients being treated through enteral nutrition. However, the direct mechanism of action for these observed anti-inflammatory effects is still not known.

Two mechanisms are currently proposed for the therapeutic efficacy of enteral nutrition in Crohns. The first mechanism is that the bowel rest allowed by the enteral feeding results in alteration of the intestinal flora and elimination/reduction of antigens. The second mechanism is that improvement in nutritional status by increase in nutrient intake and absorption aids in the induction of remission and reduction in intestinal protein loss.

Enteral nutrition usually has low compliance among adult Crohn's disease patients. Many find tube-feeding to be inconvenient, and a higher percentage of patients are more responsive to other medical treatments. Often enteral nutrition is seen as an effective adjuvant treatment in many cases. Enteral nutrition is far more widely used in the treatment of children with Crohns, and is often necessary to ensure proper nutrition and growth status.

Parenteral nutrition is used in cases of more severe disease when total bowel rest is a recommendation. It is also used in cases where patients have a poor tolerance to enteral nutrition; however, it is never recommended as a sole therapy in Crohn's disease.

Reference:
Moorthy D. Cappellano KL. Rosenberg IH. Nutrition and Crohn's disease: an update of print and web-based guidance. Nutrition Reviews. 2008; 66(7): 387-397.

Symptoms of Crohn's Disease

2008-10-17T20:10:00.003-06:00

I know that some of the articles this week pointed out the general symptoms that persons with Crohn's disease or ulcerative colitis have such as abdominal pain, vomiting, diarrhea, and hematochezia. I wanted to know more of the details on the symptoms people with Crohn's disease possess and the severity of them.

People with Crohn's disease will have diarrhea but the kind of diarrhea they will experience depends on the location that is involved, whether it be in the small intestines or colon will cause them to have large-volume watery feces or small volume but of high frequency. Many people have more than 20 bowel movements a day. There is less visible bleeding in Crohn's disease than ulcerative colitis. They may also experience primary sclerosing cholangitis which is where the bile ducts are inflamed as well, and this can lead to liver failure. Other symptoms that may be involved in Crohn's disease are aphthous ulcers affecting the mouth and will cause difficulty in swallowing.

Crohn's disease is a chronic inflammatory disease that can cause growth failure in children as well as retardation of growth. In addition, due to all the unpleasant symptoms many people experience weight loss because they either lose their appetite or do not eat. Also if their small intestine disease is severe, weight loss can be caused my malabsorption of lipids or carbohydrates.

This disease has been known to affect other organ systems such as the eye, joints, blood, endocrine system, and skin. People with Crohn's disease may experience inflammation of the eye that cause eye pain and if not treated loss of vision. Many people with Crohn's disease have inflammation of the joints and some have reported arthritis in the spine. The skin can develop skin lesions such as red nodules and pyoderma gangrenosum. There is an increased risk of obtaining blood clots as well as developing a condition where the immune system ends up attacking the red blood cells called autoimmune hemolytic anemia. Other potential symptoms are difficulty breathing, deformity of the ends of fingers, and osteoporosis.

Additionally, Crohn's disease has been reported to have an affect on the nervous system which some of the symptoms include: stroke, depression, headache, seizures, and myopathy. Furthermore, there is a large increase risk of getting cancer in the inflamed areas of the small intestines and/or colon.

After learning about all of the complications and symptoms someone with Crohn's disease has a tremendous risk of obtaining, I was amazed by all the different parts of the body that can be effected by one disease. The vast amount of different systemic and extraintestinal symptoms that Crohn's disease can cause a person to have is overwhelming. I do not feel that the articles this week went into as much depth in discussing the symptoms as they should have.

Sources:
http://www.ccfa.org/info/about/crohns
http://www.aolhealth.com/conditions/crohns-disease-major-1/symptoms

Treatments for IBD

2008-10-15T23:24:00.003-06:00

One of the things I felt none of our articles really touched upon are the many different treatments for IBD. Since Crohn's Disease and Ulcerative Colitis manifest in different ways, there are also different treatments for each disease.

For Crohn's disease, treatments include medications such as mesalamine, corticosteroids, antibiotics and immunsuppresive drugs. Mesalamine and corticosteroids are primarily used to control the inflammation, relieving the symptoms of Crohn's disease. Antibiotics are used most often after surgery, such as an ileum resection, in order to prevent flare ups caused by introduced bacteria. Immunosuppresives are used to block the inflammation, however they have side effects including nausea, vomiting, liver problems and may cause inflammation in the pancreas, which can cause additional problems. A more recent drug therapy is the use of infliximab. Infliximab is an antibody which blocks TNF (tumor necrosis factor) which is one of the primary causes of inflammation in Crohn's disease. Finally, surgery can also be used to treat Crohn's disease when pharmaceuticals fail to control the symptoms, however this only relieves symptoms for a short time.

In Ulcerative Colitis, immunosuppresants and anti-inflammatory drugs are also used, for the same reasons as previously stated for Crohn's disease. The drug Infliximab is also approved for treatment in UC for its ability to block TNF. Often times infliximabs side effects out weigh its benefits for UC patients, as it may cause increased risk for cancer as well as susceptibility to disease such as tuberculosis. Since UC is limited to the colon, many patients undergo laproscopic surgery to remove the troublesome areas. Unlike in Crohn's disease, removal of the colon completely cures the disease.

References:

Mayo Clinic Diseases & Treatments, 2008

Smoking and IBD

2008-10-13T13:18:00.002-06:00

The effects of smoking on IBD are especially interesting because of the dual effects it has on the two manifestations of IBD, ulcerative colitis and Crohn's disease. In ulcerative colitis, smoking actually alleviates the symptoms in patients. However, in Crohn's disease smoking makes the symptoms worse.

Not only does smoking effect the course of the disease, it also effects the initial risk of suffering from the disease. Smokers are less likely to get ulcerative colitis, but interestingly former smokers have an increased risk of getting ulcerative colitis when compared to people who never smoked. Smokers were also less likely to have severe symptoms, and require surgery. On the other hand people who suffered from Crohn's disease and smoked were more likely to have a progressive form of the disease. I thought it was interesting that some Crohn's disease patients who quit smoking developed lesions that are typically seen in ulcerative colitis.

The conflicting effects made me wonder if it would be better to keep smoking if you had ulcerative colitis. It seems to be a good treatment, but you also have to consider the risks of smoking itself. Smoking can cause lung cancer, increases the risk of cardiovascular disease, and increases inflammation throughout the body. I thought maybe there was a way of isolating the beneficial effects of cigarettes without being exposed to the detrimental effects at the same time.

While reading the articles I assumed that the beneficial effects were due to the nicotine in the cigarettes and I wanted to know if using a nicotine patch was just as effective as cigarettes. I did some searching, and I found out there have been a few studies that used the transdermal nicotine patches to treat mild to moderate ulcerative colitis. The treatment was fairly successful, and when used with the conventional therapies it is even more successful.

So overall, it would be a good idea that anyone with IBD should quit smoking. Although it seems like smoking is a good way to treat ulcerative colitis, in the end it isn't worth the other risks smoking carries with it. Especially when nicotine patches are almost as effective as smoking itself.

References:

Pullan RD, Rhodes J, Ganesh S, et al. Transdermal nicotine for active ulcerative colitis. N Engl J Med. 1994;330:811-815.

Sandborn WJ, Tremaine WJ, Offord KP, et al. Transdermal nicotine for mildly to moderately active ulcerative colitis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1997;126:364-371.

IBD references

2008-10-12T21:58:00.001-06:00

Sorry! Didn't mean to plagarize...

http://www.ncbi.nlm.nih.gov/pubmed/8596552

http://digestive.niddk.nih.gov/ddiseases/pubs/crohns/

http://www.ccfa.org/

Inflammatory Bowel Disease: Crohn's and Colitis

2008-10-12T21:09:00.002-06:00

Hi all:

I hope for this post to provide some introductory information about Inflammatory Bowel Disease (of which the two major diagnosed disease states are Crohn's Disease and Ulcerative Colitis) and to touch on some potential discussion topics for the next couple weeks. IBD is of particular interest to me because my younger brother was diagnosed with Crohn's Disease six years ago, so I've seen the dramatic difference between a Crohn's flare up and remission.

IBD is commonly described as an autoimmune disorder, since it is speculated that the inflammation cascades and resulting symptoms are the result of an immune system response to the constituent bacterial flora in the human body. This bacterial makeup is important in proper nutrition and absorption, but in the IBD disease states the bacteria are recognized as foreign and treated as pathogens. Since the body cannot afford to lose this bacteria, the inflammation state is persistent. This leads to the clinical expressions of Crohn's and Colitis.

Crohn's and ulcerative colitis differ diagnostically, as they are manifested in different locations and with different tissues affected. Crohn's can affect any portion of the GI tract (from mouth to anus), and is an inflammatory response associated with multiple layers of the intestinal wall. Colitis is an inflammatory response isolated to the mucosa, and is contained to the colon and rectum.

Symptomatically, Crohn's Disease can vary widely (since the inflammation can occur at any point along the GI tract), but since most cases arise in the ileum, some common symptoms can be considered 'red flags' for diagnosis, such as sudden unexplained weight loss, diarrhea, abdominal pain, and bleeding. As Crohn's Disease involves a number of inflammatory mediators, it is also common to have arthritis, skin problems, persistent fever and anemia. Crohn's Disease frequently leads to nutritional absorption problems, so a whole series of complications are common, including osteopenia (precursor osteoperosis), stunted growth, early age low bone density, postural problems, and a decreased appetite.

Symptoms of ulcerative colitis tend to be more consistent, including sharp abdominal pain, weight loss, bloody or mucousy discharge and diarrhea. Many of the same secondary symptoms associated with malabsorption and systemic inflammation seen in Crohn's are seen in Colitis, which can make diagnosis and therapy difficult.

