Lymphoma drug Rituximab for MEcfs

Dr. Øystein Fluge is Chief Physician in the Department of Oncology at Haukeland University Hospital, University of Bergen, Norway.  He received his medical degree in 1988 from the University of Bergen and has specialized in oncology since 2004.  He has conducted research at the Surgical Institute and Department of Molecular Biology, University of Bergen and has been funded as a Research Fellow by the Norwegian Cancer Society.

In 2004, Dr. Fluge and his colleague, Dr. Olav Mella, a neurologist at the same institution, noticed that a patient’s ME/CFS symptoms improved substantially while undergoing chemotherapy treatment for a concurrent diagnosis of lymphoma.  This was followed by a pilot study in 2009 with positive results. In 2011, Dr. Fluge, Dr. Mella, and their colleagues published a randomized double-blind placebo-controlled trial of rituximab in 30 ME/CFS patients demonstrating that  two-thirds of the intervention group experienced moderate to major improvements in their ME/CFS symptoms. For a medical condition with no disease-modifying treatments, this was a ground-breaking study. Currently, they are in the midst of attempting to replicate their results in a larger Phase III multi-center study in Norway.

The above was Dr Fluge's bio from the recent IACFS/ME Conference outline.

I was just wondering if you've got any of Dad's cancer/immune suppression/B cell depletion drugs still lying around?  I guess you think I'm joking.  Which drug ending in mab did he use?  It's just that by the time they figure out how to cure this thing and release the drug to the impoverished masses via Medicare, I could be dead.

Went to Coles for the first time in ages today.  I've been ordering groceries online since I couldn't walk straight, was dizzy and my heart was pounding after moving my body, even lifting an arm.  I did use the new wheelie walker at home but at the Golden Beach shops/doctors I only used a walking stick or just went ultra slow.  I only went out when I had no choice. I've had problems with breathing too as you know.  The first three things have just vanished more or less overnight when I started taking Jarrow Formula's sublingual Methyl B-12 which is not the same thing as what you can buy at the chemist because of the type of B12.  I have been taking it for 2 weeks I suppose and I am sure my brain is working a bit better too and I'm not falling asleep all the time. I do not know how much that 2 weeks has altered my serum B12.  I guess it may not show up as "Low" on the blood test I requested on Thursday but I am heading to another new doctor next week to find out.

I have read that people are getting neurological (including dementia) symptoms from low B12 even before it reaches the cut-off point for too low that the pathology labs set as standard.  I wish they would do something about that because the doctors set their standard by the pathology labs.  My doctor recently ran some blood tests but they were the same old ones and even if anything was slightly raised I would not be told.  I just got the standard reply "no action necessary".  It was hard enough to get an actual figure for my blood glucose 3 month average which was a well-controlled 6.2, one point up from last time.  What I mean to say is that if low B12 is going to be the explanation for my decline this year, then it will not be forthcoming from my regular doctor.  I'm doing this myself.  It also ties in with my MTHFR gene mutations.

The most important and respected study into CFS so far

The bottom line of the Naviaux, Gordon et al study was to discover that CFS is like a state of dauer.  So a cure is going to involve "waking me up".  And that seems to involve getting my metabolism to switch back to a time when it had not ever detected a state of lack and either become stuck in that metabolic state or still detects a threat to survival so  my mitochondria continue to inhibit some functions and accelerate others.  In this state, eighty percent of the diagnostic metabolites in the study are decreased, consistent with a hypometabolic syndrome. Pathway abnormalities include sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism. Mitochondria take care of these things by relying heavily on B12 and folate for instance so supplementing becomes more accurate at least when you have the facts.  I do not understand anything about sphingolipid and phospholipid metabolism but maybe my brain can pick up a bit from what I read.  The best news is that this is just the first in a series of research studies which will now be undertaken by the Open Medicine Foundation (Ron Davis) and Naviaux in partnership.  Joint publisher of the paper was Whitney Dafoe's doctor Gordon and it was he who introduced the two men and Whitney's illness was what put Professor Ron Davis into the role of father, carer and researcher into M.E.  Whitney is not doing so well.

Whitney Dafoe 27 September 2016 #MillionsMissing

Many of you have asked for updates on my brother, Whitney. I hesitate to post often because it is so personal to him and to our family. Today we are back in the hospital with him as he gets the tube into his stomach replaced. Since getting put onto the J/G Tube, and customizing what we put into him very carefully, his nutrition and weight has greatly improved. However, he is still unaware of the great research being done around him. The research that he brought to motion with his illness and his fathers devotion. He cannot communicate, he cannot tolerate any sound, he is extremely sensitive to light, and he can barely lift an arm off the bed. This photo of him is from this morning going into the ambulance; the first time he's been outside since his ambulance ride last January. He cried as he looked up at the sky and trees. This disease has taken everything. His health, his ability to communicate, to be held, to touch, and to be outside with nature. People ask me if I really believe my dad will find the answers to this mystery. And my answer, without hesitation, is yes. Answers will be found, treatments will be created. Just remember that all of you who are suffering are not alone. There is hope. We are fighting for you with everything we have. Posted by his sister

Reference: https://www.facebook.com/photo.php?fbid=10155403448134625&set=a.10150132705684625.287552.508159624&type=3&theater

The questions and answers about the first study published have been reproduced here from the site of the hope of my future:

ie. http://www.openmedicinefoundation.org/2016/09/09/updated-metabolic-features-of-chronic-fatigue-syndrome-q-a-with-robert-naviaux-md/

Q1. Some people still argue that CFS is not a real illness but all in the mind. Does your discovery of a chemical signature help shatter this myth? 

Yes. The chemical signature that we discovered is evidence that CFS is an objective metabolic disorder that affects mitochondrial energy metabolism, immune function, GI function, the microbiome, the autonomic nervous system, neuroendocrine, and other brain functions. These 7 systems are all connected in a network that is in constant communication. While it is true that you cannot change one of these 7 systems without producing compensatory changes in the others, it is the language of chemistry and metabolism that interconnects them all.

Q1.1. If you found that CFS is caused by chemical changes, why do you ask about childhood trauma in your new questionnaire for the expanded CFS metabolomics study? The questions made me think you were just like all the other doctors who told me that CFS was all in my head? 

