Vaccine for sexually transmitted stigma and cancer remains controversial

Dr. Cohen posted an article for this up on the IMMU7630 site, so I'm going to take advantage of the free resource.

It's not news that there's a vaccine for a few strains of human papillary virus (HPV). What is news is that even though it remains controversial in its intended market, and is now being marketed in different ways and becoming even more controversial.

The Gardasil vaccine is intended to prevent HPV type 6, 11, 16 and 18 infections in infection naive patients. These strains have been shown to cause genital warts, and cervical cancer in women. Research has shown that 100% of cervical cancers are attributed to HPV.

Over 120 different strains of HPV have been identified, so it seems like protecting against only four is not going to do much good. Types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66 have also been implicated in cervical cancers, but the correlation appears to be strongest in 16 and 18 (Which are covered by the vaccine) showing about ~70% attribution to these two strains. Additionally, strains 6 and 11 have been shown to cause about 90% of genital warts.

So here comes the controversy. Gardasil is approved for both women and men. The FDA recommended it be available to men between 9 to 26 years of age. Why do this if it is used to prevent cervical cancer? Well, men spread the disease even though most people think men don't get any cancers caused by the viruses.

That isn't the case. The vaccine covers some anal (90% attribution to HPV), oropharynx (12%) and penile cancers (40%), too. Yes, there is such a thing as penile cancer. The common treatment for it is a fate that most men would consider worse than death.

So, with all of this information, why are parents so hesitant to vaccinate their children? Is it because the viruses that can cause these cancers are sexually transmitted, and they see their children as too innocent to need this type of vaccine?

I don't have a reference for this, but last time I checked, 100% of people who have sexual intercourse were children at one time (And some still are).


http://www.nytimes.com/2010/10/29/us/29vaccine.html?_r=2&partner=rss&emc=rss

http://www.cnn.com/2009/HEALTH/09/09/fda.gardasil.males/index.html?iref=allsearch

http://www.cnn.com/2008/HEALTH/dailydose/11/19/hpv.vaccine.info/index.html?iref=allsearch

http://onlinelibrary.wiley.com/doi/10.1002/ijc.21731/full

Battle Between the Sexes

Gender is potentially playing a role in the abuse of prescribed pain medication (opioids) according to a recent studying involving 662 chronic noncancer patients (half male, half female) taking opioids for pain relief. According to researchers, women are more likely to abuse prescription medication because of psychological distress while men are likely to abuse as a result of social and behavioral problems. Based off such hypotheses, researchers hope to eventually pitch this to doctors in the hopes that, if prescriptions are administered with the patient's gender/emotional state in mind, they can work towards minimizing abuse amongst sexes.

The study demonstrated that both genders reflected similar drug behavior upon administration but had different risk factors for medicinal abuse. Women were more likely to reveal traumatizing events from sexual/physical abuse earlier in their life once medicated. Women also tended to emotionally withdraw while men engaged in anxious and criminal-like behavior. They concluded that women experiencing high stress levels and pain that is not related to cancer should be treated for mood disorders and counseled on dangers that will arise from dependence on self-medicating. Men with noncancer pain should be monitored for behavioral problems, their pills should be counted and urine samples should be taken frequently.

I think it is interesting to do a comparitive study between males and females with respect with drug abuse. I like the direction the researchers and the study was headed but I think it generalizes men and women a lot. Everybody has different reasons for abusing medication and typically responses to drug abuse vary per person. Sometimes a second response to medication can even be different than the first response. Sometimes behavior goes from one extreme to the other after one round of dosage. Behavior can be rather variable. I understand where they are coming from, though, and I could be totally wrong -- maybe MOST men and women DO demonstrate the behavior described in the study. I only have had one encounter with someone abusing prescription drugs and ironically, she admitted to being sexually and physically abused under drug intoxication. Maybe there is something to this generality! I would be interested to see more studies similar to this. Whatcha think??

http://www.medicinenet.com/script/main/art.asp?articlekey=115868

Shoot some steroids

Cortisone, a type of steroid released by the adrenal gland when the body is under stress. It can be synthetically produce in which it can then be used as an anti-inflammatory drug that is injected into the area of inflammation instead of being injected into the bloodstream. Injecting synthetic cortisone does not treat the pain, only the inflammation, which would mean that the pain decreases because the inflammation is gone. Very high concentration of this medicine can be injected at the area while keeping side effects to a minimum. The most common side effect is "cortisone flare" where the cortisone crystallizes and causes some pain for a day or two. No allergic responses occur since its a natural occurring product. Some common conditions that cortisone is used to treat are shoulder bursitis and tennis elbow. Although injection can hurt a little, it is very effective short term.
What do you guys think about the use of cortisone.


http://orthopedics.about.com/cs/paindrugs/a/cortisone.htm

Pesticides: A link to Parkinsons?