Both diseases are commonly diagnosed by endoscopy, as there are characteristic patterns of ulcer formation and inflammation for each disease state. But again, since the symptoms can be fairly common and indicative of more common problems, it sometimes can take awhile for an accurate diagnosis of Crohn's or Colitis. This makes the current genetic work particularly important.

In class I hope to discuss the current proposed models of inflammatory cascades that are expressed in IBD, the current genetic research aimed at locating a possible single IBD gene, the effects of smoking on the supression of Colitis/simultaneous increase in Crohn's activity (something that's REALLY interesting), and the relationship between intestinal bacteria and immune system development. Let me know if you have any other areas of interest that you'd like us to look into.

Stroke, Inflammation and Traumatic Brain Injury:

2008-10-09T16:52:00.000-06:00

While investigating the role of inflammation and its associations with stroke and delayed damage, I came across a couple of interesting articles that connect stroke and traumatic brain injury (TBI). By now we are all very familiar with the inflammatory response and various cytokines and cells associated with ischemic stroke. What may not be as clear, however, are the similarities between inflammation-mediated stroke reperfusion injury and other common causes of brain trauma.

TBI is commonly associated with high mortality and permanent neural deficits. In both the United States and Europe, TBI is the leading cause of death for individuals under the age of 45 and stroke is the second most common cause of death worldwide. Although traumatic tissue damage and ischemia have different causes, it has been shown that they are connected through the inflammatory pathway. Both TBI and stroke patients commonly suffer from delayed damage, mediated by the inflammatory response. Interestingly, in both cases, delayed damage often results in greater damage than that caused by the primary injury.

Besides direct mechanical injury, TBI leads to swelling of the brain due to local cellular edema. This increases the pressure on the cerebral microcirculatory vessels, which can cause ischemia (as seen with stroke). Often the blood-brain barrier is also broken down, which can lead to further swelling, hypoxia, and exacerbation of the problem. As with stroke, TBI causes up-regulation of cytokines, such as TNF, accumulation of leukocytes and macrophages, and increased expression of adhesion molecules.

This information clearly points out the need for further research regarding the inflammatory response in the brain. Whether it caused by transient ischemia or traumatic, mechanical force, the extent of many brain injuries has the potential to be greatly decreased through furthering our understanding of the delayed damage mechanism.

Finally, I think it is important to realize that post-insult inflammatory damage is not exclusive to stroke. The same inflammatory cells and mediators present in the ischemic brain can also be activated by other means and facilitate further tissue damage. I’m wondering if the connection between minor concussion (often seen in football) and any resulting inflammation related damage has been given much scrutiny. It would be interesting to determine exactly what portion of damage, resulting from minor concussion, is the result of delayed onset mechanisms.

References:

Andrews, Peter, and Rhodes, Jonathan. "The brain as a site of inflammation after acute injury". Blackwell, 2006. Pg: 275-276.

Feuerstein, Giora. “Inflammation and Stroke". Birkhauser, 2001. Pg: 181-186.

Overview of medical therapy in IBD

2008-10-08T22:49:00.012-06:00

Hi Everyone!

Pat will be providing an overview of Inflammatory Bowel Disease, mainly focusing on Crohn's Disease (CD) and Ulcerative Colitis (UC). To go along with this, I wanted to provide an overview of the current treatments used in IBD, as this is not something we will directly review in our articles.

The overall goal of treatment in IBD is to stop the abnormal inflammatory response that is responsible for the symptoms, and aid in the induction and maintenance of remission. There is debate as to the approach taken in medical therapy. Some feel it better to start with less aggressive medications and work up the line to achieve the optimal medication for the individual patient. Others feel that starting with more aggressive medications at onset of disease may help to prevent irreversible bowel injury and lead to a better long-term outcome. However, I simply would like to give you an overview of the available medications. As we learn more about this disease over the next few weeks, the door is obviously wide open for debates on treatment approaches.

Aminosalicylates

Aminosalicylates are aspirin-like medications that contain 5-aminosalicylic acid (5-ASA), a potent anti-inflammatory agent. 5-ASA agents likely have multiple anti-inflammatory effects including inhibition of cyclooxygenase, lipoxygenase, B-cells and multiple inflammatory cytokines. These agents are usually used to treat mild to moderate symptoms, and are availiable in both oral and topical forms. More solid data exists for the use of 5-ASA agents in the effective treatment of UC than in CD. Their efficacy of treatment for CD is much less clear, and often is determined by the location of the disease in the GIT.

Antibiotics

Antibiotics such as Metronidazole and Ciprofloxacin are sometimes used to treat mild to moderate symptoms of CD; however, the evidence to support their mechanism of action is limited. Antibiotics are deemed more appropriate for treatment of perianal disease and fistulas in CD because of the risk for septic complications. In contrast, antibiotics are rarely used in the treatment of active UC.

Corticosteroids

These steroids act in our body by binding to glucocorticoid receptors in many of our different cell types and activating glucocorticoid-responsive elements (GREs). This leads to a wide array of effects on the immune system including inhibition of the recruitment and proliferation of lymphocytes and monocytes and a decreased production of inflammatory mediators (cytokines, prostaglandins, etc). Corticosteroids are effective for inducing remission in CD and UC; however, long term use to maintain remission is not recommended due to their numerous side effects. One particular steroid, budesonide, is a non-systemic acting glucocorticoid that may be used for the maintenance of remission. However, proper dosing schedules or amounts have yet to be determined.

Immunomodulators

Two immunomodulators currently used in the treatment of CD and UC are 6-Mercaptopurine and Azathioprine. The metabolites of these medications interfere with nucleic acid synthesis, and they have anti-proliferative effects on activated lymphocytes. Often immunomodulators are used when the disease is moderate to severe or when a patient is unresponsive to other drug treatments (5-ASAs or steroids). These medications are effective in both induction and maintenance of remission; however, their onset of action is typically 3-4 months, so other medications must be coupled with these initially.

Methotrexate (MTX) is another immunomodulator primarily used in treatment for CD. It acts as a competitive inhibitor or dihydrofolate reductase, one of the key enzymes necessary for folate production. As a result, MTX interferes with DNA synthesis and has multiple anti-inflammatory effects as it works as an immunosuppresant.

Since all of these immunomodulators interfere with the immune system, patients are at an increased risk of infection and must have their white blood cell counts monitored.

Biologic Agents

These agents are a group of medications that act in a variety of ways to inhibit TNF-alpha. TNF-alpha is a cytokine that mediates multiple pro-inflammatory processes central to the pathogenesis of IBD. Two common biologic agents used in treatment of IBD are infliximab and adalimumab. Infliximab is an intravenous infusion whereas adalimumab is administered subcutaneously. Indications for the usage of these therapies include both the induction and maintenance of remission for patients with moderate to severe disease. These biologic agents have also proved very useful in the treatment of fistulas and extra intestinal manifestations in CD.

Ok, well I figure this will at least give everyone some good introductory information on medical therapy in IBD. I by no means presented everything about the medical treatment, and just like in many other situations, treatment must be individualized to the patient.

References

Kozuch PL, Hanauer SB. Treatment of inflammatory bowel disease: A review of medical therapy. World J Gastroenterol 2008; 14(3):354-377.

Cummings JR, Keshav S, Travis SP. Medical management of Crohn's disease. BMJ 2008; 336:1062-6.

World Stroke Day 2008 and More

2008-10-07T15:03:00.003-06:00

I found out that world stroke day is on Oct. 29 and the theme is "Little Strokes, Big Trouble" and the 6th World Congress of Stroke was held in Vienna on September 24 to 27, 2008.
Here is the Website:

http://stroke.ahajournals.org/cgi/content/full/39/9/2407

In class the other day someone asked about ischemic vs. hemorrhagic stroke and their occurrence, the American Stroke Association says that ischemic accounts for 83% of all strokes and hemorrhagic the other 17%.

Also we discussed possible treatments for hemorrhagic strokes and i looked on the Mayo Clinic Website and found out that the treatment depends on the cause and severity of the hemorrage. Medication treatments can range from blood pressure lowering meds to coagulants to just pain releivers to releive the symptoms. Also they talk about medications to prevent possible seizures. They also discuss different surgeries to treat the different types of hemorrhagic strokes such as for aneurysm, arteriovenous malformations, and general. These range from clamping the vessel to removal of hematoma to catheters through the vessel. One of the treatments for AVM really was interesting it was called coil embolization and invloved inserting a catheter through the leg and threading through the body to the brain. Then it coils around the affected AVM and a glue is injected to block the vessel. I found this article very helpful:

http://www.mayoclinic.org/stroke/hemorrhagic-stroke.html

Still while looking for treatments for hemorrhaic stroke i didn't find much on how to immediatily reduce damage except by having the person be monitored for damage just from the symptoms or having them lie down to reduce blood flow to the area. I would really like to know if anyone found anything else or it that all one can do?

We also discussed fucoidin and i found this post from last semester on it posted by dan k that i though was interesting thanks dan k. He talks about where fucoidin is found and a study that was done by Japanese scientists that showed it caused apoptosis is lymphoma cells.

http://inflammablog.blogspot.com/search?q=fucoidin

New and On-going Targeted Therapies for Breast Cancer.

2008-10-07T07:24:00.001-06:00

With breast cancer awareness month going on, I thought it would be appropriate to blog about the newest and on-going targeted therapies (mainly monoclonal antibody therapy) happening, as breast cancer is the most commonly diagnosed malignancy among women.

One of the biggest developments in breast cancer therapy to date is the use of the drug trastuzumab (Herceptin), which directly attacks the protein HER2 (human epidermal growth factor receptor). HER2 is the protein that aggressively promotes tumor growth in malignant breast cancer. Herceptin is a human monoclonal antibody which binds extracellularly to the HER2 protein to promote cell death (apoptosis). This will subsequently inhibit the proliferation of HER2 dependent tumors. This is extremely helpful, as more than 20 percent of breast cancer tumors overproduce this certain protein.