The answer to this question has several layers. Perhaps the most important is founded on our discovery that the brain controls metabolism. Any factor that causes a chronic change in how the brain works will produce objective chemical changes in the blood. Reciprocally, any chronic change in any of the 7 systems listed in Q1 will produce compensatory chemical changes in the blood that are coordinated by the brain, but can also change brain function. Profound personal loss, grief, depression, fear, chronic pain, anxiety, and PTSD all cause chemical changes in the blood that we can measure with metabolomics. In the case of PTSD, scientists have found that one of the strongest predictors of risk of a veteran coming home from Iraq or Afghanistan with PTSD was a history of childhood psychological trauma. We are trying to study this chemistry of risk objectively. The science behind the expanded CFS metabolomics study demands that we ask both CFS subjects and normal controls about psychological trauma to see if this can increase the susceptibility to CFS later in life, and to see how previous trauma might influence current metabolomics.

Q2. How does chronic fatigue syndrome fit in with other kinds of hypometabolic states or syndromes? 

All animals have ways of responding to changes in environmental conditions that threaten survival. We discovered that there is a remarkable uniformity to this cellular response, regardless of the many triggers that can produce it. We have used the term, the cell danger response (CDR) to describe the chemical features that underlie this response. Historical changes in the seasonal availability of calories, microbial pathogens, water stress, and other environmental stresses have ensured that we all have inherited hundreds to thousands of genes that our ancestors used to survive all of these conditions.

The body responds differently to the absence of resources (eg, caloric restriction or famine) than to the presence of pathogens and toxins. We can classify two responses: a single-step response to the absence of resources, and a two-step process in response to the presence of a threat. Both responses are completed by a return to normal metabolism and function. When resources are severely curtailed or absent, the full CDR is bypassed, and the flow of nutrients through metabolism is decreased to conserve limited resources in an effort to “outlive” the famine. This is often called a caloric restriction response. On the other hand, when the cell is faced with an active viral, bacterial, or fungal attack, or certain kinds of parasitic infection, exposure to certain toxins, or severe physical trauma, this activates the two-step response. The first step is to acutely activate the CDR. Innate immunity and inflammation are regulated by the metabolic features of the CDR. Activation of the CDR sets in motion a powerful sequence of reactions that are tightly choreographed to fight the threat. These are tailored to defend the cell against either intracellular or extracellular pathogens, kill and remove the pathogen, circumscribe and repair the damage, remember the encounter by metabolic and immunologic memory, shut down the CDR, and to heal.

In most cases, this strategy is effective and normal metabolism is restored after a few days or weeks of illness, and recovery is complete after a few weeks or months. For example, only a small percent of people who are acutely infected with Epstein-Barr virus (EBV) or human herpes virus 6 (HHV6), or Lyme disease go on to develop chronic symptoms. If the CDR remains chronically active, many kinds of chronic complex disease can occur. In the case of CFS, when the CDR gets stuck, or is unable to overcome a danger, a second step kicks in that involves a kind of siege metabolism that further diverts resources away from mitochondria and sequesters or jettisons key metabolites and cofactors to make them unavailable to an invading pathogen, or acts to sequester toxins in specialized cells and tissues to limit systemic exposure. This has the effect of further consolidating the hypometabolic state. When the hypometabolic response to threat persists for more than 6 months, it can cause CFS and lead to chronic pain and disability. Metabolomics now gives us a way to characterize this response objectively, and a way to follow the chemical response to new treatments in systematic clinical trials.

Q3. You talk about the chemical signature being similar to a state of hibernation. What sort of animals exhibit a similar signature in hibernation?

I wouldn’t use the term hibernation to describe chronic fatigue syndrome. Humans do not hibernate. But I can see how it would be a way that people might get a general idea of the chemistry that we found. Hibernation is just one of a handful of hypometabolic states that has been studied in different animals. There are many others that go by names like dauer, diapause, torpor, estivation, caloric restriction, etc. Many environmental stresses will trigger hypometabolism in humans. In our experience, the metabolic signature of dauer is more similar to CFS than some of the other hypometabolic states that have been studied. One of the main points of our metabolomics study of CFS was to give other scientists a new tool to analyze all of these hypometabolic states, developmental stages, and syndromes so that the similarities and differences can be objectively studied, and rational new therapies developed.

Q4. Are men and women really that different in CFS? 

Yes. About 40-50% of all the metabolites that we measure in our method have a different normal concentration in males and females. This is not all related to testosterone and estrogen. Literally hundreds of metabolites are tuned to different concentrations in men and women. At the pathway level, we found that men and women shared 9 (45%) of the 20 biochemical pathways that were disturbed in CFS patients. Eleven pathways (55%) were more prominent in males or females. We find that to do metabolomics properly, you need to have an adequate number of age- and sex-matched controls. If healthy males and females are lumped together as controls, the power to see metabolic differences in CFS and many other diseases is much decreased. Likewise, the metabolism of a 25-year old male is different from a 35-year old male, and categorically different from a 25-year old female. In each decade of life there are many metabolic changes that occur as part of normal development and aging. When proper age- and sex-matched controls are used, metabolomics is one of the most powerful new tools available to physicians and scientists to study chronic complex disease.

Q5. How do the metabolic changes you identified in CFS relate to the recent interest in epigenetics and methylation pathways? 

All the covalent chemical modifications of DNA and histones that regulate gene expression are the result of metabolic changes controlled by mitochondria. For example, all DNA and histone methylation depends on the availability of S-Adenosylmethionine (SAMe). [SAMe supplementing makes me feel horrid] Phosphorylation reactions depend on the availability of ATP [D-Ribose forms ATP and it is my favorite supplement to give me energy.  It costs too much else I'd live on it in my coffee.]. Acetylation depends on the availability of Acetyl- CoA. Demethylation depends on the availability of oxygen [I run out of oxygen] and alpha-ketoglutarate. Other demethylation reactions require the availability of FAD+ and generate peroxide. Deacetylation depends critically on the availability of NAD+. DNA ADP-ribosylation also depends on the availability of NAD+. The master fuel regulator AMP kinase (AMPK) activity depends on the build-up of AMP or the de novo purine biosynthesis intermediate AICAR (aminoimidazole carboxamide ribotide). mTOR is another key barometer of cellular fuel status. mTOR activity requires the availability of leucine. All of these metabolites that regulate epigenetics and gene expression are controlled primarily by mitochondrial metabolism. This makes sense because all cellular activities must be responsive to local resource availability and remain flexible to respond to potential threats that alter cellular health, and mitochondria are the prime monitors and regulators of cellular metabolism.

