Sunday, February 27, 2011
Is XMRV Research Dying?
The recent weeks have left one to wonder - is XMRV becoming a dead issue like all other previous "causes" of Chronic Fatigue Syndrome? On the other hand, the neuropsychiatric psychobabble has begun to drown out good science.
Saturday, February 19, 2011
Watershed Paper Provides Conclusive Evidence of Underlying Pathology of ME/CFS and Fibromyalgia
The study "Adrenergic and Sensory Receptor Expression on Leukocytes Increases After Moderate Exercise in Chornic Fatigue and Fibromyalgia" by Alan Light et. al clearly demonstrate the physiological processes behind Chronic Fatigue Syndrome. Like many of the good papers that have come out, Dr. Light found himself having difficulty getting it published.
In simplified terms, you've got the muscles, a messenger in between, and then the recipient (nerve endings). The situation that results in Fibromyalgia and ME/CFS is as follows: Following muscle injury, white blood cells pick up certain chemical signals from the muscles, and pass them on to the nervous system, specifically the sympathetic nervous system. Using currency as an example: Excercise A produces 5 units of fatigue, and white blood cells in the muscles read 5 units of fatigue, and is supposed to pass on 5 units of fatigue to the central nervous system, but instead passes on 50 units of fatigue to the nervous system, or alternatively the white blood cells misread the signal, and pass on 50 units of fatigue to the nervous system. So in essence, the sympathetic nervous system is receiving a forged document.
How does the mechanism fit in? In both CFS/ME and Fibromyalgia, acid-sensing ion channels, P2X4 and P2X5 purinergenic receptors, adrenergenic receptors, transient vanilloid type receptors and IL-10 were upregulated. The only difference was that in Fibromyalgia, P2X4 (Pain signals) and TRPV1 (receptor responsible for binding capsaicin - causing burning pain) was dominant, while in CFS P2X5 (Fatigue signals) was dominant. The effects were that changes occurred within 30 minutes of exercise in both disease cohorts, while in normal subjects, there was a considerable delayed onset, returning to baseline within 48 hrs. The amounts measured in endurance athletes after running a marathon did not even come close to the levels attained in disease cohorts. Incidentally, activation of P2X4 receptors has the effect of lowering blood volume, and increasing vascular resistance.
The effect is that the brain perceives the body to be under tremendous stress - it is well established that stress fundamentally disrupts the HPA axis (There is nothing better than pain for disrupting the HPA Axis!). The brain then sends signals for bodily functions to slow down - which involves downregulating mitochondrial function. It also means an increase in serum cortisol early on, followed by a period of adrenal fatigue. Essentially, earlier studies on pain amplification in Fibromyalgia shed some light, but we now have a mechanism. It was earlier thought to be as the result of too much substance P at the nervous system level. It is mechanism that has been around since the mankind: when it hurts or when fatigued, the body sends a signal to the rest of the body to slow down.
How does this fit in with XMRV? Much research needs to be done on this. XMRV enters the cell via XPR1, which is a G-protein coupled receptor, which in turn invokes a reaction cascade in the cell. Retroviruses rely on retroviral promoters to replicate once they are integrated in human DNA. XMRV could act by enhancing the transcription of receptors involved in pain signals if the sequence of the XMRV promoter also binds to the same region that codes for pain receptors on the human genome - alternatively, XMRV triggers a signalling cascade through a G-Protein coupled receptor that upregulates pain receptors. The effect can be further enhanced by cytokines triggered by XMRV.
These findings create optimism in finding small molecule therapeutics for both disorders, however it does not address the underlying viral pathology. The ideal drug design target would be inhibitors of P2XR4 and P2XR5 - however the risk of side effects is always there with small molecule therapeutics. One of the therapeutics Lyrica (Pregabalin), works by blocking pain transduction by Gabaergic mechanisms. However, it is a dirty drug, targeting other systems as well.