This is not the only type of therapy being done today to target this certain type of protein. Other monoclonal antibody-based therapies include another drug called pertuzumab. This certain type of antibody will bind to different sites of the cancer cells preventing proliferation of the tumor. This drug has been shown to be quite effective when used with trastuzumab to fight against the cancer cell lines that are resistant to trastuzumab. It has shown much success with the over-production of the HER2 protein.

Another type of targeted therapy, not using an antibody, is the use of a tyrosine kinase inhibitor. For the HER2 protein to activate tumor cell proliferation it has to be acted upon by a certain enzyme; this case being tyrosine kinase. This certain type of enzyme will act as a growth stimulating factor subsequently activating proliferation of the tumor cells. So by inhibiting the tyrosine kinase enzyme, you can stop the tumor from proliferating. A drug called Lapatinib is currently being clinically tested. It has shown much success in inhibiting the tyrosine kinase enzyme and causing growth arrest as well as cell suicide. Again, certain cell lines of breast cancer can become resistant to the drug trastuzumab, and combining the drug with Lapatinib will increase the effectiveness of trastuzumab.

The last type of therapy that I wanted to talk about is actually one of the newest therapies being worked on. It has been shown that high levels of IGF-1 (insulin-like growth factor) can increase the risk for breast cancer. The IGF-1 receptor is responsible for numerous cellular processes including proliferation and protection from apoptosis. Basically it keeps tumor cells alive and metastasizing. Current research is showing that using an antibody that could potentially block the IGF-1 receptor could help the effectiveness of trastuzumab, and stop tumor growth.

The importance of advancing these therapies becomes evident as more breast cancer cell lines are developing resistance to the drug trastuzumab, which has been around for a couple of decades. As more and more research is being done, and more targeted therapies are being developed, the survival rates for breast cancer patients are rising; yet this is just the beginning for breast cancer therapy.

Difference in Global Mortality in the Influenza Pandemic of 1968-1969

2008-10-05T12:26:00.001-06:00

This week in IMMU 7630, we’ll be talking about flu pandemics. To preview/review, influenza viral particles have surface proteins called neuraminidases and hemagglutinins. There are 9 known neuraminidases (called N1, N2, etc.) and 16 known hemagglutinins (H1, H2, etc.). Viruses are named for the neuraminidases and hemagglutinins on their surface (H1N1, H3N2, H5N1, etc.). Pandemics occur when a known flu virus, such as the H1N1 virus, reasserts with an unknown flu virus (often a wild bird flu), such as H2N2. The new virus is an H2N2 and not related to the H1N1 strain. Humans have no pre-existing immunity to this new virus, and this can cause a pandemic or epidemic.

One example of this was the 1957/58 Asian flu virus which originated in China. It occurred when 3 genes from wild duck flu virus reasserted with five genes for circulating human strain (it was an H2N2 viruThe death rate was highest in the elderly (those 65 or older).

In 1968/69, there was a new pandemic, caused by the “Hong Kong Flu”. It was an H3N2, occurring when two genes from a wild duck flu virus reasserted with the six genes from the circulating H2N2 virus. Although there were ~1-4 million deaths worldwide, there were substantially less deaths in the US than in 1957/58 pandemic (~34,000).

The impact of this pandemic in different countries, by different age groups was looked at by C. Viboud et al (http://www.journals.uchicago.edu/doi/pdf/10.1086/431150?cookieSet=1). This pandemic had two seasons – 1969/68 and 1969/70. Interestingly, the mortality rates by country differed for these two seasons. The authors examined excess deaths from influenza and also looked at the proportion of excess pneumonia and influenza mortality (P&I mortality) in The United States, Canada, Japan, England, Australia, and France.

For each country, the authors examined the proportion of excess pneumonia and influenza mortality (P&I mortality) in persons <65 years of age. They found that this P&I mortality increased 2.2-4.6 fold during the first H3N2 pandemic season, as compared to the last H2N2 season. This “age-shift” is often characteristic of pandemics, indicating that a new virus form is circulating that a large proportion of the population has not been exposed to.

It has actually been speculated that during the 1968/69 pandemic, older people might have actually had some pre-existing immunity to the H3N2 virus from the 1957/58 virus. There was only a shift in the hemagglutinin; the neuraminidase remained the same. Many people might have had antibodies and memory T-cells to the H2N2, and they might have cross-reacted with the H3N2 virus. Unfortunately, this paper did not look at smaller age groups to try to discern this.

The remainder of the paper was spent focusing on the geographic differences in the pandemic. In the United States and Canada, the majority of the excess deaths from influenza occurred in the first year of the pandemic (70% and 54%, respectively), while in Japan, England, Australia, and France, the percentage of total excess deaths in the first year were much smaller (32%, 23%, 22%, and 15% respectively). The pandemic seemed to affect the North American continent quickly in the first year, while Europe, Asia, and Australia had more deaths from the flu the second year. This phenomenon is referred to as a “smoldering” pandemic.

This difference in pandemic is probably caused because in North America and Canada, people had very little pre-existing immunity to either the neuraminidase or hemagglutinin gene; thus, many of them got sick the first year. In contrast, people in Europe, Asia, and Australia would have had high pre-existing immunity. Phylogenetic analyses of the neuraminidase gene did show that there was genetic drift during this time period; that is, there are two genetically distinct gene clusters for the N2 gene, one in 1968/69 and the other in 69/70.

This led the authors to hypothesize that people in Europe, Asia, and Australia had high exposure to the H2N2 virus during its last pandemic season, and that the emergent H3N2 virus was fairly similar to the H2N2 virus. In contrast, people in North America did have as much exposure to the late H2N2 virus and thus less pre-existing immunity to the new H3N2 virus.

The severe second pandemic season in Europe, Asia, and Australia was still puzzling. To analyze this, the authors looked at phylogenetic relationships of the hemagglutinin H3 gene and the neuraminidase N2 gene. For the neuraminidase N2 gene, they found two distinct gene clusters, with different antigenic sites. The first cluster was present in the first pandemic season 1968/69, while the second, with a new antigenic site, was found in 1969/70. This genetic drift might explain why the pandemic was more severe in Europe, Asia, and Australia the second season. People now needed to make new antibodies to the new antigen. Interestingly, since the hemagglutinin gene did not drift much during this time, a substantial proportion of the North American population would have already made antibodies to it and would still be protected.

The “smoldering” response suggests that if a vaccine could have been made after year 1 in Europe, Asia, and Australia, a good percentage of the deaths could have been prevented. This is an interesting idea, although it unfortunately does not help us to predict new future pandemics.

After thinking about this paper and what we have learned in class, I was trying to think about how vaccine repsonses to infectious agents like influenza might be improved on a yearly basis. In the case of the 1968/1969 pandemic, the mortality varied around the world because the virus drifted differently. There have also been instances in the United States where the yearly vaccine is very different than that year's virus and is thus ineffective. Do we need to have a more global effort when it comes to vaccine production? Or, each year, do we need to make a vaccine that is a combination of vaccines in order to catch more variation in virus? Obviously, both of the ideas might be complicated and cost-prohibitive. It would be hard to justify either during non-pandemic years.

Glucose uptake and stroke survival

2008-10-01T22:36:00.004-06:00

Dr. Ritter,

I was wondering if a factor in the high mortality rates of diabetic stroke victim could have to do with poor uptake of glucose to leukocytes and other cells, which would aid in recovery. As we know, these cells require glucose as a source of energy, and poor cellular glucose uptake is a major problem of diabetes (especially type II). With a decreased amount of energy it seems the cells involved in the mending processes would be greatly hindered. Is there any research looking in to this or am I just completely mistaken?

The Importance of Stroke Awareness

2008-10-01T18:05:00.005-06:00

What is a stroke and how does it occur?

A stroke occurs when a portion of the brain dies due to a lack of oxygen. Usually an artery that supplies the brain with oxygen carrying blood has been damaged or blocked by a clot (Ischemic Stroke); this is how most strokes occur. The other, small percentage, happens when an artery in the brain bursts (Hemorrhagic Stroke).

In an Ischemic stroke a blood clot or fatty deposits on a vessel wall, are formed in the heart or neck and are moved/swept upwards to the brain where it then blocks an artery. Protective mechanisms of the brain immediately begin to fight back by raising the blood pressure in hopes of clearing the artery. In the meantime, cells around the brain are beginning to shut down due to a lack of oxygenated blood. This occurs in 85% of strokes.

With a Hemorrhagic stroke, the problem is a little more disastrous. In this case, an artery is ruptured, preventing normal flow of blood and allowing it to leak into the brain tissue. This causes the brain to swell. If the swelling is continuous, the skull can crush the centers for consciousness and breathing. 13% of strokes are hemorrhagic.

Symptoms or Warning signs of a stroke

A simple acronym used to determine if someone, or yourself, is having a stroke is called FAST. Facial weakness: ask the individual to smile. If one side of their face seems to droop, then it is one of the beginning onsets of a stroke. The next step is Arm and leg weakness. Ask him or her to then raise both arms. If they have trouble bringing one of their arms up, it is another symptom. Speech problems is the next big one. Ask the person to repeat a simple sentence that, in any other circumstances, they would have no problem completing. For example, "It's a cloudy day." The last step in FAST is Timing. Timing is critical: TIME IS BRAIN. There is only a small window of time that the most effective treatment for a stroke can be administered; three hours of the onset of stroke. The drug administered is tPA, a de-clotting agent. However, there is a concern with tPA. In 6% of cases, tPA causes bleeding in the brain and can be fatal. This is dangerous, especially if it was found that the patient had not even had a stroke. There is no easy way to determine if someone is having a stroke. The best way is thorugh an M.R.I and the confirmation of a neurologist. But since both are unlikely to be found on hand, the responsibility lies with the emergency room doctor.