With regard to cytoplasmic methylation reactions that involve folate and B12 metabolism, mitochondria also play a key role by regulating the release of formate, the balance of NADPH to NADP+, NADH to NAD+, FADH2 to FAD+, propionyl-CoA to succinyl-CoA, and glycine to serine. Ultimately, all of these mitochondrial reactions influence the tide of substrates available for methionine [I like that supplement but although it is cheaper than glutathione is mostly unaffordable to me], cysteine, glutathione, and taurine metabolism. The ebb and flow of these metabolites determines the balance between cell survival and death, controlling epigenetic modifications and gene expression. These reactions are illustrated in supplemental online Figure S6 of our paper.

Q6. How might your results help with treatment of CFS? 

This first paper was not focused on treatment. However, metabolomics reveals a new window into the underlying biology of CFS that makes us very hopeful that effective treatments will be developed soon and tested in well-controlled clinical trials. Metabolomics will be an important component of any clinical trial of new treatments for CFS. It will also play an important role in analyzing the similarities and differences of classical laboratory models of hypometabolic states like dauer.

Q7. How would you respond to Dr. Ronald Davis’s recent statement: “What is important to note is that in the absence of evidence of an active infection, it is plausible that the long-term antimicrobial treatments often used for ME/CFS patients are doing more harm than good.” 

I am in complete agreement. Many antibiotics like tetracyclines, erythromycin, and the fluoroquinolones (eg, Cipro), and antivirals like acyclovir, fialuridine, AZT, and ddC also inhibit mitochondrial functions when used chronically (usually for more than about 3 weeks). Because mitochondria are descendants of free-living bacteria, their machinery for protein synthesis, RNA synthesis, and DNA replication are susceptible to many antibiotics, and for reasons unique to mitochondrial DNA synthesis, they are also sensitive to antivirals. Chronic use of these drugs can do more harm than good if there is no longer good evidence for an active infection. When mitochondrial functions are critically impacted by long-term use of certain antibiotics, a ripple effect in metabolism and gene expression is produced that can further impair energy production by mitochondria, converting an active cell danger response that occurs during active infection to a hypometabolic survival response.

In the field of mitochondrial medicine we are particularly sensitive to these issues of iatrogenic toxicity because some of the drugs that inhibit mitochondrial functions are very commonly used in patients without mitochondrial disease. For example, statins, valproate, and metformin can each produce problems in patients with pre-existing mitochondrial dysfunction. Most doctors do not think about how some antibiotics, antivirals, and other common drugs can inhibit mitochondrial function when they are used chronically. Our patients with mitochondrial disease are often the ones who educate their doctors about the mitochondrial dangers of many common drugs.

I know this is a sensitive area for many people struggling with CFS. It is important to emphasize that individual medical decisions must be governed by individual responses to treatment. Medical decisions should be informed by science, but cannot be based solely on abstract scientific concepts without also considering the clinical variables that are relevant to the care of each specific patient treated as an individual. Some patients do better on drugs that we would consider to be inhibitors of mitochondrial function. This may not have anything to do with the conventional pharmacologic classification of the drugs as antibiotics, antivirals, anticonvulsants, antidepressants, neuroleptics, or anticholesterol agents. Most drugs have metabolic effects beyond their primary action. Because the field of metabolomics is so new, these “pharmacometabolomic” effects of drugs have not yet been studied well.

Q8. Since mitochondria have two main jobs in the cell—energy metabolism and cellular defense—is it possible the one function can be overactive at the expense of the other? 

Yes. This is a key concept. Our lab classifies all complex chronic disease as being the result of either mitochondrial underfunction or mitochondrial overfunction. Each type has both genetic and environmental causes, but environmental causes outnumber genetic causes in the clinic 10:1. Only expert centers in mitochondrial medicine will typically see the many genetic forms of mitochondrial oxidative phosphorylation and metabolic disorders. Most academic centers will see more of the “ecogenetic” mitochondrial disorders caused principally by environmental factors. These disorders range from autism to asthma, depression and autoimmune diseases, to Parkinson and Alzhemier disease, and many more.

Mitochondria lie at the hub of the wheel of metabolism, coordinating over 500 different chemical reactions as they monitor and regulate the chemical milieu of the cell. It turns out that when mitochondria detect “danger” to the cell, they shift first into a stress mode, then fight mode that takes most of the energy-producing metabolic functions of mitochondria off line. Even normal exercise stresses mitochondria transiently and reminds the cell how to heal. Cells “go glycolytic” under conditions of stress, using oxygen less and sugar more for energy production. Mitochondria are highly dynamic in the cell. They will fuse with one another and divide, moving about the cell, changing their location according to cellular needs. Sometimes mitochondria will proliferate so a cell has more mitochondria than normal. Other times they will become hypersensitive to minute changes in one or more chemicals in the environment, overreacting to a stimulus that would normally be undetected by cells that have a normal mitochondrial setpoint.

What does all this mean? It means that mitochondria don’t do just one thing. Sometimes, when one function is overactive the other is decreased. This is experienced by athletes in training. Overtraining increases the energy function of mitochondria, but causes a decline in the defense function and they become more susceptible to colds and many other infections. On the other hand, in CFS, many patients report a surprising resistance to the common cold and many other common types of infection. This increase in the antiviral defense function of mitochondria comes at the expense of the energy function.