In simplified terms, you've got the muscles, a messenger in between, and then the recipient (nerve endings). The situation that results in Fibromyalgia and ME/CFS is as follows: Following muscle injury, white blood cells pick up certain chemical signals from the muscles, and pass them on to the nervous system, specifically the sympathetic nervous system. Using currency as an example: Excercise A produces 5 units of fatigue, and white blood cells in the muscles read 5 units of fatigue, and is supposed to pass on 5 units of fatigue to the central nervous system, but instead passes on 50 units of fatigue to the nervous system, or alternatively the white blood cells misread the signal, and pass on 50 units of fatigue to the nervous system. So in essence, the sympathetic nervous system is receiving a forged document.
How does the mechanism fit in? In both CFS/ME and Fibromyalgia, acid-sensing ion channels, P2X4 and P2X5 purinergenic receptors, adrenergenic receptors, transient vanilloid type receptors and IL-10 were upregulated. The only difference was that in Fibromyalgia, P2X4 (Pain signals) and TRPV1 (receptor responsible for binding capsaicin - causing burning pain) was dominant, while in CFS P2X5 (Fatigue signals) was dominant. The effects were that changes occurred within 30 minutes of exercise in both disease cohorts, while in normal subjects, there was a considerable delayed onset, returning to baseline within 48 hrs. The amounts measured in endurance athletes after running a marathon did not even come close to the levels attained in disease cohorts. Incidentally, activation of P2X4 receptors has the effect of lowering blood volume, and increasing vascular resistance.
The effect is that the brain perceives the body to be under tremendous stress - it is well established that stress fundamentally disrupts the HPA axis (There is nothing better than pain for disrupting the HPA Axis!). The brain then sends signals for bodily functions to slow down - which involves downregulating mitochondrial function. It also means an increase in serum cortisol early on, followed by a period of adrenal fatigue. Essentially, earlier studies on pain amplification in Fibromyalgia shed some light, but we now have a mechanism. It was earlier thought to be as the result of too much substance P at the nervous system level. It is mechanism that has been around since the mankind: when it hurts or when fatigued, the body sends a signal to the rest of the body to slow down.
How does this fit in with XMRV? Much research needs to be done on this. XMRV enters the cell via XPR1, which is a G-protein coupled receptor, which in turn invokes a reaction cascade in the cell. Retroviruses rely on retroviral promoters to replicate once they are integrated in human DNA. XMRV could act by enhancing the transcription of receptors involved in pain signals if the sequence of the XMRV promoter also binds to the same region that codes for pain receptors on the human genome - alternatively, XMRV triggers a signalling cascade through a G-Protein coupled receptor that upregulates pain receptors. The effect can be further enhanced by cytokines triggered by XMRV.
These findings create optimism in finding small molecule therapeutics for both disorders, however it does not address the underlying viral pathology. The ideal drug design target would be inhibitors of P2XR4 and P2XR5 - however the risk of side effects is always there with small molecule therapeutics. One of the therapeutics Lyrica (Pregabalin), works by blocking pain transduction by Gabaergic mechanisms. However, it is a dirty drug, targeting other systems as well.
New Monkey Study
On one of my previous posts, I mentioned that a protein called APOBEC3 strongly exhibits retroviral replication. A recent study by Robert Silverman of the Cleveland Clinic confirms this finding. Five macaque monkeys were infected with XMRV - they showed an initial viremia, subsequently the virus became very difficult to find in the blood, but when the monkeys were sacrificed, the virus could easily be found in the spleen, lungs, lymphoid tissues, and prostate.
Ironically, the same patterns in certain blood cells were noted that exists in a cohort of ME/CFS patients. Also, the virus shows an initial acute phase, followed by periods of reactivation. Unfortunately, none of the animals displayed any clinical symptoms. The plausible explanation is that the length of the study was insufficient, or their immune systems were not presented with a challenge, or there was a lack of a necessary herpesviral co-infection to cause disease.