Risk Factors: The controllable and the out of hand

Stroke risk factors that are uncontrollable have to do with increasing age, male sex, race (especially African Americans), and family history of stroke. There are, however, factors that can be modified through medical treatment and lifestyle changes. These include high blood pressure, cigarette smoking, diabetes, obesity, Aspirin, high blood cholesterol (a leading factor in stroke), and heart disease. You can also reduce your risk by conducting annual physicals with your physician, keeping a healthy diet, being aware of your family history, and maintaining a healthy weight.

**If your interested in learning more about stroke, I found a pretty awesome video link. It won't take up much of your time and your not obligated to watch it :)

Crucial Facts about Stroke Video:

http://video.on.nytimes.com/?fr_story=1597c973a409a01c13d05376ef6312ad307251c1

References:

American Stroke Foundation- http://www.americanstroke.org

The Stroke Awareness Foundation- http://www.strokeinfo.org/

Stroke and Inflammation: delayed mechanism of tissue damage

2008-09-30T15:32:00.003-06:00

We now know that stroke-induced damage often takes place long after the initial ischemic event has subsided. I thought a brief overview of some potential mechanisms accounting for this delayed onset damage would be interesting and helpful in understanding this complex process.

Until relatively recently all tissue damage associated with an infarct was presumed to have occurred within the first few hours following the event. After this time, all structural deficits were thought to be fixed, leading to few treatments targeted specifically at mechanisms of delayed damage. More recently, however, it has been shown that delayed mechanisms of damage can significantly increase the degree of tissue damage caused by acute, transient strokes.

Through the use of modern neuroimaging methods, it has been shown that there can be significant growth of the infarct for more that 24 hours after the initial event. Also, other neural damage resulting from the initial stroke has an even longer timeline. These recent elucidations clearly point out the need to better understand delayed mechanisms of damage and provide new brain protective strategies.

One key player, linked to delayed damage associated with acute stroke, is inflammation. Listed are a few of the central arguments for implicating inflammation in the delayed damage mechanism:

1.) Inflammatory cells can be found in the brain after stroke.
2.) Anti-inflammatory strategies can protect against experimental stroke.
3.) Disruption of genes linked to inflammation (iNOS, from posted review article) can protect against stroke.
4.) Inducing brain inflammation causes neural tissue damage.

The stroke-induced inflammatory response is a complex process usually taking place after blood flow has been restored. Reperfusion of the ischemic cells with oxygenated blood (either spontaneous or by means of TPA) induces formation of reactive oxygen species (ROS). These ROS can then stimulate the surrounding cells to secrete inflammatory cytokines, eventually leading to increased leukocyte infiltration into the brain. This type of prolonged stroke-induced inflammation in the brain can result in several detrimental effects. For one, infiltration and aggregation of leukocytes may directly lead to further injury through their secretion of harmful substances. Also, the blood brain barrier can be compromise by the activation of cytotoxic releasing inflammatory cells. This can lead to edema (an accumulation of fluid) in the brain, which can further exacerbate damage caused by low oxygen levels.

Due to the 3-hour timetable for TPA (tissue plasminogen activator) effectiveness, 95% of strokes cannot be treated specifically. Also, a study done by the WHO concluded that the best acute care for stroke patients can only slightly improve outcomes. Both of these statements further justify the continued research towards better understanding the many factors involved in delayed damage mechanisms associated with stroke-induced inflammation.

This accounts for the sudden onset of inflammation following and directly related to a stroke. Has anyone found information regarding chronic systemic inflammation and its role in stroke?

References:

Dirnagl, Ulrich, and Elger, Bernd. "Neuroinflammation in Stroke". Springer, 2004. Pg: 87-95.

Tang, Xian Nan, Wang, Qing, and Yenari, Midori A. "The Inflammatory Response in Stroke". J. Neuroimmunol. 184(1-2): 53-68.

Inhibitors in Hemophilia: A Potentially Devastating Problem

2008-09-29T22:05:00.002-06:00

Hemophilia A affects about 1/5000 males, is typically inherited, and is normally treated with factor VIII (F8) replacement therapy. However, factor replacement therapy has a major side effect-inhibitors occur in approximately 25% of those with severe hemophilia A, and are a direct result of factor replacement therapy. Inhibitors are antibodies that neutralize the function of F8, which means that the F8 replacement that is being used to treat bleeding episodes (to stop the bleeding or prevent the bleeding) isn’t effective (and so the bleeding doesn’t stop)!

Why do inhibitors develop in hemophilia?
Severe hemophilia is the result of a mutation in the F8 gene that renders the protein useless. Some mutations result in the complete loss of the protein (large deletions and nonsense mutations) whereas others result in a protein that isn’t functional (missense mutations and splice site mutations). If a mutation results in complete loss of the F8 protein, then when F8 is introduced as part of replacement therapy, the protein is foreign to the body!

So, what about the immunology?
First, not all antibodies to F8 are inhibitors (they aren’t all dangerous). Actually, about 15% of healthy blood donors have non-pathogenic F8 antibodies. CD4+ T-cells play a role in anti-F8 antibody synthesis. Like any other protein, F8 is processed into peptides by an antigen-presenting cell, presented with MHC class II to a CD4+ T-cell, and, with a proper CD4+ T-cell receptor and with costimulation, the CD4+ cell directs B cells to make antibodies. Both Th1 and Th2 cells contribute to the production of anti-F8 antibodies, and the proportion of the Th1/Th2 response is unique to the individual. In addition, it appears that the pathogenic immune response to F8 is the result of failure to activate regulatory CD4+ cells specific for certain F8 sequences.

Why does it matter?
Inhibitor development, especially if the inhibitor develops at a high titer, can be devastating for those with severe hemophilia. In extreme cases, where factor replacement therapies don’t work, some patients turn to “immune tolerance therapy,” in which the patient is exposed to high doses of F8 daily for weeks and even years, sometimes in conjunction with immunosuppressive drugs. The idea is to tolerize the body to the F8 (teach the body not to mount an immune response to the F8), and according to the National Hemophilia Foundation, works about 60-80% of the time. Interestingly, patients who respond successfully to immune tolerance or immunosuppressive therapies tend to have a predominance of Th1-driven antibodies, whereas those who fail to respond to these therapies tend to have a Th2-driven response.

References
National Hemophilia Foundation (http://www.hemophilia.org/)
M.T. Reding, “Immunological aspects of inhibitor development,” Haemophilia, 12 (Suppl. 6) 30-36, 2006.

Hepatitis C Vertical Transmission

2008-09-29T11:10:00.003-06:00

As a Pediatric Gastroenterology Fellow I have an interest in Hepatitis C (HCV) Vertical Transmission (transmission from mother to child). I am in the midst of designing a study to look at the immune activity in mothers at the time of delivery and infants over the first 12-18 months of life. I hope to find a difference in those who become chronically infected and those infants that do not.

This study is my main motivation for taking Immunology as the study is very focused on immune function. HCV challenges both the innate and cell-mediated immune systems. We currently know little about either in the pediatric patient.

Let me share some of the background with you.

HCV is a single-stranded RNA virus in the flaviviridae family. The virus has significant viral heterogeneity, including 6 major genotypes and numerous subtypes. The most common subtypes found in the United States (US) are 1a and 1b.1 The high replication rate (1010—1012 virions/day) and error prone polymerase allows for a robust production of minor viral variants. 2 It is estimated that 3% of the world’s population is chronically infected with HCV.3 The prevalence in the US is 1.8%, making it the most common blood borne infection in the US. The prevalence in the general pediatric population varies between 0.1% and 15% worldwide.4 The US pediatric HCV prevalence is 0.2% for children less than 12 years old and 0.4% for those between 12-19 years old.5

Vertical transmission of Hepatitis C virus (HCV), accounts for the majority of new cases of Pediatric HCV. Vertical transmission rates are between 2 and 14%.6 If the mother is known to be anti-HCV antibody (Ab) positive, but is HCV RNA negative, vertical transmission is very rare.7 Several studies have shown an increased risk for vertical HCV transmission associated with maternal HIV infection and IV drug use.1, 8, 9 Maternal alanine aminotransferase (ALT) and viral load have been shown to affect vertical transmission rates, with an elevated ALT >110 IU/L and a viral load of greater than 105 copies/ml associated with an increased risk for vertical transmission.6 The European Pediatric HCV Network found an increase in vertical transmission to female infants compared to male, with females twice as likely to become infected.3 This supported Granovsky’s findings that female infants were infected more frequently than males (8% vs. 3%).10 The European Network found that the duration of rupture of membranes was longer in maternal child pairs with transmission of HCV (> 6 hours) compared to those without, although this difference was not statistically significant.3 No significant correlation has been found for the type of delivery or breastfeeding. 1, 5 Maternal HCV genotype has not been shown to impact the rate of vertical transmission.6

The diagnosis of vertical transmission, transmission of infection from mother to infant, of HCV is complicated by transplacentally acquired maternal anti-HCV antibodies that can persist for up to 18 months following delivery. Seventy percent of vertically infected infants will have a positive HCV RNA PCR by 1 month of age and 90% by 3 months of age.1 If infected, children and their mothers have identical HCV genotypes.8 The diagnosis of chronic Hepatitis C is established by 2 positive HCV RNA PCRs from serum 3 to 4 months apart in an infant who is at least 2 months of age and/or by detection of anti-HCV antibodies after the infant is 18 months old.9,1
All infants born to Anti-HCV Ab positive mothers will have circulating IgG antibodies to HCV at birth. 99% of children lose the Anti-HCV antibodies within 18 months of delivery if they are negative for HCV RNA. Chronic infection is most often asymptomatic in childhood; however elevation of transaminases is quite common.4 Typically liver disease remains mild for the first 1 or 2 decades.5 A small portion of perinatally infected children have developed advanced liver disease during childhood accounting for 9 liver transplants in North America between 1995 and 2001.5 HCV remains a leading diagnosis resulting in liver transplant in the adult population.