Energy production and cellular defense are two sides to the same coin—when you are looking at one side, the other side is temporarily hidden. Mitochondrial cannot perform both energy and defense functions at 100% capacity at the same time. Health requires a dynamic balance of both these functions. It is plausible that when a particular patient seems to benefit from longterm use of a drug known to be toxic to mitochondria, that the drug helps rebalance cell defense and cell energy functions by decreasing the over-activity of one function and permitting an increase in an underactive function. My experience is that this is rare in CFS, but exceptions occur and are important to understand if doctors are to get better at treating all patients. Both patients and doctors should carefully evaluate the pros and cons of long-term antimicrobial therapy if the signs of an objective infection have disappeared. Any drug has the potential to be therapeutic or toxic.

Q9. Does the fact that some antibiotics can inhibit mitochondria mean that treatments for Lyme disease that last too long might actually convert an acute Lyme infection to a chronic post-Lyme syndrome and chronic fatigue syndrome?

Yes. There may also be dangers of using long-term antiviral drugs for the same reason. Not all patients will respond the same way, but doctors should know of the theoretical risk and inform patients before continuing any chronic regimen that lasts longer than any objective signs of an infection.

Q10. If all roads lead to mitochondria in CFS, are there “mito cocktails” or supplements I can take now that could help me while scientists are working out more definitive treatments? 

We have learned through hard experience that the answer to this question is not simple. Many patients with CFS have suffered for years or decades. Their metabolic reserves are severely depleted. We have found that if we give the same mito cocktails that we give to patients with genetic forms of mitochondrial disease, the jolt is too much for most people with CFS and they experience a paradoxical flare in their symptoms. Just a simple thing like taking just 25 mg of vitamin B6 and 100 mg of magnesium can send some people into heart palpitations and a feeling of being unwell for hours after a single dose, while a baby with a mitochondrial disease takes twice this much every day without difficulty.

The guiding philosophy to starting any new treatment for CFS is to “Start low, and go slow.” A helpful analogy is to think of metabolism in CFS like a car that has not been used all winter and all the gas and fluids are gone or low. If you try to start the engine before the fuel tank and fluids are topped off you can do damage. I think that effective treatments for CFS will ultimately require a 2-step process. First, we have to refill the metabolic tank, then we need to turn the key. The first step will be guided by personal metabolomics testing. The second step will be based on new discoveries in the lab that have focused on the role of mitokines that maintain the cell danger response in CFS and other disorders. Mitokines are signaling molecules that trace to mitochondria. They have metabolic functions inside the cell, and informational functions outside the cell.

Q11. Many ME/CFS experts have improved the symptoms in some patients by treating with antivirals and Ampligen (polyIC double stranded RNA). I think this proves that ongoing viral infections are causing our symptoms. It is not merely “tired patients” who are stuck in a lowered metabolic state because of a past trigger (which now is gone). 

We devoted a section of our paper to this and related questions about infections. The section title was, “A Homogeneous Metabolic Response to Heterogeneous Triggers”. It concluded with the sentence, “Despite the heterogeneity of triggers, the cellular response to these environmental stressors in patients who developed CFS was homogeneous and statistically robust.” As background for this conclusion, I recommend reading our paper on this topic entitled, “Metabolic features of the cell danger response” (PMID 23981537).

The first response our body mounts against a viral, bacterial, or any kind of infection is metabolic. Yes, our chemistry is our first line of defense. Our chemistry reflects our instantaneous state of health. Innate immunity is coordinated by mitochondria and is an essential first step in developing adaptive immunity to any infectious agent. Without innate immunity there can be no antibodies and no NK cell activation, no mast cell activation, and no T cell mediated immunity.

In addition, all antivirals have metabolic effects that have nothing to do with inhibiting viral DNA or RNA synthesis directly. Many antiviral drugs inhibit the key metabolic enzyme SAdenosylhomocysteine Hydrolase (SAHH). Inhibition of SAHH causes an increase in intracellular SAH levels. SAH is a potent inhibitor of DNA, RNA, protein, and small molecule methylation. This affects both viral and host cell epigenetics, gene expression, mRNA translation, and protein stability. The inhibition of methylation reactions in the cell also affects neurotransmitter (dopamine, norepinephrine, and serotonin) and phosphatidylcholine membrane lipid synthesis, folate and B12 metabolism, and many other reactions. So by giving antivirals, doctors are not just inhibiting viruses, they are also inhibiting many host cell metabolic functions. Sometimes the inhibition of host cell functions can attenuate ME/CFS symptoms for a time, but in other cases, using potent antiviral drugs inhibits mitochondrial and methylation reactions and can delay a full recovery from ME/CFS.

You also asked about Ampligen. Ampligen is a form of double stranded RNA called poly(IC) tempered with one U for every 12 Cs. We have studied the action of polyIC extensively and have published this in our studies of autism and virology. PolyIC and Ampligen act by binding to an innate immune receptor called TLR3, creating a simulated viral infection. If you expose a pregnant animal to a single dose of polyIC at the beginning of the second trimester, she develops a 24-hour flu-like illness then completely recovers. However, her pups have social and cognitive abnormalities similar to autism for life. If you look at their brains, you find that they have activated microglia and brain inflammation for life. In adults, Ampligen also binds the TLR3 receptor, and activates an incomplete antiviral response characterized by activation of interferon and other cytokines. Long-term use of polyIC carries a risk for toxicity because of chronic innate immune stimulation. In certain clinical situations like cancer or Ebola virus infection the toxicity is actually part of the therapeutic effect. Chronic interferon release causes flu-like symptoms, and the inhibition of mitochondrial protein translation. This can lead to secondary mitochondrial dysfunction. As I noted in an earlier Q&A response, sometimes the inhibition of mitochondrial function can make some people with ME/CFS feel better temporarily because some symptoms can come from unbalanced overactivity of some of the hundreds of functions mitochondria perform. However, in the long term, any pharmacologic inhibition of mitochondrial function will delay a full recovery.