Ironically, the same patterns in certain blood cells were noted that exists in a cohort of ME/CFS patients. Also, the virus shows an initial acute phase, followed by periods of reactivation. Unfortunately, none of the animals displayed any clinical symptoms. The plausible explanation is that the length of the study was insufficient, or their immune systems were not presented with a challenge, or there was a lack of a necessary herpesviral co-infection to cause disease.
Monday, January 17, 2011
British Negative Studies are Scientific Fraud
What hinders good research? Ego. Period. Simon Wessely is a good example. He has a belief - that Chronic Fatigue Syndrome is a neuropsychiatric condition. So why would he want to try and replicate the XMRV findings then - Ego. To reinforce his beliefs. How do you do this - answer: pervert the results. How do you pervert scientific findings - answer: break the rules that in order for a scientific study to be valid, you have to copy exactly. So he obtained negative results, further reinforcing his beliefs that CFS is not infectious.
But why the motive? In countries like the UK, much of the research is government funded, and the National Institute For Clinical Excellence (NICE) has a lot of control over what research goes on. In recent years, budgets have become increasingly constrained. In one of my previous posts, I mentioned about some findings on CFS that were suppressed - I directly challenge any UK bureaucrat who has access to any of these to post them on WIKILEAKS. Currently, the UK health care system has become increasingly under strain from high drug costs for biologics to treat anything from cancers, to psoriasis, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, and Psoriasis. For them, treating CFS would mean another huge cost factor to expand coverage of HIV drugs to CFS patients, as well as perhaps Rituximab. As long as the neuropsychiatric psychobabble can drown out the voices of good science, it is a cost they do not have to face.
But why the motive? In countries like the UK, much of the research is government funded, and the National Institute For Clinical Excellence (NICE) has a lot of control over what research goes on. In recent years, budgets have become increasingly constrained. In one of my previous posts, I mentioned about some findings on CFS that were suppressed - I directly challenge any UK bureaucrat who has access to any of these to post them on WIKILEAKS. Currently, the UK health care system has become increasingly under strain from high drug costs for biologics to treat anything from cancers, to psoriasis, rheumatoid arthritis, ankylosing spondylitis, multiple sclerosis, and Psoriasis. For them, treating CFS would mean another huge cost factor to expand coverage of HIV drugs to CFS patients, as well as perhaps Rituximab. As long as the neuropsychiatric psychobabble can drown out the voices of good science, it is a cost they do not have to face.
XMRV Could Likely Be an emerging zoonotic disease
Recently, a small study has revealed that ticks might be one way XMRV is passed on. The study is being done by Dr. Eva Sapi and Dr. Joe Brewer. The connection was discovered with a sample of chronic lyme disease patients showing 90% infectivity rates with XMRV and MLV's. It is coincidental that the symptoms of Chronic Lyme, and Chronic fatigue syndrome are almost impossible to differentiate. It also explains why despite antibiotic treatments, these patients fail to show improvements. Ticks are already known to carry a form of viral encephalitis.
This points to a likely zoonotic host for XMRV - XMRV could be a new emerging zoonotic disease. Figuring out the host will require the cooperation from veterinary researchers. From transplant medicine, it is already known that pigs are full of endogenous retroviruses. Deer are the primary host of ticks, although they can attach to mammals, birds, and occasionally reptiles and amphibians. A study done in Connecticut shows that lyme disease incidence dropped in proportion to deer population - a 74% reduction in deer population resulted in a 90% drop in Lyme disease in humans.
A hunter from Nevada messaged me last summer, where he denotes "In 1984, there were deer everywhere. I would see deer killed on the road daily. The following year, there was a die-off. We had gone hunting, and at the time my son was 16 - he became ill that fall, and he never got better. Six years ago, he was diagnosed with Lymphoma, and became better after aggressive chemotherapy."