Curious about the affects of boxing and Parkinson's disease I searched for an article that could maybe explain in detail why many boxers suffer from Parkinson's disease later in life. However, my quest for this information brought me to an article on Web MD about pesticides and their possible influence on Parkinson's disease. Being a review article it does not go into much detail about the manners in which they believe prolonged exposure to pesticides can be linked to the disease. I found this interesting in that I have not heard of this possible link until now. I then searched other sources for further information and found that a study with more than 300 Parkinson's sufferer found that sufferers were more than twice as likely to report heavy exposure to pesticides over their lifetime. The strongest associations were between people with Parkinson's who had been exposed to herbicide and insecticide chemicals such as organochlorides and organophosphates. No links were found between Parkinson's disease and drinking well-water or living or working on a farm, two commonly used proxies for pesticide exposures. They also believe that genetic disposition for Parkinson's also plays a role in the onset of the disease after prolonged pesticide exposure. Although evidence is not definite I find this possible link very crucial and hope to see more research conducted behind these findings.

Smoking and Crohn's Disease

Smoking and increased sugar intake have been found to be the only consistent environmental risk factors for Crohn's disease. There has been an association found between smoking and increased added sugar intake; 51% of people who have an increased sugar consumption in their diet reported being a smoker and in the group of people who reported no increased sugar added to their diet, 20% were smokers. This study used patients from a cohort that they had been following for 2-4 years, with no new patients diagnosed with Crohn's disease were used. This narrowed the ability to see the impact of those who start smoking after being diagnosed with Crohn's disease versus those who have already been smoking for a number of years and are newly diagnosed with Crohn's disease. In many Crohn's disease patients now, they have a knowledge of the link between Crohn's disease and smoking and increased sugar intake, so it is hard to run new studies on the link between Crohn's disease and smoking.

Opioid, Darvon, Linked to Dangerous Heart Rhythms

The painkiller, Darvon, a narcotic painkiller similar to morphine and oxycodone, and related brand, Darvocet (propoxyphene + acetaminophen), was reported to have been taken off the market as it is potentially linked to acquired dangerous/fatal cardiac dysrhythmia (by adversely altering electrical activity of the heart), suicide and accidental overdoes. The FDA has also ordered companies compounding drugs with the active ingredient for Darvon, propoxyphene, to be removed from shelves.

Despite acknowledgment of potential cardiac dangers from propoxyphene administration and shelf removal, the director of FDA's office of surveillance and epidemiology said patients should continue taking their Darvon prescription until their doctor prescribes an alternative pain reliever. Thoughts on this?

In 2009, the FDA rejected the notion to remove Darvon from shelves and decided to add a bolder warning label regarding overdose to the drug as an alternative.

Since the removal of the drug, drugmakers are working to compound alternative pain killers.

What do you guys think? Do you think the FDA's initial choice in slapping a "bolder" warning label on Darvon would lead to less overdoses? Personally, I do not find that alternative to be an efficient measure in preventing overdoses of consumers. There are warning labels on cigarettes and alcohol regarding birth defects yet people still continue to to smoke and drink while pregnant. If the drug is demonstrated to alter the electrical activity of the heart, it should be removed and an alternative drug should be administered instead. I like my electrical activity the way it is, thank you!

http://www.msnbc.msn.com/id/40274692/ns/40278426

When good cells go bad

Our primary defense against the outside world is our immune system. It is a complex system created with the sole purpose of protecting our bodies from various foreign invaders. Over many years of evolution, it has become particularly good at identifying, isolating, and eliminating potential threats. However, what if those same defenses turned on us? What happens when the immune system can no longer tell the difference between friend or foe? This occurs during autoimmune conditions, when the immune system attacks one’s own cells and tissues. To date, several disorders are linked to this condition; one example brought to light recently occurs during the onset of type 1 diabetes (T1D) in children. Evidence that regulatory CD4+ T cells (Tregs) suppress the activation of autoreactive T cells and maintain self tolerance has led to the hypothesis that Treg dysfunction is a major factor underlying the development of T1D (Sakaguchi et al.)

The best characterized Tregs are those that express the FOXP3 transcription factor, but although FOXP3 appears to be an accurate marker of Tregs in mice, it is also expressed by activated nonsuppressive T cells in humans (Ziegler et al.) This research, reported in the Journal of Immunology, demonstrated how dysfunctional Tregs are a key contributor to the onset of T1D in children. In humans, it has been shown that nonsuppressed T cells express a transcription factor FOXP3 and it has been established that cells that overexpress IL-17 can lead to T1D (Marwaha at el.) T1D patients have been shown to have elevated levels of IL-17-producing cells but there was no relevance shown. Recently other research groups have shown that cells that express FOXP3 can produce IL-17, and that Treg cells can transform into IL-17-producing cells (Voo et al.) This lead to a further discovery that a specific subset of Treg cells can avoid suppression and produce IL-17. This type of cell is known as (CD45RA^-, CD25^int, FOXP3^low). In this study, it is shown that populations of this particular subset is increased in patients with the onset of T1D. Overall, it is evident from this research that our greatest defense can also be our greatest threat if not regulated properly. Although this discovery could benefit T1D patients in the future, researchers have yet to come up with a strategy to circumvent this regulatory dysfunction.

Baby Aspirin > Aspirin

Aspirin (acetylsalicylic acid) is an anti-inflammatory that suppresses prostaglandins and thromboxanes. Inhibiting prostaglandins is responsible for the anti-inflammatory effects, while inhibition of thromboxanes inhibits platelet clotting.

Aspirin is recommended daily for people with a high risk of CV disease to prevent blood clots. A study by HealthCare Gill Heart Institute at the University of Kentucky recommends taking a baby aspirin (81mg) instead of a full dose (325g) to minimize adverse effects of aspirin such as GI bleeding. Even diabetics were not recommended to take the full aspirin dose.