Third, latent and reactivated viral and bacterial infections can occur, but in the case of ME/CFS that has lasted for more than 6 months, this may be the exception rather than the rule. Some doctors and scientists have not done a good job at educating patients and other scientists about the difference between serological evidence of infection in the form of antibodies like IgM and IgG, and physical evidence of viral replication like PCR amplification of viral RNA or DNA, or bacterial DNA. We have learned in our autism studies with Dr. Judy Van de Water that supertiters of antibodies do not mean new or reactivated viral replication. Supertiters of IgG antibodies mean that the balancing T-cell and NK cell mediated immune activity is decreased. This is a functional kind of immune deficiency that causes an unbalanced increase in antibodies. This is like the famous figure-and-ground illusion that shows the silhouette of two faces that also create the form of a vase. Both things happen. But which is cause and which is effect? Increased IgG antibodies to CMV, EBV, HHV6, Coxsackie, etc. are not good evidence of a reactivated viral infection. While Coxsackie is an RNA virus related to poliovirus, antibody titers can increase to this virus too, even though it cannot establish a chronic or latent infection. This can be proven in most cases by trying to measure viral DNA or RNA by PCR in the blood or swollen lymph nodes. In most cases, supertiters of IgG are PCR-negative. There are exceptions to this generalization.

Chronic PCR surveillance studies in healthy humans are showing that little waves of viral replication happen periodically throughout our lives. We have been, and are regularly infected by hundreds of viruses over a lifetime. Sometimes this is obvious and causes a symptom like blisters or an ulcer around the mouth. However, most of the time these waves of viral replication are silent and produce no symptoms at all because they are handled in the background by the innate and cell-mediated immune system. Even the deadly poliovirus infected 150 to 1800 people, producing only mild or unnoticed infections, for every one person who developed paralytic disease. In most of the cases of ME/CFS that I have seen where IgG antibody titers have been measured before, during, and after antiviral therapy, the antibody titers remain high after treatment, even though the patient may report symptomatic improvement. I believe the symptomatic improvement after antiviral treatment may have more to do with the metabolic effects of antivirals in ME/CFS than their action on viral replication. The good news is that this hypothesis can be studied scientifically and put to the test easily using the tools of PCR and metabolomics.

Good science needs to remain open, ask the questions without bias, design good experiments, take careful measurements, then have the courage to follow the data wherever they may lead.

Q12. I read that your study shows that diet can cure ME/CFS. I have suffered and studied this disease for many years. I’ve tried every diet under the sun. You are categorically wrong. 

Please refer to our paper in PNAS, which is free to download for anyone. Or go to our website at: naviauxlab.ucsd.edu and click the CFS button. You can download the paper and this Q&A from the website.

Our studies show that metabolism might be the final common denominator for ME/CFS. It is important to remember that “diet” and “metabolism” are not the same. Diet is what we eat. Metabolism is the performance state of the matrix—the dynamic state of flow in the network that constitutes all the biochemical reactions that our cells use to conduct the business of life. Doctors in the field of biochemical genetics have been treating inborn errors of metabolism for over 50 years. Correct treatment of metabolic disorders is complex and takes advantage of both the resource and the signaling functions of foods, supplements, vitamins, cofactors, and metabolic drugs. Mitochondria lie at the hub of the wheel of metabolism. Because mitochondria are also the concertmasters of innate immunity and inflammation, it makes them uniquely positioned to help the cell decide whether to devote energy and resources to “peacetime” metabolism, or cellular defense. We have several ideas about how to approach the treatment of CFS. We will be testing these in carefully designed clinical trials. For more thoughts on treatment, see the answer to Q10 above.

A nice list of references for M.E

Originally created by Debbie Watton and provided by Chronic Fatigue Syndrome and Fibromyalgia NSW

I can't Stand The Rain by Mama Chill

Don't you just love these lyric, this lady and how she copes and thrives despite having Myalgic Encephalomyelitis (M.E)?

Check out some of her music videos below and head to the itunes store if you love her stuff too.

I CANT STAND THA RAIN, ON MY WINDOW, BRINGING BACK SWEET MEMORIES
I CANT STAND THA RAIN ON MY WINDOW, BRINGING BACK THOSE MEMORIES
SAY WINDOW PANE DO YOU REMEMBER HOW SWEET THINGS USED TO BE
NUTHINS THA SAME SINCE THAT DECEMBER, YEAH, WHEN I GOT M.E

SEE, I USED TO HAVE A LIFE THAT WAS BACK IN THA DAY
BEFORE CIRCUMSTANCE CHANGED AND TOOK IT AWAY
NOW I CANT PLAY CANT WORK A NINE TO FIVE
BUT I STILL THANK GOD FOR KEEPING ME ALIVE
COZ I'M A SURVIVOR NO MATTER HOW HARD IT GETS
LIFE IS STILL BEAUTIFUL, DON'T LET ME FORGET
COZ SOMETIMES WHEN I'M DROWNING I CANT SEE THA VIEW
AND THAT'S WHEN I NEED YOU MY FRIENDS TO PULL ME THROUGH
I STILL GOT A FEW BEEN THERE FROM THA START
THEY WOULD NEVER LEAVE OR DELETE ME FROM THEIR HEART
OR THEIR FACEBOOK OR TWITTER, WHATEVER THA BUZZ
TRUE FRIENDS LIKE FAM WILL ALWAYS HAVE LUV
AND I WISH I COULD JOINEM OUT ON THA DANCEFLOOR
WISH I COULD DO ALL THA THINGS I DID BEFORE
INSTEAD OF HERE LISTENING TO THA TEARS COMING DOWN FOREVER MORE

AND I CANT STAND THAT RAIN ON MY WINDOW BRINGING BACK SWEET MEMORIES
I CANT STAND THA RAIN ON MY WINDOW BRINGING BACK THOSE MEMORIES

YA LOOK AT ME WITH SUSPICION I KNOW THAT YOU DO
COZ IF YOU CAN'T SEE THA TRUTH HOW DO YOU KNOW IF IT'S TRUE?
IT'S LIKE A BOOK AND A COVER, WAIT UP AND TAKE A READ
IF YOU TAKE A LOOK INSIDE YOU'LL FIND ALL THAT YOU NEED
TO CHANGE YOUR MIND COZ YOU'LL FIND THAT WALKING IN MY SHOES
AINT ABOUT BEING CRAZY, IT'S ABOUT CRAZY VIEWS
OF THA IGNORANT PEOPLE THAT DON'T UNDERSTAND
HOW I CAN LOOK THIS GOOD BUT BE ILL ON THA OTHERHAND
YOU CANT SEE CANCER OR HEART DISEASE
YOU WANNA SEE ME IN HELL FOR YA NEED TO BELIEVE?
I AINT DUCKING AND DIVING AN SWINGING THA LEAD
WHAT I GOT IS PHYSICAL AND NOT IN MY HEAD
I WISH YOU COULD SEE PASSED THA LAUGHTER I EMBRACE
I WISH YOU COULD SEE IT'S A COMPLEX CASE
IF YOU CANT TRY AN UNDERSTAND, STAY OUTTA MY FACE

