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.
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