While overdose is not as large a concern as with acetaminophen, there are still issues with dosing that are being revised, even for a drug that has been in use since the 1800’s.

http://www.webmd.com/heart-disease/news/20070508/baby-aspirin-may-be-best-for-heart

Killer Tylenol!

After today's discussion on Tylenol and how easier it is to overdose from it instead of say, Ibuprofen. I looked up a couple websites.

The first is an excellent review on the pathophysiology of Tylenol and how we metabolize it. Interestingly, 90% of acetaminophen is metabolized in the liver and it also mentions that "acetaminophen poisoning is the most common cause of acute liver failure and overdose deaths."

http://emedicine.medscape.com/article/1008683-overview

This next article talks about how a man apparently took Tylenol as recommended and still had liver failure and in need of a transplant!

http://abcnews.go.com/Health/PainNews/story?id=7699582&page=1

This last one is just some more interesting history on other ways Tylenol can kill you, but not exactly...

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

Updates in Treg Mediation in Parkinson's?

The article I reviewed, Neuroprotective activities of CD4+CD25+ regulatory T cells inan animal model of Parkinson’s disease, identified Tregs as a potent modulator of microglial activity in MPTP mice, the animal model for Parkinson’s disease. In the conclusion, the author states that the “importance of the observations in the present study rests with the idea that they can be readily translated to the clinic,” noting the recently discovered mechanisms of Tregs in the disease as potential areas for clinical manipulation. However, as noted in class, we are not able to simply inject Tcells into Parkinson’s patients. I have looked for information regarding the use of Tregs in neurodegenerative diseases, primarily Parkinson’s disease, since the study was published in 2007. Cell death of dopamine secreting cells is the primary problem in Parkinson’s, and as such, the primary treatment is still dopamine supplementation rather than inhibition of cellular death. Sources like Google Health, Web MD and Mayo Clinic, which provide information to the general public, do not even mention the inflammatory regulation of the disease, indicating that influencing concentrations of T regulatory cells has yet to become a viable option for treatment, despite the articles assertions that the study could be “readily translated to the clinic.” Furthermore, I have had difficulty locating follow up studies regarding the induction of T regulatory immune responses in neurodegenerative diseases. I would be interested to know if anyone has heard of further developments in these studies, or if the article was simply overenthusiastic in its belief that studies could translate to human trials.

In vitro vs. In vivo Alzheimer's Research and the Brain Environment

One of the major problems with research related to Alzheimers Disease pathogenesis is being able to appropriately mimic the pathogenic brain environment in vitro. Alzheimer Disease is related to the activation of microglial cells via its interaction with fibrillar Amyloid Beta plaques. However, the microglial cells have an array of phenotypically distinct activated states. In one case the microglial cells are activated in the classical M1 state, which is a state that corresponds to high expression of pro-inflammatory cytokines, another is called the M2 activated state which has a more immunoregulatory profile. The phenotypes get even more complex when now the M2 state can be subdivided into categories M2a, M2b, and M2c, all with there own distinct cytokine releasing profile. These different activation states are all regulated by the glial cells surrounding environments. This hasn't been a problem in vitro, because researchers can make there own environments and measure what comes of the activated cells, however in vivo they don't have this luxury because all these environments and activation states are working together, which is why it has been so difficult to successfully define the pathogenic mechanism of Alzheimer's.

A good example of this was stated in an article recently published in the Journal of Neuroscience, it was saying that Toll like receptors (TLRs) have a definitive role in the activation of glial cells response to Amyloid Beta plaques in vitro, but in vivo mice models with AD the situation is much less clear. Some transgenic mice with inactivated TLR's saw an increase plaque accumulation while others had extremely delayed plaque deposition. This obviously shows that however in vitro research can show such concrete findings, things get so much more complicated in the in vivo environment. I wasn't really aware of this, I always thought that we were at such an advanced stage of research that these types of problems were long gone. So to me this is a little disheartening, it says that we are a long ways away from finding a distinct cause, let alone a cure for this horrible debilitating disease.

The Journal of Neuroscience Article explaining this: ishttp://www.jneurosci.org/cgi/content/abstract/30/46/15369

Dogs and Neurodegenerative Diseases

Neurodegenerative disease in dogs?? This question posed in discussion on Monday led me to ponder if such evidence had ever been found. On the website "Science Daily" I was able to find a review article published in August of this year titled, "Gene Responsible for Neurodegenerative Disease in Dogs, Possibly Humans, Discovered". The article was about Dr. Natashy Olby an associate professor of neurology at North Carolina State University who, along with a team of researchers, located a the gene responsible for a variant of Neuronal Ceroid Lipofuscinoses (NCL). My curiosity in exactly what NCL lead me to Web MD which describes NCL as a "group of neurodegenerative disorders" that are associated with variable yet progressive symptoms including seizures, dementia, visual loss, and/or cerebral atrophy. The pathophysiology of NCL is described as apoptosis and dysregulated sphingolipid metabolism. Although NCL, is rare in humans it is known as a disease in canines that results in mental and motor deterioration and eventually death in that affects American Staffordshire terriers. It is most common in children, although there is an adult-onset form called Kuf's disease. In this rare adult case, neurons in the brain die which then leads to loss of vision, epilepsy, dementia and loss of coordination. Researchers were able to locate this specific gene in canines through the use of genetic analysis. Being a review article, it did not go into detail as of how this genetic analysis was conducted. However, Obly claims that this mutation in canines is the novel nature of the mutation which means that researchers can now take and test samples from humans with NCL to determine whether this same mutation causes Kuf's disease in people. For more information on the pathophysiology of NCL and the mechanisms you can visit the Web MD site.

http://emedicine.medscape.com/article/1178391

So is it sodium or Potassium??