COZ I CAN'T STAND THA RAIN ON MY WINDOW, BRINGING BACK SWEET MEMORIES
I CANT STAND THA RAIN ON MY WINDOW BRINGING BACK THOSE MEMORIES

IT'S A GOVERNMENT COVER UP THEY ALREADY KNOW
IT'S A VIRUS INSIDE US, JUST DON'T WANT IT TO BLOW
COZ THEY KNOW ITS IN OUR BLOOD THAT'S WHY WE'RE BANNED FROM GIVING IT
I KNOW ITS F*CKING PHYSICAL COZ I'M THA ONE LIVING WITH IT
TRY AND HUSH IT UP AND MAKE OUT THAT WE'RE CRAZY
BUT WE AINT SHUTTING UP TIL THA TRUTHS OUT BABY, TIL THA TRUTHS OUT BABY, TIL THA TRUTHS OUT BABY.


 Jus Human lyrics


There's life in ME.  You can see it. You can feel it just as much as the death.  Living on the edge.

Find Stacy Hart (a.k.a Stinkyplank) on itunes as Mama chill
She hope's you'll choose to be a lover of life.
And I hope she is not "Running on Empty" nowadays.

She describes herself as Urban Artist Mama Chill, Songwriter all genres, M.E sufferer, Dream Therapist, Hornet&Gooner, Vegetarian, Chocolate eater, luv to Laugh coz lifes too short ;) xxx

She is popular in Watford, Herts, UK and cherished by M.E Sufferers worldwide as their voice to be heard.

Louise Ramage was an online friend who I felt close to. So sad, RIP Louise.

Louise had Myalgic Encephalomyelitis (ME).  She took Percocet for the pain. She lived near Vancouver and seemed to have as much disappointment with the medical system as I do here in Australia.  She was hopeful when a complex diseases clinic opened up nearby but she soon realised that they could not help.

I know exactly how you feel. I'm not young anymore and I find it harder and harder to cope and it seems things are just getting worse. I hate to say this...but you might understand my thoughts ~ at times I think of getting a gun and pulling the trigger. I don't really want to die of course but just have some quality of life. You don't have to worry as I wouldn't do such a thing...plus you can't just go buy guns here in Canada....we're not like the U.S. I tell you the States are all gun happy. I just don't have much faith or hope either but we just have to keep on trying. I called my daughter yesterday in tears. I feel I must be a burden. Sometimes with this illness I'll just break down and call either Leeanne or Dick. I always apologize for complaining...so grateful my daughter and b/f keep siupporting and loving me. Let's just pray something changes. That New Complex Disease Center will be opening in early 2013 but I'm not stupid and I realize there is no cure so I'm not even hopeful with that. I'll go in the hopes that they can learn more about this illness and pray it will help others in the future. Who knows...perhaps they'll have a few suggestions....I'll be grateful for any help at all ~ but I know not to expect miracles. No one should have to suffer like like this Judy...unbelievable how cruel the medical community is to keep sweeping it under the carpet and making those who have M.E. belittled and treated like we are all psych cases. Hoping this new center will educate drs. One can dream. January 2013

It had gotten to the stage that she lived only for the odd good day as she explained:

Judy I know how you feel. I've been in such a long horrid crash. I sometimes just get so I'll I think I should check into the hospital but then I realize they would just think I'm crazy and anyhow what can anyone do? I have to see my Dr. today and hope I don't end up in tears ~ I cry so easily when I'm so sick...my emotions are all over. I think a crash is worse than pain because at least with pain you can usually get some relief...but there is nothing you can take for a crash...it just feels like your dying...so exhausted beyond description...so weak. I get to the point I don't even want to talk to anyone as it's too much energy. Have a "to do" list on my coffee table here and some things involve phoning people...but I'm just not up to it. I have to discuss pain meds with my Dr today and unsure what he'll want to do. He asked me to research pain meds and I found it depressing. Know I'm thinking of you...this illness is so hard...I just live for the odd days I get here and there where I don't feel so sickly. I really pray you get a break soon...it can really pull you down. xxx

We relived some of our good memories together and we celebrated when we were well enough to create some new memories with our families.

....seeing you there with that cracker brought back memories of my family all around the table for Christmas dinner in the past. We always had those crackers and we would wear our silly hats and go round the table and read off the jokes.2011

2011 when we became Facebook friends.  Louise and her daughter.

Judy this illness is so terrible. I'm so glad that both you and I both were able to enjoy Christmas...I tell you it was a fluke I was able to go...if my daughter had the dinner on Christmas day it definitely would have been a "no show" for me.........I am just so frustrated Judy. I can't hack this stupid pain and lack of sleep. I find taking percocet a double edged sword. I so need them but then of course you build up a tolerance and they just don't work as effectively as they once did and trying to keep usage of them down gets harder and harder. Sometimes I feel like getting and a gun and pulling the stupid trigger. I have so many different pain syndromes ~ it just never ends. Today I woke up to severe RLS...absolutely brutal. Feels like maggots crawling from my feet straight up to my lips and cheeks. Then if it isn't RLS I'll have severe fibromyalgia, or bone pain, or nerve pain, or severe joint pain. Sometimes I just don't even know what kind of pain I'm experiencing. I just get so frustrated and scared. Then the "crashes" are horrendous...you know all about that. Seems we just live to exist...that's why being able to get out for Christmas was such a blessing (for you and I)! 27/12/2012