One study from Italy began the investigation into the role of fetal immune activity in the vertical transmission of HCV. This study demonstrated Hepatitis C virus-specific reactivity of CD4+ lymphocytes in children born to HCV-infected women. HCV-specific T-cells were more frequent and vigorous in children than in their HCV positive mothers. This study demonstrated that vertical exposure to HCV induces a Hepatitis C virus-specific cell-mediated immune response. The authors hypothesized that development of a robust HCV directed cell-mediated immune response during fetal life may contribute to the relatively low frequency of vertical transmission.14 There are no other published systematic studies of immune cell function in infants at risk for vertical transmission. Currently, there are several completed and ongoing trials investigating the immune cells function in the role of HCV clearance in adult patients.

Meyer demonstrated clearance of infection in male German youth from 16 to 24 years old with a weak HCV-specific CD4+ t-cell response.15 In this study there was no difference between acute and chronically infected subjects CD4+ response. 15 This study proposed that the low levels of viremia are controlled by the innate immunity without a strong adaptive immune response. 15

Fetal immune activity has been shown to be biased towards the Th2 response for protection of the fetal-maternal interface. The Th2 predominant response results in suppression of Th1 activity. 16 Fetal CD4+ T-cells have low cytokine production and decreased numbers of mononuclear phagocytes resulting in a weak innate immune response. While the fetal immune response to HCV has not been fully examined, the decreased Th1 activity may play a role in chronic infection resulting from vertical transmission.16

The immune response seen in chronic HCV has been shown to be weak and directed at a limited number of epitopes when compared to the response seen in spontaneous clearance.17 The immune response seems to quickly compartmentalize to the liver with evidence that HCV may upregulate homing molecules involved in T cell recruitment.17 There are conflicting reports regarding the role of HCV specific CD8+ T cells in chronic infection.17 CD8+ T cells have been associated with variable amounts of liver injury and a range of viral loads.17

Viral clearance is generally attributed to a robust induction of cell-mediated immune response including type 1 interferon, cytotoxic T lymphocytes (CTL) and natural killer cells (NK).15, 18, 19The role of dendritic cells includes viral recognition and activation of pathways for IFN – Beta production and Nk/CTL induction. The role of dendritic cells in childhood HCV infection has not yet been evaluated.18

Cytotoxic lymphocytes include cytotoxic T lymphocytes (CTLs) and natural killer cells (NK cells) that are responsible for eliminating damaged cells and play a key role in mediating host response to viral infection. CTLs are MHC-Class I restricted CD8+ T cells that migrate into affected tissue in association with the MHC Class I complex and suppress viral replication by cytolysis and secretion of antiviral cytokines. One study in adults demonstrated a functional T-cell threshold that predicted recovery from acute HCV infection.20 NK cells work through rapid and potent cytotoxic activity and by production of inflammatory cytokines, such as IFN-γ.17 NK cells provide a first line of defense against viral infections, and are critical for the development of Antigen-specific memory.19 The activity of NK cells is controlled by receptors (NKRs) that mediate activation or inhibition upon ligation of surface molecules on target cells.17, 21Alterations in NK function can create a situation where the virus may have a replicative advantage leading to a high level of viremia that cannot be controlled by memory T cells.18

CD4+ T lymphocytes regulate CTL memory via cytokine production and by assisting antigen-presenting cells. CD4+ T cells also are important in IL-2 production. In adults with HCV, levels of HCV-specific CD4-derived IL-2 were significantly higher in patients who cleared the HCV infection.20 These data suggest that CD4+ lymphocytes might play a role in the prevention of vertical transmission of HCV or the resolution of infection.

Understanding the role of cell-mediated immunity in the regulation of vertical acquisition or clearance of HCV is the first step in identifying infants at risk for chronic infection. This study will describe cell-mediated immune activity that could provide the first step in a process leading to early treatment regimens that target infants at highest risk for chronic HCV infection.

References
Airoldi J, Berghella, V. Hepatitis C and pregnancy. Obstetrical and Gynecology Survey. 2006 2006;61(10):666-671.
2. Uebelhoer L HJ, Callendret B, Mateu G, Shoukry N, Hanson H, Rice C, Walker C, Grakoui A. Stable cytotoxic T cell escape mutation in hepatitis C virus is linked to maintenance of viral fitness. PLOS Pathogens. September 2008 2008;4(9):e1000143.
3. Network EPHCV. A significant sex - but not elective cesarean section - effect on mother-to-child transmission of hepatitis C virus infection. J. Infect Dis. 1 Dec 2005 2005;192:1872-1879.
4. Fischler B. Hepatitis C virus infection. Seminars in Feral and Neonatal Medicine. 2007 2007;12:168-173.
5. Jonas M. Children with Hepatitis C. Hepatology. Nov 2002 2002;36(5, Suppl 1):S173-S178.
6. Hayashida A, Inaba, N., Oshima, K., Nishikawa, M., Shoda, A., Hayashida, S., Negishi, M., Inaba, F., Inaba, M. Re-evaluation of the true rate of hepatitis c virus mother-to-child transmission and its novel risk factors based on our two prospective studies. J. Obstet. Gynaecol. Res. Aug 2007 2007;33(4):417-422.
7. Yeung LT KS, Roberts EA. Mother-to-infant transmission of hepatitis C virus. Hepatology. 2001 2001;34:223-229.
8. Resti M, Azzari, C., Mannelli, F., Moriondo, M., Novembre, E., Martino, M., Vierucci, A., . Mother to child transmission of hepatitis C virus: prospective study of risk factors and timing of infection in children born to women seronegative for HIV-1. BMJ. 15 Aug 1998 1998;317:437-441.
9. Mast E, Hwang, L., Seto, D., Nolte, F., Nainan, O., Wurtzel, H., and Alter, M. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J. Infect Dis. 1 Dec 2005 2005;192:1880-1889.
10. Granovsky MO MH, Tess BH, Waters D, Hatzakis A, Devoid DE, Landesman SH, Rubinstein A, DiBisceglie AM, Goedert JJ. . Hepatitis C Virus Infection in the Mothers and Infants Cohort Study. . Pediatrics. 1998 1998;102:355-359.
11. Narkewicz M, Cabrera, R., Gonzalez-Peralta, R. The "C" of Viral Hepatitis in Children. Seminars in Liver Disease. 2007;27(3):295-311.
12. Bortolotti F, Verucchi, G., Calogero C., Cabibbo G., Indolfi, Z., Giacchino, R., Marcellini, M., Marazzi, M., Barbera, C., Maggiore, G., Vajro, P., Bartolacci, S., Balli, F., Maccabruni, A., Guido, M. Long-term Course of Chronic Hepatitis C in Children: From Viral Clearance to End-Stage Liver Disease. Gastroenterology. June 2008 2008;134(7):1900-1907.
13. Yeung L, To, T., King, S., Roberts, E. Spontaneous clearance of childhood hepatitis C virus infection. Journal of Viral Hepatitis. 2007 2007;14:797-805.
14. Della Bella S, Riva, A., Tanzi E., Nicola, S., Amedola, A., Vecchi, L., Nebbia, G., Longhi, R., Zanetti., A., Villa M. Hepatitis C virus-specific reactivity of CD4+ lymphocytes in children born from HCV-infected women. J. Hepatology. 2005 2005;43:394-402.
15. Meyer M, Lehmann, M., Cornberg, M., Wiegand, J., Manna, M., Klade, C., Wedemeyer, H. Clearance of low levels of HCV viremia in the absence of a strong adaptive immune response. Virology Journal. 11 June 2007 2007;58(4):1-11.
16. Marodi L. Innate cellular immune response in newborns. Clinical Immunology. 2006;118:137-144.
17. Ishii S, Koziel, M. Immune responses during acute and chronic infection with hepatitis C virus. Clinical Immunology. 2008;128:133-147.
18. Ebihara T, Shingai, M., Matsumoto, M., Wakita, T., Seya, T. Hepatitis C Virus-Infected Hepatocytes Extrinsically Modulate Dendritic Cell Maturation To Activate T Cells and Natural Killer Cells. Hepatology. July 2008 2008;48(1):48-58.
19. Rauch A, Laird, R., McKinnon, E., Telenti, A., Furrer, H., Weber, R., Smillie, D., Gaudieri, S., and the Swiss HIV Cohort Study. Influence of inhibitory killer immunoglobulin-like receptors and their HLA-C ligands on resolving hepatitis C virus infection. Tissue Antigens. 2007;69:237-240.
20. Smyk-Pearson S, Tester, I., Klarquist, J., Palmer, B., Pawlotsky, J., Golden-Mason, L., Rosen, H. Spontaneous recovery in acute human hepatitis C virus infection: functional T-cell thresholds and relative importance of CD4 help. J. Virol. Feb 2008 2008;82(4):1827-1837.

Lymphatic Pump Increases Immune Response

2008-09-28T22:31:00.002-06:00

In the past decade there has been a growing interest in osteopathic manipulative medicine. A Doctor of Osteopathic (DO) have the same benefits and training to practice as an Allopathic Doctor (MD), but are trained to treat holistically by examining the whole body versus the symptomatic approach of allopathic medicine. In addition, DOs have the benefit of manipulation to induce the body’s self-healing process and to reduce injury and diseases. A few manipulation techniques include: muscle energy (muscle contraction), strain-counterstrain (localizing and reliving painful spots), myofascial release (gentle force to reduce neurological muscle tightness), and lymphatic pump treatment (increase lymph flow). The lymphatic pump treatment (LPT) is particularly interesting in terms of treating patients with edema and infections.

The lymphatic system is organized as a network of fluid collecting vessels in order to maintain macromolecular homeostasis, lipid absorption, and lymphocyte transportation. The lymph system serves as a reservoir of surplus tissue fluid, known as lymph, and the removal of cellular debris from cellular breakdown and infection. Unlike the circulatory system where the heart pumps blood through the body, the lymphatic vessels depend on the contraction/relaxation or compression/expansion of the lymphatic vessels via skeletal muscle movements and lymphatic valves. In summary, the movement or contraction of the skeletal muscles allows the lymph to flow against a gradient or gravity, and the valves on each vessel segment prevent the backflow of the lymph.