Scientists at Salk Institute for Biological Studies have recently found an connection between two ion channels which may be the reason for many symptoms that classically characterize Multiple Sclerosis. As we have gone over in discussion, Multiple Sclerosis is a chronic demyelinating disease in which the immune system attacks the insulating myelin sheaths of axons in the CNS. This consequently is the cause of the many neurological symptoms that accompany MS such as; numbness, tingling, muscle weakness, paralysis and vision loss. Myelin sheaths speed up the signals that axons transmit. However, once damaged, axons are no longer able to generate an impulse (causing loss of sensation and weakness) or may become hyper excitable and then overcompensate by firing even in the absence of input which causes twitching. In either scenario, the improper transduction of signals is the root of many symptoms MS patients suffer from on a daily basis. In this particular study Terrence J. Sejnowski, the head of the Salk Institutes Computation Neurobiology Laboratory and leader of the study, created a computer model of axonal transmission with myelinated and demyelinated sections. They then used a program that modeled every part of the axon by breaking it into segments. They did this in order to keep track of the ions (particularly sodium and potassium) going in and out of each section. In many previous studies, scientists had focused on the sodium channel in particular. This being because the sodium channel is responsible for initiating the action potential. Hence, many MS drugs also focus on sodium channels. However, in this study scientists were surprised to see that it wasn't merely the amount of sodium, but the ratio of densities between the sodium and potassium channel that sets the ground state current of the neuron, which then determines whether the neuron can fire properly. They found this when their study demonstrated that drops in sodium levels that were followed by a drop in the leak current levels (potassium levels) maintained the signal of the neuron. They then found that if the sodium levels dropped and the leak current (potassium) didn't, signal transmission may fail. Therefore they were able to conclude that, "Trying to influence the balance between the two ion channels is a completely new approach, and drugs that target leak current could be as important as those targeting sodium current" - Sejnowski. Sejnowski and his group plan on further investigating the sodium/leak current as it can have application to other medical issues along with Multiple Sclerosis and other demyelinating diseases. With this study they could possibly open up a whole new perspective on signal transduction in MS which could hopefully bring about creation of new medicines to help MS patients alleviate the chronic symptoms that accompany this so far incurable disease.

AGE, not Advanced Glycation End-product..but, AGED GARLIC EXTRACT!!???

Recently, in Tucson, I discussed the role of Advanced Glycation products and their role in promoting inflammation in the body. Furthermore, these products (AGE) were known to have several degenerative mechanistic roles - in particular, the active release of histamine from Mast Cells. AGE products can also motivate this direction from using ROS (reactive oxygenic species) in pushing the release of histamine from these mast cells.

Lately, I was looking up some preventative measures against AGE and ROS mediated inflammatory processes and I was able to find a cure that used the same anachronism as AGE: aged garlic extract. It is believed that Garlic, under proper conditions, can be a tool in preventing ROS compounds from reacting and having the numerous counterbalances on the body. This is mainly tied to its anti-oxidation effects.

http://www.needs.com/product/HWC06-ESS-06/l_Garlic

If one things about it, Garlic could also prevent measures of advanced glycation, since the chemistry of these compounds can be comparable to ROS. They just seem to be highly oxygenated components that haven't experienced a proper experience with cellular metabolism.

From my perspective, I see this as being an active stride against neurodegenerative disease. But, the article seems to be more concerned about it preventing cardiovascular disease and aging - not to say that it couldn't have a pivotal role in keeping neurological order in tact. Let's keep in mind here that these are all inflammatory-related diseases.

Reduce, Reuse, Recycle - Where the Heck is all that DNA Coming From?

Traditionally, two types of cell death have been characterized. Necrosis, that is thought to be unregulated and passive, occurs when a cell is damaged or harmed. Necrosis may lead to inflammation because of the deleterious effects of spewing intracellular contents. In contrast apoptosis is described as programmed cell death, or ordered cell death. The membrane blebs and the chromatin breaks apart, the cell breaks up, but neatly with the cellular contents being enclosed in membrane bound vesicles called apoptotic bodies. Apoptotic bodies are engulfed and endocytosed by phagocytic cells such as Macs and DCs. Multiple proteins, genes, and pathways have been discovered that are important in apoptosis. Lately, one of the hottest topics in immunology has been autophagy. At first it was seen simply as a means through which the cell could respond to stress, eating itself in lean times. Research has been intense in the past five years, and other purposes for this mechanism have been described such as in the controlled destruction and turnover of aging organelles and damaged proteins (3).