This points to a likely zoonotic host for XMRV - XMRV could be a new emerging zoonotic disease. Figuring out the host will require the cooperation from veterinary researchers. From transplant medicine, it is already known that pigs are full of endogenous retroviruses. Deer are the primary host of ticks, although they can attach to mammals, birds, and occasionally reptiles and amphibians. A study done in Connecticut shows that lyme disease incidence dropped in proportion to deer population - a 74% reduction in deer population resulted in a 90% drop in Lyme disease in humans.
A hunter from Nevada messaged me last summer, where he denotes "In 1984, there were deer everywhere. I would see deer killed on the road daily. The following year, there was a die-off. We had gone hunting, and at the time my son was 16 - he became ill that fall, and he never got better. Six years ago, he was diagnosed with Lymphoma, and became better after aggressive chemotherapy."
Saturday, January 15, 2011
HIV Drug also effective against herpesviruses
Sept 23, 2010 - Institute for Research in Biomedicine - Barcelona, Spain
It was discovered that the drug Raltegravir (Isentress) is effective against all herpesviruses through a different mechanism than that of HIV. As it turns out, all Herpesviruses (HHV-1, HHV-2, Eppstein-Barr virus, Cytomegalovirus, HHV-8) contain the UL89 protein, which is responsible for DNA maturation. Without it, the virus cannot leave the cell to continue infection. This discovery will lead to the discovery of a class of safer drugs to treat herpesviral infections. For CFS patients, it provides a one-two punch, knocking out XMRV and Herpesvirus co-infections.
Previously, certain drugs against herpesviruses were trialled in CFS patients with only small improvements at best. The drawback to the current generation of drugs are that they are fraught with side effects. Foscarnet is extremely nephrotoxic; Ganciclovir and Valganciclovir (Valcyte) causes myelosuppresion, GI symptoms, as well as neurological symptoms; and Valacyclovir and famciclovir lack broad spectrum anti-viral efficacy. Many persons taking Valcyte report horrendous side effects, comparable to AZT. Typically, Valcyte costs $800 a month, and Isentress costs $950 a month. Raltegravir on the other hand has a very favorable side effect profile - when taken alone, it does not cause fat redistribution or raised cholesterol like other classes of HIV medications. It is rather unfortunate that very little research has been devoted to developing new classes of antiherpesvirals with better side effect profiles, since there is evidence that XMRV proliferates in EBV transformed B cells. It is also of note that B cell depletion through Rituximab provides a substantial improvement in CFS patients that lasts 3-4 months, but then returns, which leads to the conclusion that Lymphoblasts may very likely be where the secrets of CFS lie - unfortunately I do not know of any significant ongoing studies that have been conducted using bone marrow aspirations on CFS patients.
Saturday, January 8, 2011
Will The Li-Ka Shing Institute of Virology Score big
Two current studies are underway at the University of Alberta - one by Dr. Andrew Mason, and the other by Dr. Lorne Tyrell and Dr. Michael Houghton (Co-discoverer of Hepatitis C virus). Dr. Mason's study is about trialling antiretrovirals, finding causation, transmission, and prevalence. The study by Tyrell and Houghton is to show cause. In a recent talk, Dr. Tyrell states that "I have suspected that CFS is a communicable viral disease since the Incline Village Outbreak at the beginning of my career, and I am confident that we are closing in fast, and excluding viral pathogenesis at this point would be utter foolishness."
For those that my not know: The University of Alberta is located in Edmonton, Alberta. Alberta boasts of a booming oilfield industry, and no shortage of revenue. The University of Alberta has been the home of several major medical milestones, and is one of the top ranked centers worldwide for molecular biology, and genomics.
For those that my not know: The University of Alberta is located in Edmonton, Alberta. Alberta boasts of a booming oilfield industry, and no shortage of revenue. The University of Alberta has been the home of several major medical milestones, and is one of the top ranked centers worldwide for molecular biology, and genomics.
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