Studies have shown that LPT indirectly increases lymph flow and patient’s immune response to infections, but have not shown firm evidence that patients benefit from LPT. Current and ongoing research, however, are finding that LPT not only increases lymph flow but increases leukocyte count and flux.

H. Fred Downey et al. has conducted studies on dogs to determine if LPT and exercise changes lymph flow with or without the expansion of extracellular fluid volume (ECE). They have concluded that LPT with ECE greatly increases lymph flow rate than just LPT alone and is found to be similar with exercise; however, exercise was found to have higher lymph flow rate than LPT.

In another study conducted by Lisa Hodge et al., LPT was found to increase leukocyte count and flux. During LPT, lymph was collected and discovered to have an increase in macrophages, neutrophils, total lymphocytes, and T and B cell counts. They concluded that the increase in lymph flow during LPT enhanced the mobilization of lymphocytes and maybe responsible for patients’ improved immune responses.

With these data, it can be suggested that LPT would most benefit patients who are well hydrated and are partially or wholly immobilized (astronauts or individuals with paralysis or muscular diseases). Many have suggested that moderate exercise during a viral or bacterial infection helps to “sweat out the illness”, or in scientific terms increase lymphatic and lymphocyte flow to fight off the infection.

I have never tried LPT or exercised at the peak of a cold (the thought of exercising when feeling terrible just does not sound appealing), but has anyone in our group tried or knows anyone who have done these strategies and recovered quickly from a viral or bacterial infection?

References:

Degenhardt, Brian. (2000). Osteopathic manipulative medicine: Optimizing patient-focused health care. The Advisor, 21(1). Retrieved September 28, 2008, from
http://www.aacom.org/about/osteomed/Pages/Degenhardt.aspx

Downey, H. Fred. (2008). Lymph flow in the thoracic duct of conscious dogs during lymphatic pump treatment, exercise, and expansion of extracellular fluid volume. Lymphatic Research and Biology, 6(1), 3-13.

Hodge, Lisa. (2007). Abdominal lymphatic pump treatment increases leukocyte count and flux in thoracic duct lymph [Abstract]. The Journal of Immunology, 178(99), 13. Retrieved from PubMed database.

Knott, Marty E. (2005). Increased lymphatic flow in the thoracic duct during manipulative intervention. Journal of the American Osteopathic Association, 105(10), 447-456.

Zawheja, David. (2005). Lymphatic biology and the microcirculation: Past, present, and future. Microcirculation, 12, 141-150.

website

2008-09-28T21:35:00.000-06:00

sorry it didnt post the website
http://aje.oxfordjournals.org/cgi/content/abstract/160/4/376

Stroke and Inflammation

2008-09-28T21:06:00.002-06:00

Thank you so much for the overview on strokes! it really helped to have it in easy to understand an relevant format.
I just wanted to start off with the lay articles:
The first being the "Timing is Key" I never knew that there was a window of around 3 hours to get to the hospital while having a stroke. I always thought it was a spontaneous occurrence that couldn't be stopped after it had started. Also, I knew there were symptoms but I didn't know that they were precursors that once identified could help save the person from farther damage.
The second article which talks about the higher occurrence of stroke in Mexican Americans already has a post on it but i found this article that helps:

this article kind of explains a difference and it also states that "there are no existing data regardingthe cerebrovascular disease burden faced by Mexican Americans,and estimates regarding the impact of stroke on the nation aretherefore limited."

While reading the article on Nitric Oxide, I was somewhat confused and had to read it twice and I'm still sort of unclear on whether which is beneficial and which is not. Even at the end of the paper it says that it can be both. At one point is says that NOS1 and NOS2 are beneficial and that NOS3 is not but it then stays that studies are in conclusive. Just wondering if anyone figured it out?

The last articles discusses the inflammatory effects of stroke, but I'm wondering if there are any inflammatory precursors for stroke. I found on the American Heart Association website (http://www.americanheart.org/presenter.jhtml?identifier=4648) and they discussed CRP's (C-reactive proteins) and their effect on the cardiovascular system, which we have talked about before. I just think it's a good cross over between diabetes that we discussed before and now stroke. It is interesting the the same CRP's can lead to multiple issues in the body that can cause a variety of events.

Video links depicting 2 different types of stroke

2008-09-28T18:06:00.003-06:00

Animation of a hemorrhagic stroke
http://www.stroke.org/site/DocServer/Hemorrhagic_stroke_ani.mpg?docID=2821
Animation of an ischemic stroke
http://www.stroke.org/site/DocServer/Ischemic_Stroke_ani.mpeg?docID=2822

I would also recommend looking over the fact sheet from this site (http://www.stroke.org) for an overview.

Stroke overview

2008-09-28T16:15:00.009-06:00

Thought I would post a brief review about the various types and causes of stroke before the upcoming week.

There are 2 types of stroke: Ischemic and Hemorrhagic, each with several subtypes. At this point in time we believe that inflammation plays a larger role in Ischemic rather than hemorrhagic stroke.

In an Ischemic stroke blood clots form, block arteries and cut off blood flow. An ischemic stroke can occur in one of two ways. The first is an Embolic stroke during which a blood clot forms somewhere in the body (most commonly the heart) and travels through the blood stream to the brain. The clot eventually travels in the brain to blood vessels small enough to block its passage. Once lodged, the clot causes a stroke known as an embolus. The second type of ischemic stroke is a Thrombotic stroke. In a thrombotic stroke blood flow is impaired due to a blockage in one or more of the arteries supplying blood to the brain. The process that leads to the blockage is known as thrombosis and the subsequent clot that is formed is known as a thrombus.

Strokes that are caused by blood clots can happen as a result of blood vessels that are clogged with build up of cholesterol. The body reacts to these build ups as multiple, tiny and repeated injuries to the vessel wall; responding as it would to any other wound in the body and forms a clot. Two types of thrombosis can cause stroke: large vessel thrombosis and small vessel disease (or lacunar infarction). Large vessel thrombosis is the most common and best understood type of thrombotic stroke. Large vessel thrombosis is most often caused by a combination of long-term atherosclerosis that is followed by rapid clot formation. Patients that suffer a thrombotic stroke are also likely to have coronary artery disease and a heart attack is frequently the cause of death in patients who have suffered this type of brain attack. The second cause of thrombosis is small vessel disease or a lacunar infarction. This type of disease occurs when the blood flow is blocked to a very small arterial vessel. The term lacunar infarction comes from the Latin word lacuna which means hole and describes the small cavity remaining after the product of deep infarction have been resolved by other cells in the body. Small vessel disease is most likely linked to hypertension, however we know the least about this disease.

The second major type of stroke is a hemorrhagic stroke, caused by the breakage or "blow out" of a blood vessel in the brain. A hemorrhage can be caused by a number of disorders that affect the blood vessels, including long term hypertension and cerebral aneurysm. An aneurysm is a very weak or thin spot on a blood vessel wall that is usually present at birth. Aneurisms develop over a number of years and usually do not cause any detectable problems until they break. There are two types of hemorrhagic stroke: subarachnoid and intracerebral. An intracerebral hemorrhage causes bleeding from within the brain itself with hypertension usually being the primary cause of this hemorrhage. In a subarachnoid hemorrhage an aneurysm bursts in a large artery or near the thin, delicate membrane surrounding the brain. Blood spills into the area around the brain, causing the protective fluid to become contaminated with blood.

Information taken adapted from http://www.stroke.org 9/28/08

2008-09-28T14:56:00.003-06:00

The lay article "As if One Stroke Weren't Enough..." stated Mexican-Americans and African-Americans are much more susceptible to stroke than non-Hispanic white Americans. From other classes I also know that people in the Mediterranean area are also much more likely than Americans to suffer from stroke and it made me think that maybe there is some sort of genetic component that these people have that white Americans do not. Is anyone aware of research to this matter?

News realse and article about Metabolic Syndrome

2008-09-24T15:13:00.002-06:00

When I was looking into metabolic syndrome I wondered: how at risk are people to this disorder? I found a news release that directed me back to our topic of life style choices. It's a summary of an article that was published this summer about alcohol consumption (also posted).

News release: http://www.nlm.nih.gov/medlineplus/news/fullstory_67737.html

Article:http://jcem.endojournals.org/cgi/search?sortspec=relevance&journalcode=jcem&author1=amy+fan&fulltext=&pubdate_year=&volume=&firstpage=

I thought that they used an ample number of subjects and were very honest about the limitations of accuracy from some of the methods used in the study. Does anyone have any opinions on the design of the investigtation?

Prenatal Stress and postnatal outcome

2008-09-23T22:02:00.000-06:00

I went to a presentation today by Chris Coe and he talked about prenatal stress and postnatal outcomes. The presentation covered a wide variety of topics ranging from psychological to immunological, so he was not able to go into much detail about any one topic. I do want to share with everyone the part about the immunology of the infant in a stressed mother.

Chris performed an experiment on pregnant monkeys. Once a day in the afternoon a loud noise would go off three times. He had three groups of monkeys: a control, ones stressed in early pregnancy, and ones stresses in late pregnancy. He said the stress was no more stressful than an average day for humans, and it would not alter the weight or the length of the pregnancy.

The results showed that stress anytime during a pregnancy can alter the immune response and overall health of the baby. When stressed the body naturally pulls iron out of the blood, and takes it to the muscles and organs. Stress deprives the baby of the necessary iron in the blood and can be born with an iron deficiency that can lead to anemia. Babies that are born with an iron deficiency do not receive enough iron from the mother after birth so they usually become anemic at about 6 months. The anemia affected the production of NK cells. The baby was born with a reduced number of NK cells and due to the anemia late in infancy the NK levels were reduced even more. This affected the infants response to pathogens.