Relatively recently a new programmed death mechanism has been uncovered that is unique to leukocytes. Neutrophils and mast cells have been shown capable of activating ETosis. When executed by a neutrophil, it is refered to as NETosis, or the eventual death of the cell due to the formation of neutrophil extracellular traps. In response to bacteria in their environment, neutrophils are capable of casting net like structures on extracellular bacteria. Great high resolution scanning electron micrographs of the NETs are in (2). They consist of smooth fibers with strung globular domains. The smaller fibers have a diameter of 15-17 nm that can assemble into bundled fibers with a diameter up to 50nm. The globular structures have diameters of up to 25 nm. Fonseca et al. demonstrate that the structures consist of DNA and histones, as well as proteins such as elastase (localized to the globular domains) lactoferrin, and gelatinase. The NETs can kill both gram positive bacteria such as Staphylococcus aureus, and gram negative bacteria such as Salmonella typhimurium and Shigella flexneri. The proteases present in NETs, such as elastase, are also capable of disarming secreted bacterial virulence factors such as IcsA and IpaB. In addition, histones in the NET have strong bactericidal property (2). The NETs also physically trap and sequester bacteria, while keeping proteases released by the neutrophil from spreading through tissue (2). The development of NETs follows the decondensation of chromatin and the disintegration of the nuclear envelope and other intracellular membranes (1). Remijsen et al found that NETosis occurs after the initiation of autophagy and superoxide production.

Part of the important function of powerful phagocytes such as this is to clean up and recycle cell debris. In fact this process in pAPC is one route in which autoimmunity may occur (presentation of self-Ags on Macs or DCs leading to activation of Tcells against self). One of the important functions of apoptosis is also another method in which this cellular debris is controlled and degraded in a “safe” manner.

Though NETs would presumably be functional in all people (to achieve optimal immune function) perhaps it goes awry in some. With the uncontrolled dissemination of DNA and histones into tissue, could ETosis be a mechanism through which autoimmunity is initiated. Self DNA appears to be a target of autoimmunity, as SLE patients produce anti-DNA.

(1) Neutrophil extracellular trap cell death requires both autophagy and superoxide generation.

Remijsen Q, Berghe TV, Wirawan E, Asselbergh B, Parthoens E, De Rycke R, Noppen S, Delforge M, Willems J, Vandenabeele P.

Cell Res. 2010 Nov 9. [Epub ahead of print]

(2) Neutrophil Extracellular Traps Kill Bacteria.

Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A.

Science. 2004 Mar 5; 303(5663):1532-5.

(3) Regulation of mammalian autophagy in physiology and pathophysiology.

Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC.

Physiol Rev. 2010 Oct;90(4):1383-435. Review.

Diseases in Animal Models

I had never really thought of the complications that could arise when studying a disease that we either don’t know the source or can’t directly translate the disease to an animal model. In an article from Nature Neuroscience, the authors describe how chronic exposure to rotenone, a pesticide, can be used as a more accurate model for Parkinson’s than the MPTP, the standard animal model. They note that MPTP produces symptoms that are almost identical to idiopathic Parkinson’s. It functions by inhibiting Complex I in the inner mitochondrial membrane, which shuts down the electron transport chain, leading to loss of ATP and formation of ROS. However, they also point out that MPTP tends to elicit a systemic response as well, targeting platelets and other tissues. The paper goes on to describe how rotenone, which also inhibits complex I, can be used to produce a better animal model. Both these methods induce a problem that mimics Parkinson’s. Yet the actual cause of Parkinson’s is unknown, so how applicable are studies that improve symptoms if the symptoms are induced by a different mechanism. I know Dr. Cohen talked about the difficulties of inducing diseases like diabetes in animal models, and I’m sure the same holds true for many diseases. I was wondering, for those of you who are involved in research, if not having an exact model of the disease makes switching to human trials more difficult than if the disease can be directly translated to animal models, even if the study seems to be producing successful results?
Article
www.nature.com/neuro/journal/v3/n12/full/nn1200_1301.html

A non-immune mediated sequestering of Amyloid Beta

In a paper published in 2003, "Novel Therapeutic Approach for the Treatment of Alzheimer's Disease by Peripheral Administration of Agents with an Affinity to B-Amyloid", it was reported that in a mouse model of Alzheimer's, amyloid sequestering proteins were effective in removing CNS plaques without inducing inflammation.

In brief, the researchers utilized the idea of a CNS:Periphery dynamic system in which a shift in equilibrium could result in removal of an offending agent. To accomplish this, mice with advancing plaque formation were treated with two bovine derived factors with known ability to sequester amyloid. Mice were treated with one or the other, a third group was treated with vehicle solution.

The results showed that the treatment was effective in removing the plaques, although it was unclear whether the damage could be undone. Although this presents an interesting target for future therapy, the use in humans will depend on the mouse model being an accurate depiction of Alzheimer's pathogenesis. It was also mentioned that the treatment was most likely most effective as a prophylactic treatment, rather than a rescue treatment.

When the bee stings...

Haha, AlfonsoR595, scooped me on posting about venom first, but that's okay because (fortunately) I was writing a post about how insect venom can be pro- and anti- inflammatory and it's potential uses. This is especially in response to all of the postings about rheumatoid arthritis, and adds to the therapies for multiple sclerosis that we touched on on Tuesday. Enjoy!