I have to go see my Dr on the 2nd and am already worried about that....I always think to myself "am I going to be in a crash", "am I going to get enough sleep", "am I going to be in pain", "will I be able to do the drive"? This is how we live now...it almost seems weird to look back on my life and remember that I use to have no thoughts about such things. If I had to shop then shopped. If I wanted to plan to meet up with friends well then I did. I only managed to have one bbq here for my daughter and her family since I moved here 7 months ago. I had to keep calling them on what I call my "good days" until finally I managed to get them over when they had no plans. This is why we have lost so many of our friends. We can't plan to meet up with them...we just live an existence day by day, hour by hour never knowing what is coming next.
I'm so frustrated...I have been waking up every day since the 24th before 2 am because of pain. I can't just turn around in bed and try to get back to sleep. That would be too easy. Instead I have to get up and take 2 Percocet and then I'm up for the day. For some reason Percocet stimulates my brain and I'm very seldom able to sleep on them. It makes for such a long day Judy. I really want to live...but I don't like just existing.
BTW those antibiotics will give you brutal bowel attacks. It's not going to be a pleasant treatment so all we can do is keep praying and hold onto faith that this treatment helps you. I'm glad we touched base again. You can always talk to me if your going through a hard time of it ok? Sometimes I don't look at FB everyday...it so depends upon how I feel. I wish I could say something positive to you Judy. Love you...hang in there...and here's to HOPE 30/12/2012

Louise was fond of horses before ME

I think about those things as well...but I think if ever I was to be healthy Dick and I would start a life together. I definitely would spend allot more time with little Jacob. I'm 55 so nically think I would look for some work...it could just be part-time...just anything to keep busy and also so I would be more social. So use to lying on the couch all the time it would definitely be a change haha. Just having a part-time job would help me out financially as well. Anything is better than this! July 2013

2015 at her daughter's wedding

The neuromuscular effects of ME on Louise she called Blepharospasm.  It drove her nuts and it was very painful.  She could barely afford treatment.

I got botox for my bleuphrospasm on Friday morning. It was a Christmas gift from my daughter. I used to get it every 3 months but that was about 8 years ago. In about 8 more days it'll start to kick in and my eyes won't be closing up on me. He charged me for medical purposes hence the cost was about half the amount someone would pay if it was done for cosmetic purposes but even with that it was a fortune. Now I remember why I just decided to have my eyes contract constantly and close up on me![and forget about treating it]

The botox will work...it should start to kick in on Sunday....typically takes 2 weeks to fully work...but I always start to feel results in 10 days...it feels so good. You can feel the muscles in your upper and lower eyelids being forced open. Initially your eye lids won't totally close up...but it's so much relief from the constant strong contractions I get without it. He was so nice and stuck a little amount in the worry lines I have between my eyes and also a few other spots. If you're going to have a medical problem such as bleuphrospasm it actually helps out with eye wrinkles too . Once when I use to see my neurologist for injections I joked to him and asked him to get some of those eye wrinkles out at the same time lol...to which he replied that when using botox for bleuphrospasm it actually is used in areas they use to get rid of eye wrinkles ~ BONUS...if you're going to have a medical condition like that at least it gives a cosmetic look at the same time. wink emoticon But since I haven't had botox for about 10 yrs I have more wrinkles because of the continual contractions...also add in the age factor! I better get some pictures done during those 3 months because there is no way I van get it done every 3 months. I was thinking if I could have it done 2 times a year at least that would be 6 months of relief which is a whole lot better than the 10 yrs I've gone thru without any. When my eyes are really bad I go blind...so I am looking forward to feel the results and being able to see.

People are so weird Judy...so anytime my eyes are closing up tight and strangers will actually come up to me and ask what's wrong with my eyes...if I had more guts I'd ask what was wrong with their face haha. Actually I wouldn't....I'm not so rude!

This was the last public post that she made on June 23rd 2016

Ok I've been training Skye (her cat) to "come" on command, to "sit" on command and also to "high 5" on command. I don't push him as I don't want to bore him. Another video but he's definitely understanding what he's been trained to do.

Ignore his hair floating across my floor ~ the shedding never ceases! With all that said...here is Skye doing his thing:

https://www.facebook.com/louise.ramage1/videos/10154193873555930/

For all who wish to send cards of condolence to Louise's family, here is the address of her daughter.
Leeanne St. Cyr
17325 64A Avenue,
Surrey, B.C.
Canada
V3S 0P5

Louise was a long-time supporter of Invest in ME (IiME).  The button below will allow you to make a donation to their Biomedical Research Fund through PayPal.  Click for more information

Health, Healing & Hummingbirds

Health, Healing & Hummingbirds: Scientific information on improving serious disease through nutrition and treating the causes of disease – summarised from 100 of the world’s most cutting-edge health books

"This photo sort of means a lot to me. I had rested hugely for 2 days beforehand (to do a mothers day thing with my mum), and even put tinist bit of makeup on and a nice dress and some jewellery even (for my mum!), plus had the new not-just-ill-person-no-choice-basics hair which in my case was blue hair - a luxury I have not had for well over TEN YEARS. So it feels very 'real me' sort of. Like I am finally able to start reclaiming small bits of choice in my life, lost for so long. As I sloiwly improve I am seeing more clearly all I have lost..and so happy when I get even a tiny bit back...which is what this pic represents to me. Hugs:)"

 I did have purple hair for ages many years ago, and am going to do a violet thing next, can't wait:) Yes, am sick of jammies and wearing clothes that mostly I wd never chooce myself but have bene given, or someone else has picked out or whatever.

 Being so ill often means putting tons of effort into dissociating form your body...retreating from the pain, and trying to mind over matter it away a bit. So starting to reclaim it again in a small positive way is kind of big....musings! 

Did you know that Jodi got published in the local community paper?  She lived in WA.

"Of course after explaining twice to the local journalist that 'CFS' is not another term for M.E., and please could she not say I have 'CFS' in the article because I don't and this mislabelling/misdiagnosis has pretty much ruined my life, and her saying, oh yes of course I wont do that and thank you for educating me....yep, she did exactly that. Not a huge surprise, but a bit disappointing and I hope nobody I know reads the thing (that doesn't know me online). On the plus side, apart from this one (albeit significant) issue, it is an absolutely kick arse article. And the fact it mentions 'CFS' even if wrongly, will at least get more ill and possibly also misdiagnosed people to go to the site I hope."