This experiment also showed that cytokine levels were reduced in the infant. This shows that the adaptive response is altered. There was an increase in the TH-2 cells indicating that prenatal stress can lead to an increase in allergies and asthma in the child or adult. This was also demonstrated in another study were adults were asked about how their pregnancy went, if the mom was stressed or if they had a short gestation, normal, or long gestation and how that related to the health of the adult. In an interesting twist the adults that had a longer than average gestation usually had allergies or asthma as well as the adults with a short gestation.

This led me to wonder of the increase in asthma and allergies in children and adults is a result of the working culture we are in? Would we see a decrease in the number of children with allergies and asthma if the pregnant mother did not perform stressful activities?

Obesity and Diabetes II

2008-09-23T18:16:00.002-06:00

The one issue we discussed yesterday in class that really caught my attention was the cultural differences and disposition to obesity and diabetes. It was the last research article that I enjoyed the most. The article compared the CRP levels (a possible marker for silent inflammation) of South Asian and European men and women. The article stated that the median CRP level in South Asian women was nearly double that in European women (1.35 vs 0.70mg=1, P .0.05). I found this interesting because we didn't cover much information on the subject in class, so I did some research of my own and found this article...

http://www.medscape.com/viewarticle/540922

A section of this article addresses an interesting topic we discussed in class regarding how normal BMI's may need to be altered to account for gender and cultural differences. Under the section titled "Asian Americans and Pacific Islanders" there is a table that highlights this. My only question to this would be how they accounted for the differences. What criteria did they consider?

I also liked how the article addressed possible reasons for why different cultures might have a higher incidence of diabetes. They talked about genetic differences, access to healthcare, and socioeconomic barriers to buying healthy foods and medication. The article is broken down into different sections by each race that was studied and it talks about the different initiatives that are underway to try and slow down the diabetes epidemic. If you have the time, it's a great article to read. Let me know what you think!

Inflammation, Diabetes and Heart Disease

2008-09-22T09:06:00.003-06:00

In the article "Profinflammatory cytokines are increased in type 2 diabetic women with cardiovascular disease", nondiabetic and diabetic women with and without cardiovascular disease are tested for plasma cytokine concentration (IL-1beta, IL-6, TNF-alpha). This article was particularly interesting to me because of how it described the snowball effect with diseases. During the last discussion, someone briefly mentioned how the inflammatory system had somewhat of a snowball effect (on the cellular level) where if one cytokine was present, more would be produced as an effect which would then signal for something else, etc, etc. In this article, it was suggested that inflammation effects many diseases/pathways at one time. For example, inflammation in type 2 diabetes can cause circulates cytokines which can aggravate atherosclerosis. Therefore hinting that if you have inflammation and type 2 diabetes, it would be likely for you to develop/encourage athersclerosis and heart problems. I think that this is the scary truth, but nonetheless, very fascinating. Note: Although this article does mention correlations, it states that there has been no studies that have grasped the correlation of cytokine concentrations in women with both cardiovascular disease and diabetes
In addition to disease relationships, this article reported some facts. Here are a few that I found pertinent.
- 17 million people in U.S. have diabetes. 95% of those people have type 2 diabetes.
- in 2000, CVD was #1 cause of death among women in U.S. (American Heart Association)

2008-09-19T01:13:00.002-06:00

During our first discussion about Type II Diabetes and its relation to inflammation we spent quite a bit of time talking about diet. As this subject continued to come up I was constantly reminded that the issue was not entirely about subjective decision making but also had many social implicatiaions. One factiod that stuck in my mind was that inflammatory factors stay elevated for up to four hours after eating fast food. Well I found this article that specifically focuses of the inflammatory effects of the "Western Diet" and wanted to share it and wanted to know what you all thought about the increasing importance of AGEs and AGE receptors.

Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs: http://ajpendo.physiology.org/cgi/content/short/295/2/E323

2008-09-17T15:24:00.002-06:00

I came across a recent article in science which described how certain type of cells within the thymus that express autoimmune regulators (AIRES) that act as safety net for eliminating autoreactive immune cells.

Science 8 August 2008:Vol. 321. no. 5890, pp. 776 - 777DOI: 10.1126/science.1162966
Prev Table of Contents Next
Perspectives
IMMUNOLOGY:A Breath of Aire for the PeripheryBruno Kyewski*
The term "self-tolerance" encompasses all mechanisms that protect the body against attack by its own immune system. The adaptive arm of the immune system generates immune cells that express antigen-specific receptors by a random mechanism that requires quality control--selecting a "personalized" repertoire of receptors directed against foreign but not self-antigens (1). Central and peripheral tolerance to self are distinguished according to the site where tolerance is imposed (2). Central tolerance for T lymphocytes occurs in the thymus, where their primary antigen receptor repertoire is generated. Here, developing T cells that recognize and react to self-antigens are eliminated or diverted into T regulatory cells that suppress activation of the immune system and prevent self-reactivity. Although the thymus displays a vast array of self-antigens, including those whose expression is otherwise restricted to specific tissues, this collection is nevertheless incomplete. On page 843 of this issue, Gardner et al. (3) report how peripheral lymphoid tissues act as a safety net, preventing T cells specific for antigens not presented in the thymus from escaping elimination.
Medullary thymic epithelial cells, a particular thymic stromal cell type, express a diverse set of genes that are otherwise restricted to certain tissues and/or stages of development (4). This so-called promiscuous gene expression in the thymus is partly regulated by a transcriptional regulator called the Autoimmune regulator (Aire). Mice deficient in Aire develop a multi-organ autoimmune syndrome, similar to that of humans with functional mutations in the Aire gene (5).
Aire is highly expressed in thymic medullary epithelial cells. However, the functionally relevant expression of Aire in cells of peripheral lymphoid organs has been controversial (5-9). Gardner et al. now identify cells in peripheral lymph nodes, spleen, and Peyer's patches (lymphoid structures of the gut), that express Aire and mediate deletion of auto-reactive T cells. The authors genetically engineered mice in which the promoter of the Aire gene drives expression of a fusion protein composed of green fluorescent protein and islet-specific glucose-6-phosphatase related protein (Igrp), an antigen specific to the pancreas. Of the medullary thymic epithelial cells and peripheral cells that expressed the reporter protein, 85% and 25% expressed endogenous Aire, respectively. Most of these peripheral cells, called extrathymic Aire-expressing cells, were stromal-type epithelial cells, located at the interface between T and B cell areas in peripheral lymphoid tissues. These cells also expressed receptors characteristic of antigen-presenting cells, but differed in several markers from the medullary epithelial cells in the thymus. Surprisingly, some of these extrathymic Aire-expressing cells were highly mobile within the lymph node microenvironment, and at the same time were able to delete T cells specific for the reporter protein.
Complementary tolerance. The transcriptional regulator Aire controls the expression of complementary pools of self-antigens in the thymus and peripheral lymphoid tissues that sequentially imprint central and peripheral T cell tolerance, respectively.
CREDIT: C.BICKEL/SCIENCEPerhaps the most intriguing result of this study relates to the target genes controlled by Aire in the thymus versus the periphery. The number of genes in the latter is about one-tenth of that in the thymus, and their degree of Aire-dependent regulation is less pronounced. Moreover, although there is little overlap between the gene pools, both are clearly enriched in genes encoding for tissue-restricted self-antigens (see the figure). The distinct composition of both gene pools favors a role for peripheral tolerance that is complementary to tolerance developed in the thymus. A recent study by Lee et al. also identified a fraction of nonhematopoietic cells in mesenteric lymph nodes that express Aire and certain tissue-restricted self-antigens, and mediates peripheral T cell deletion (9). However, these cells were less rigorously enriched, and differed phenotypically, compared to those identified by Gardner et al. Moreover, the data of Lee et al. are more in line with the concept that peripheral tolerance serves as a backup for central tolerance rather than being complementary.
The study by Gardner et al. still leaves some important questions that need to be answered before a definitive role can be assigned to Aire in peripheral tolerance. Why do only 25% of peripheral cells in the transgenic mice that express the fluorescent reporter protein also express endogenous Aire? Is it due to ectopic expression of the reporter construct in otherwise Aire-negative cells? Is endogenous expression of Aire too low to be detected, or is expression of Aire and the reporter protein not synchronized? The relatively low concordance between the reporter and endogenous Aire expression may also contribute to the apparently relatively low degree of gene expression induced by Aire in the peripheral cells, which for most genes is less than twofold compared to the background expression in Aire-deficient mice.
Although tolerance induction is thought to be exquisitely sensitive to low numbers of self-antigens that are presented to T cells in the context of the major histocompatibility complex, it will be essential to show that the low expression level of endogenous tissue-restricted self-antigens in peripheral Aire-expressing cells are "tolerogenic." After all, at first glance, the autoimmune phenotype of Aire-deficient mice was fully reproduced by transplanting Aire-deficient thymic stromal cells (with no functional evidence for Aire in extrathymic sites) (5). Given the different composition of self-antigens displayed in peripheral cells, the autoimmune phenotype caused by lack of Aire in the periphery may have been subtle and previously overlooked. Notwithstanding these caveats, the study by Gardner et al. raises intriguing questions about the role and function of Aire and the nature of the peripheral cells that express this factor (10).
The emergence of the extrathymic Aire-expressing cells in vertebrates is interesting, given that organized secondary lymphoid organs evolved much later than the thymus (11). Aire is a single-copy gene with orthologs in mammals, birds, and fish whose structure has been conserved in vertebrates over more than 400 million years (12). No ancestral Aire genes have been reported in invertebrates. This suggests that Aire and its role in tolerance were acquired early during vertebrate evolution, most likely concurrent with the emergence of the adaptive immune system. One question is whether Aire's only role is to ensure central tolerance, or whether it has been coopted for other functions. The study by Gardner et al. now presents a strong argument in favor of the latter--Aire also seems to contribute to establishing peripheral tolerance.

tobacco

2008-09-17T15:16:00.002-06:00

it was interesting that tobacco plant is used for making antibodies. IS this because tobacco is one of the plants which can be regenerated froma single cell. Can potatoe plants be used for this purpose. i have heard taht they can also be regenerated from a single cell