____________________________________________________________________

How about ditching the pills and using "bugs as drugs"? A review article published this year in Alternative Medicine Review, briefly discusses Oriental medicine's traditional use of bee and ant venom for treating arthritis and inflammation-related pain. They report the accumulations of others’ findings that the constituents in insect venom have anti-inflammatory properties, including SUPPRESSION of phospholipase A (PLA releases arachidonic acid which can be modified in downstream events to form inflammatory mediators), DECREASE in inflammatory cytokines tumor necrosis factor-alpha (TNF-α is a signaling molecule that promotes activation of NF-ĸB, which binds DNA and activates transcription of genes that result in inflammatory responses of heat, swelling, redness, pain, and loss of function in the local site), and REDUCTION in interleukin-1beta (IL-1β, when processed, can induce COX-2 which contributes to inflammatory pain hypersensitivity). In short, insect venom can inhibit various pathways that result in decreased inflammation.

However, I found this idea of using insect venom to combat inflammation to be very counter-intuitive, because don’t bee and ant venom induce inflammation and allergic reactions when you’re stung? After all, inducing pain, discomfort, and inflammation are these insects’ defense mechanisms so that a threatening intruder flees. Well, some of the peptides in the venom do directly mediate inflammation. One such molecule is mellitin, which accounts for 52% of whole insect venom and is implicated in inducing inflammation by lysing red blood cells. The insects’ defense mechanism also partially relies on your immune system’s reactivity. Many components of insect venom are immunoreactive and neuroactive peptides and your immune system will produce antibodies against them after the first sting, but usually without any serious symptoms the first time. Insect venom causes harm during repeated exposure to insect stings, when the body’s antibodies react to the presence of these foreign peptides and release histamines that cause inflammation, local immune cell response around the sting site, and the physical symptoms of an allergic reaction.

Interestingly, despite the apparent conflict in how it can be simultaneously pro-inflammatory and anti-inflammatory, insect venom has been widely studied and used in treating chronic inflammatory diseases, especially treatment of rheumatoid arthritis. Some multiple sclerosis patients actually undergo live bee sting immunotherapy, and bee venom is sold in over 20 products including creams, ointments, salves, or injection forms for treating human ailments. Recent studies are also finding that bee venom can inhibit tumor growth and be used as a chemotherapeutic agent against malignancy.

E.P. Cherniack (2010). Bugs as Drugs, Part 1: Insects. The “New” Alternative Medicine for the 21^st Century?

A. Mirshafrey (2007). Venom Therapy in Multiple Sclerosis. Neuropharmacology.

Venom make me feel...good?

So after Monday's discussion on the Bee sting article, I got curious and looked into other articles where animal venom actually reduced inflammation. This was an odd concept for me since I always pictured animal bites as being huge inflamed gashing wound. But as I thought about it a little more, I guess an animal who's venom decreased inflammation would be more "deadly" since it would have the same potency while still avoiding the "victims" natural immune response.

Anyway, this is the article that I found:

http://www.academicjournals.org/ajpp/PDF/pdf2010/March/Dkhil%20et%20al.pdf

Also, this article on cobra venom reducing arthritis was cool too:

http://news.discovery.com/animals/cobra-venom-arthritis-pain-relief.html

Thoughts?

Left-Handedness: Its Association With Allergic Disease

It has been hypothesized that inconsistent cerebral dominance is related to immune disorders and the high prevalence of autoimmune diseases have been found in the left-handed individuals.

In the method, the Edinburgh Handedness Inventory was used to evaluate 313 atopic patients’ left-and right-handedness. The results from atopic patients were compared to 350 control individuals with same age and sex. It was found that more left-handed individuals were atopic patients.

As a result of this experiment, the number of left-handed individuals was higher among atopic group than non-atopic group. Therefore, it was concluded that there was an association between left-handedness and allergic diseases like rhinitis, asthma, eczema and urticaria.

Its mentioned in the article that incidence of left-handedness was found to be more common in males than females. Geschwind and Behan proposed a theory to further explain male left-handedness. During male fetal development testosterone production decreases the development of the left hemisphere, mostly the language region. In addition, they proposed that increased levels of testosterone could interfere with the development of immune system by suppressing fetal thymic growth. As a result of defect thymocyte development, thymus cannot properly go through the negative selection process, which can lead to autoimmune diseases.

Although the findings of this study supported the hypothesis, I think more research is needed to validate this study with many more subjects.

Jocelyn, Smith. University of York, Department of Psychology, Heslington, York YOl SDD, U.K. http://www.sciencedirect.com/science

The fist case of Yellow Fever trasmitted through breast-feeding

I found an interesting article that describes the first laboratory-confirmed case of the Yellow Fever vaccine being transmitted through breast milk. The infant is also the youngest reported case of yellow fever associated neurological disease (YEL-AND). The mother was vaccinated shortly after giving birth when a yellow fever (YFV) epidemic spread to the mother's home town in Brazil, which was a nonendemic area. Five days later the mother developed a low fever, headache, and malaise (all normal side effects of the vaccine); three days later the infant started showing symptoms including fever, arability, and seizure-like activity. The infant was admitted to the hospital for meningoencephalitis. YFV was confirmed by type-specific antibodies in the serum and CSF; virus was also detected in the CSF by RT-PCR. The sequence that was found by RT-PCR was identical to the 17DD yellow fever vaccine virus; the vaccine is live, attenuated. The infant recovered without any long-term neurological damage.

YEL-AND has been reported in children under six months old occurring at a rate of 50-400 cases per 100,000 vaccinated. Vaccination of children under six months old is not recommended by the CDC because of the increased risk of YEL-AND. The advisory committee on immunization practices also discourages vaccinating breast-feeding mothers to avoid possible transmission to the infant, as seen in this case.

The detection of YFV in breast milk has not been seen before, although West Nile Virus (WNV), another flavivirus, has been detected in breast milk before. There is one probable case of WNV transmission through breast milk. Both YFV and WNV are normally transmitted by container breeding mosquitoes. I think that it is interesting that there is evidence of another mode of transmission for these two viruses. It would be interesting to see if other flaviviruses such as Dengue, Japanese Encephalitis, and St. Louis Encephalitis can be detected in breast milk as well.

"Transmission of Yellow Fever Vaccine Virus Through Breast-Feeding---Brazil,2009." Morbidity and Mortality Weekly Report. 12 Feb. 2010

Depression and Immune Function

Obviously stress, depression, and other psychological factors are difficult to study objectively and even more so in conjunction with something as complex as the immune system. However, there have been new studies recently that suggest that our preconceived notion that immune function is compromised during depressed states may not be true. In fact, it has been shown that depression ramps up immune response, cytokine production, and overall dysregulation in most cases. We are also starting to understand the roles of certain immune mediating medications (IL-2, interferon, etc) that are, in fact, inducing symptoms of depression. The results are not as subjective as one might think. The article is a quick read and not overloaded with technical jargon.

http://www.biopsychiatry.com/immunesystem/index.html

Clever parasites keep their enemies closer

I found an interesting article that talked about the method of infection by the intestinal parasite H. polygyrus. When it infects a host it releases a mimic of TGFB, this cytokine is fundamental in the development of T regulatory cells. The idea here is that to avoid the hosts defenses that are bent on destroying the parasite it releases this mimic cytokine to promote the one inflammatory cell that can “help” them, the Treg. By promoting the Tregs the surrounding environment is much friendlier because the other T helper lines are told to stand down. The researchers tested to see it if was similar enough to human TGFB by running an ELISA, but nothing was found showing two things. It is created by non host and it is not simply the parasite accumulating the cytokine from the periphery and releasing it in bulk. They also analyzed the effect of the mimic on the SMAD 2/3 pathway and it showed activation on the pathway showing that it is a viable mimic that binds the receptors. Also when they brought down the ability for the mouse to respond to the TGFB the burden load of the parasite was much lower indicative that the immune response was better able to clear the infection. This is a very novel (and clever) way to evade host defenses by means of upregulating the anti inflammatory response and a slightly easier life for the parasite.

Atricle from:

The Journal of Experimental Medicine

Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway. John R. Grainger, et al.

Published September 27, 2010 // JEM vol. 207 no. 11 2331-2341
The Rockefeller University Press, doi: 10.1084/jem.20101074

On binge drinking and the brain

The link between brain ischemia, and inflammation as a result of cellular stress markers has been well established. Historically the origins of brain damage and decreased cognitive ability in those that engage in chronic binge drinking was poorly understood. Some evidence from the mid-seventies showed that ischemic brains (similar to those observed in post-mortem alcoholics) showed a significant increase in resident leukocytes.

In this study, rats were given high doses of ethanol while observing brain venules with intravenous microscopes. The researchers found that leukocyte adhesion and rolling velocity were increased, and decreased respectively proportionally to ethanol dose. They also observed a concentration dependent relationship between ethanol levels and microvascular rupture. These effects were quite disturbing even in concentrations that would render someone unable to drive under law (~0.08%). That is, assuming that rats share similar concentration/subjective intoxication relationships with humans.

This study, and several other related studies seem to highlight that repeated binge drinking can result in significant immune dysregulation at the blood brain barrier. Of great interest, is that depletion of circulating leukocytes seems to offer a protective effect against the microvascular damage.

I find it interesting that alcohol induces such a marked pro-inflammatory state, and will definitely have me thinking twice when the time comes to order either another drink or a water. Any thoughts?

Sources: http://dl.dropbox.com/u/6429973/sdarticle.pdf

Anecdotal account of a lethal autoimmune condition

A 20 year old man, B.M., developed a severe inflammation of his right knee, necessitating surgery. No infection was present. Subsequent medical evaluations determined that a prior Chlamydia infection had provoked an autoimmune response, and over the next 20 years he lost mobility because of ongoing damage to his knees, ankles, toes, spine, neck and shoulders. At this point the damage wreaked by his disease began to take its toll on his internal organs. His kidneys ceased to function, being physically clogged by precipitated amyloid protein, and his spleen, four times normal size, was surgically removed. A kidney transplant ultimately failed, because of the presence of cytomegalovirus in the transplanted kidney, which the antirejection drugs allowed to proliferate and destroy its function. The individual spent his last 8 years on peritoneal dialysis, and even superficial wounds were extremely slow to heal. He died at age 50 from sepsis from the open wounds on both feet through which his heel bones protruded. He weighed 102 pounds. His initial diagnosis was Reiter's Syndrome (a condition where autoimmunity develops in response to infection in another part of the body), but the symptoms presented much later in his disease were not entirely consitent with the earlier diagnosis. Doctors began to think his condition was more consistent with symptoms of Systemic Lupus Erythematosus, however, his extreme and eventually lethal condition may not have fit any of the recognized categories of an autoimmune disorder.
This was a real individual: he had a degree in electrical engineering, and was employed by General Electric, writing computer code for safety systems for freight rail systems.