Obesity and Diabetes

2008-09-14T23:44:00.002-06:00

I just wanted to give a brief overview of how obesity, inflammation, and type 2 diabetes are related for this week’s class. After reading a few research articles on the subjects I found that obesity essentially causes chronic inflammation. This has been verified in studies by high plasma concentrations of molecules such as tumor necrosis factor, interleukin-6, and C-reactive protein. In fact, it is the adipose tissue itself that acts like an organ and secretes hormones and cytokines that can cause this inflammation. The resulting chronic inflammation has been found to be the cause of insulin resistance and type 2 diabetes. Since this is a relatively new subject in science, the exact mechanisms and causes are not fully understood and are currently being investigated.

http://www.idf.org/home/index.cfm?unode=c659495d-7467-45c0-8a19-5b3d8ea3d172

I came across this article while searching for more information on diabetes and obesity. The article comes from the International Diabetes Foundation. Some of the statistics in it are extremely alarming. For example, the article states that diabetes and other diseases that result from obesity are responsible for more deaths annually worldwide than AIDS. It also explained that obesity and diabetes caused by obesity are worldwide epidemics. I may be alone in this, but I always envisioned obesity and resulting health problems to be more prominent in the US and parts of Europe. However, the article states that it’s becoming a major problem in “low to moderate income countries” like South Africa, Egypt, and Mexico. The article really conveys a sense of urgency and calls for a worldwide effort to change diets and lifestyles. I’m just curious to hear everyone’s views on the matter. What do you think?

Finally, I was wondering if anybody was able to come across any information on how to effectively screen for this “silent inflammation.” I know blood tests can reveal markers like C-reactive protein but as the previous post states, C-reactive proteins do not indicate inflammation exclusively.

Obesity and Inflammation

2008-09-14T18:48:00.005-06:00

Hello everyone!!
I have read the obesity/diabetes articles and I want to share some ideas from the articles that I found interesting (but you don't have to).
In the articles "Obesity and the Flu", "Visceral Fat Pronounced Guilty of Systemic Inflammation" and "In Diabetes, a Complex of Causes", visceral fat/skeleton was labled as an endocrine organ. I recently heard that fat had a metabolic function, but I did not know that it was therefore classified as an organ. This is a relatively recent discovery in the scientific world, and will provide new hypotheses for years to come.
In our last class, on Monday, September 8th, we discussed a short article titled, "The Inflammation Age" from Better Nutrition. At the end of this article, it suggested that a simple blood plasma test that investigated levels of CRP (C-reactive protein) was the best tool to understand your risks of inflammation. However, Zoe pointed out to the class that the method may be skewed. Why do many of the articles given to us about obesity/diabetes and the relationship with diabetes suggests that levels of CRP can be an efficient way of detecting inflammation? After further investigation, I gathered that abnormal CRP levels can be the consequence of different things, such as viral infections and liver failure. Therefore, this test proves to not be very specific. As Zoe mentioned, this test may not accurately detect what we are looking for.
In addition to the above, I would like to pose a question for the future. What do you think is the most efficient way to treat obesity and diabetes? There have been multiple medications that have been tested and used. Exercise and diet have been tried countless times. Different surgical methods have been discovered and performed. I think that since all of the treatments have various routes, diverse side effects and risks, and distinct goals, it is very hard to compare them. Maybe each patient has a "best" treatment for themselves and their condition.

A Clinical Application for Immunology

2008-09-10T16:54:00.001-06:00

In class this Tuesday, we spoke briefly about immunological assays and how they have become widely used in the clinical world. Because I recently worked in a clinical lab using these techniques, I thought I would share the large part that they actually played.
Before coming to UCD, I worked for a clinical lab that concentrated on organ transplantation. When most people think of immunology and organ transplants, we think of anti-rejection drugs and antibody cross-matching (such as blood typing). As a part of the Infectious Disease department, our job was to make sure that organ donors did not have any infectious diseases (such as HIV and Hepatitis). It may not be inherently obvious as with cross-matching, but immunology plays an important role in this process. To do this, we used a process called Enzyme Immunoassays, or EIAs. This process is basically an antibody-antigen reaction.
When testing for these infectious diseases, the easiest, fastest, and most generally reliable method is to look in the blood for the antibody. A manufactured protein, similar in structure to the disease antigen is affixed to the bottom of a plate. When the serum or plasma of a patient is added, after a period of incubation, any antibody present in the patient’s blood will become bound to the antigen. Everything else is washed away, leaving only the antibody-antigen complex. This complex can be conjugated to a color development reagent, allowing visible representation of the amount of antibody in the blood.
This method of testing is very fast and efficient. If needed to be done quickly, all of the tests required by the FDA for whole organ transplantation can be done within six hours. (This is very handy for someone on a list waiting for an organ.) It is also possible to perform this kind of test on multiple patients at one time, as they can be done on 96-well plates. Unfortunately, some down-sides become apparent with this method of testing. For one, it relies on antibodies made to viruses, instead of the actual virus. There is a period time called the “window period” in which the virus is in the body, but our immune system has not been able to make a detectable amount of antibody. It is rare, but possible that an organ donor could have died without knowing they had recently contracted a disease, and their blood was drawn for testing during this window period. A solution for this is a method of Nucleic Acid Testing (NAT) called Transcription Mediated Amplification which detects the genetic material of viruses using a technique similar to PCR. This can detect the presence of a virus much earlier than EIA testing, but is not available for all infectious diseases.
Another drawback to using EIAs to detect diseases is the phenomenon of cross-reaction, which we also discussed in class. As you might imagine, there are proteins that are similar in structure to antibodies. Cross reactivity is one of the main causes of false positive results in EIAs. For example, if a blood sample is hemolyzed (the red blood cells have lysed), the protein fragments released could become bound to the antigen and the patient would appear to be reactive. There is not much that can be done about this, especially if a person has a medical condition that causes them to produce proteins similar to the antigen being tested for. As more nucleic acid testing becomes available, it will be easier to detect diseases, and fewer organs will have to be discarded because of false positive results.
If anyone happens to comment on this or have a question, I'll be out of town for the rest of the month :)

Antiphospholipid antibodies in children

2008-08-28T14:24:00.009-06:00

I'm going to break the ice here and make the first student post because class this week got me all excited! Just this past week the lab I work in submitted an abstract about antiphospholipid antibody syndrome (APS) in children. In short, this syndrome is characterized by blood clots associated with so-called “antiphospholipid antibodies” (although, these antibodies generally don’t bind phospholipid, but rather phospholipid-binding proteins…for an excellent, in depth review see:
http://www.ncbi.nlm.nih.gov/pubmed/12871358?ordinalpos=27&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum ).

To be diagnosed with APS a person must present with a thrombosis (blood clot). They then need to have positive tests for antiphospholipid antibodies on two separate occasions that are at least three months apart. So, by definition, the people with APS consistently have these antiphospholipid antibodies, which are not usually present in normal, healthy people.

These so-called “antiphospholipid antibodies” are not necessarily directed against phospholipids - that is just the term that has been given to the population of antibodies that seem to be common in people with APS. For our discussion, it isn’t essential to understand what the antibodies are directed against because how each antibody may activate blood clotting isn’t entirely understood. For our purposes, all that needs to be understood is that these patients have abnormally high levels of autoantibody for long periods of time. This is true even when these APS patients are compared to other children who have had blood clots.

Our study focused on children who were diagnosed with APS. APS is a rather complex syndrome that is fairly common in adults with thrombosis but has been little studied in children. Our lab (which includes fellow classmates ChrisB7630 and MeghanC7630) started studying APS in children in hopes of finding a relationship between certain antiphospholipid antibodies and thrombotic outcome, with the long-term goal of using this data to improve clinical care for children affected with APS. Our findings (as presented in our abstract which follows in a comment - beware, it is quite technical!) found that, in general, children who have persistently positive (positive for at least three months) IgM antibodies are more likely to have had recurrent blood clots. After class we started to wonder if maybe the high levels of IgM themselves are responsible for recurrence, as high concentrations the big IgM molecules could make the blood "sticky". Or maybe having consistently high IgM levels is indicative of some sort of underlying inflammation that may have a role in thrombosis.

I’m very much looking forward to this class! I’m excited to see what light others can shine on our work. Yay!

Do bugs control your immune response?

2008-08-28T10:59:00.001-06:00

We are multicellular creatures (metazoans) with about 30 million million cells. Each cell lives in its own tiny microenvironment which is slightly different from all others; no two cells are identical in position, function, or future. All cells depend for survival on interactions with their neighbors, mediated either by direct contacts or through soluble molecules like chemokines and cytokines, growth and survival factors. This makes me think that all instances of damage or infection that stimulate the innate immune system will be different, too. If it’s an RNA virus, for example, or an E. coli, the array of Pattern-Recognition Receptors that are stimulated will be different, and the soup of chemokines and cytokines made by affected cells will therefore be different, too, though they probably overlap. So no two innate responses will be exactly the same. Different individuals’ genetic makeup will also play a role. Now, we know that the link between the innate and the adaptive (antibodies, T cells) immune responses are the dendritic cells. They ingest fragments of the invaders and, influenced to mature and differentiate by the local chemokine and cytokine soup, leave the inflammatory site and travel to the lymph nodes, where they show their burden of antigen to the adaptive immune system’s T cells for evaluation and response. What I want to suggest is that no two arriving dendritic cells will be exactly alike, as they matured in different microenvironments. Thus they may stimulate the T cells which contact them differently, and this could result eventually in very different kinds of immune responses. For example, in one case the response may be mostly antibody, and in another, mostly T cell-mediated, as in Poison Ivy. Is it possible some pathogens have learned how to manipulate the immune system so that the response against them is ineffective? I’m thinking about HIV: everybody who is infected makes antibody to the virus, but it isn’t protective. T cell responses would be protective, the way they are to other viruses, but against HIV they are very weak.