Postoperative Cognitive Dysfunction; a possible link between anaesthetics and Alzheimers disease

Our discussion of neurodegenerative disease on Monday left me thinking about my uncle who was recently diagnosed with dementia. I, like any other naive college senior, thought that my uncle was suffering from dementia related to old age. However, what I came to learn was that my uncle was actually diagnosed with anaesthesia-induced dementia, what is also known as Postoperative Cognitive Dysfunction (POCD). I don't know about any of you, but I had no idea that there was such a condition. We all know that anesthesia can induce memory loss, and have other side effects, but I did not know that there was an actual clinical diagnosis of anaesthesia-induced dementia. I did some research and found that this has been a highlight of the research world and that POCD shares a molecular mechanism with Alzheimer's Disease.

Most anaesthetics involve the use of antagonists of the muscarinic and nicotinic neuronal acetylcholine receptors. When active, these pathways serve to regulate Amyloid-B protein synthesis. Thus, there seems to be a link between the inhibition of these pathways and the increase in the Amyloid-B protein in its insoluble form (the precursor for plaque generation). Also some anaesthetics have been shown to affect oligomerisation of the amyloid beta peptide to it's insoluble beta sheet form.

Some anaesthetics have also been shown to induce apoptosis in neuroglioma cell lines in the brain. Apoptosis is said to increase the cleavage of amyloid precursor to B-amyloid peptide, which increases its aggregation into plaques, causing further apoptosis, resulting in a vicious cycle of apoptosis, aggregation of beta amyloid, and further apoptosis.

POCD is most prevalent in the elderly because they already have a higher concentration of the Amyloid protein in their brain. The incidence of POCD is increasing because with the longer life expectancy in humans, older and older people are undergoing more serious surgeries so we are seeing more cases of the unfortunate disease. However, because there seems to be this mechanistic link between POCD and Alzheimer's, it is giving researchers insight and more ideas into the progression and molecular causes of Alzheimer's Disease. If you would like to read the review on POCD, the link is below.

http://xa.yimg.com/kq/groups/1099152/1976222979/name/alzg.pdf

Therapy for Neurodegenerative Disease

As we all know, there aren't any substantiated cures for many Neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's, etc.). But, recently in Tucson, some of Zoe Cohen's students recently read an article about some patients who underwent a surgical procedure in using fetal cells in the brain. The exact reasoning as to why the procedure worked was not really explained, but the surgery did prove to be a success.

After discussing this article, I went ahead and looked into other aspects of how therapies can be revived or articulated to help combat neurodegenerative diseases. Since a significant portion of these diseases are initiated from certain genes (like Huntington's and Parkinson's), some reasoning for the use of fetal tissue was explained in one particular aspect of this journal. Another approach contemplated a usage of RNA interface, which could keep certain genes , or defective genes, from being expressed under normal conditions.

I'm posting the article where alot of this is shown, but keep in mind that this doesn't really solve the problem. It just sheds light on therapeutic approaches.
http://bjp.rcpsych.org/cgi/content/full/178/5/392

More on Infliximab

We've heard the drug Infliximab mentioned a few times in our class readings (IBD, arthritis, nuero-degenerative disease...) It is an anti-TNFa drug often used to combat inflammatory diseases. The following article discusses effects of Infliximab on body composition and BMD.
http://7thspace.com/headlines/361040/infliximab_therapy_increases_body_fat_mass_in_early_rheumatoid_arthritis_independently_of_changes_in_disease_activity_and_levels_of_leptin_and_adiponectin_a_randomized_study_over_21_months.html

The conclusions from the study find that overall body fat mass increases while patients are taking the drug. Muscle and bone loss was prevented as well. The interesting part is that the fat mass increase is not associated with an increase in atherogenic lipids. In fact, there was an increase in adiponectin that the researchers suggest is a possible reason for the protective effects for heart disease in patients on Infliximab.

On a side note, there are no citations for this article. After a google search for these terms, there were no results outside of this article.

Biologic response modifiers (BRMs) target TNFα

The most recent treatment of rheumatoid arthritis (RA) has been the development of drugs called biologic response modifiers (BRMs). They are a subset of the class of drugs known as disease modifying anti-rheumatic drugs (DMARDs), which are a variety of arthritis medications known to treat arthritis symptoms and slow down progression of joint destruction.

BRMs are medicines which are based on compounds that are made by living cells. Some of BRMs are used to treat rheumatoid arthritis by targeting specific component of the immune system called TNFα, which can increase inflammation and tissue damage.

Enbrel® (entercept) is a TNFα blocker that contains man-made protein and binds to TNF-alpha. It acts like a sponge to remove the TNF-alpha molecules from the joints and blood. It has proven effective at preventing the progressive destruction of the joints in patients with rheumatoid arthritis. Enbrel is given by self-injection once or twice per week. Studies show it may cause irritation at the injection site. Other common side effects include headache, dizziness and nasal and throat irritation. There have also been reports linking Enbrel to multiple sclerosis inflammation of the optical nerve.

BRMs are not for everyone, in some people, they may not work at all. For others, one biologic may not work but another may be effective. BRMs can cost at least $10,000 and more per year.

http://nydailynews.healthology.com/arthritis/arthritis-treatment/article4150.htm?pg=2