"Just as proof I was not a goth really, as we were discussing here....here is a silly pic a friend of mine took of me in my backyard, just before ME hit. I would usually wear one super bright bit of clothing, and have the rest be fairly neutral so it wasn't too much. But for a laugh I decided to get the brightest loudest things out of my wardrobe and put them all on at once, and then pose, stupidly. Used to love that skirt so much! Very scary as a whole ensemble though:) Here is an even sillier pic." Recently posted on Facebook showing what she was doing at 18-19 years old.

"If not now, when?  If not here, where?  If not you, then who?"

I feel like I have been dismissed again #millionsmissing respect and dignity

Many of us feel that the establishment has often silenced our perception of what is happening in our bodies.  I felt like that today.  I went to the doctor.  My lady doctor.  I felt too ill to go but I hoped my note would keep me on track and I had run out of pain killers so I had to go before I would go into withdrawal

I had no wheezes or sounds in my lungs so I guess she did not believe me about months of that.  But I did tell her the Rhinocort worked.  She did not seem to object to me using it again but it is no longer available on prescription.

I told her I felt feverish, she did not take my temperature.  

I told her I had a sore throat and that they had Crimson Crescents (see previous post for photo).  She said they were normal and that it is lymphatic tissue in that area.  In fact my whole throat is normal  (even though it is sore and I cannot sing any more).

I told her that it hurts a lot to lift anything with my right hand.  She did not comment when I said I wanted to talk mainly about my mobility today.  I guess I told her I was getting breathless and/or dizzy but I can't really remember about that.  It was pretty obvious there was something wrong with my walking but she did not even ask what was wrong.

I asked for the neuro surgeon report but she said it was marked confidential but she could read it to me.  I let her read it, waiting to hear the words he spoke to me - that the arachnoid cyst on my spine is the initial cause of my leg pain and the pain between my shoulder blades.  It was not mentioned.  No wonder GPs get a false impression.  The letter came across sounding like I had gone in looking for spinal surgery and was recommended against it.  It was me who baulked at the idea of spinal surgery and asked for a delay.  All he said in the report was that a review MRI in 12 months was suggested.  I paid for that private consultation and I am concerned about the strange sensations I get around my back and rib cage, from tingles to itches to stings especially back right.

I told her I had palpitations when I walk and that I was taking Deralin again to help which it does.  I asked her if I could put up the dose because they are bothering me still.  She did not answer that but I think she went to consult her computer. She certainly did not take my blood pressure.  She did not give me the OK to put up the dose so if I have a heart attack you take note of this.

I told her I felt very ill, that running out of energy could make me feel nauseous and that I was seriously considering getting the mobility scooter back.  She just accepted that without comment.  I asked for a Parking sticker.  She did not answer but she asked about where the scooter was.

Why do you #putoutyourshoes on May 25th?

I told her I was really ill and am no longer able to recover from an outing and more or less begged her to do something.  She asked what.  I told her I thought I needed antibiotics and she said there was no indication for that.  We talked about negative mycoplasma Pneumonia blood tests being unreliable and I got a bit narky and so did she.  I did not back up anything I said with the findings of Dr. Kazuhiro Matsuda because I could not remember his name to tell her.  Do you know how hard it is to think fast when I am like this?  I am finding it impossible to even stick up for myself.  I am just as likely to go into a trance and stare for a few seconds.  It happens all the time...before I went on pain killers too if you are wondering.  

I asked what I could try and then suggested steroids. She said something about my steroid use in the past and said things are different now and I couldn't have them either but then she asked ME how much and for how long do I want them.  How would I really know I thought to myself?  I was grasping at straws when I said 5mg a day for a week.  If I was being treated for Crohn's as in the past I knew it would be a whole lot more.  But she agreed to it being an appropriate way to treat this relapse.  I don't know why.  I also know she would not have suggested it if I hadn't have broken down and said "what am I going to do to try and get better?".  I am just hoping it gets me well enough to make it to the pain specialist next week.  Why do I have to fight so hard just to try and maintain what quality of life I have left?  The nightmare is getting worse Mum.

I told her I needed a diabetes A1C blood test because I was overdue.  She asked what my blood sugar was like.  All I could tell her was that it was 6.4 when I took it yesterday half an hour or so after half a breaky biscuit.  It seemed like fine figures to me but then we got into another awkward discussion about patient blood glucose monitoring.  The Australian Doctor magazine suggested that those with diabetes 2 who are not on medication should not even monitor the blood sugar level at all let alone daily.  I did not want to tell her I read it on the official doctor mag so I was vague with my reply about the Internet but I told her Dr Craig did not want me to have a machine.  She obviously disagrees with the AMA and does not even know it!!!  I disagree with the AMA in that regard too (and plenty more).  Anyway I have not seen a high reading for months and months so I am expecting a good result from the quarterly average.

Look what got published since.

Dr J had a go at me again for going to too many doctors - meaning the one down town that gave me my results for the lung scan and my LLMD (in Maleny she still says) who I have not seen for years now.  It was mainly because she did not remember what I was talking about when I brought up the lung nodule and she used that as an excuse for not having an answer on the tip of her tongue about what this lung nodule is in need of.  I told her I need a rescan because I was due for it.  She blubbered about not ordering the original CT (hi res) so that is why she felt out of depth about it but I reminded her that she said she would have her records up to date about it twice now. Otherwise I could have got into see Craig sooner.  And for the second time I asked her if she wanted me to go back down town to the original doctor?  She said no.  I then looked at her in the face and said "None of this doctor stuff is my fault". No more said after that.  She looked up the records and wrote out the referral I needed.  I am not planning on making an appointment at Pacific Radiology until I feel better and next week may not be good because I have got two things on already.  One is the pain specialist and the other is a social work visit.
And I have to fit in poor Connor who has a belated birthday present for me and who I had to stop from coming due to his virus and my relapse.

Fukuda vs Canadian vs International symptom variation confounding research efforts.

I had to walk further than I thought today because the local QML was conducting a procedure for the next 45 mins and they suggested going further up the road.  You could have walked.  I took the car.   There were other blood tests and a urine test but not the NK cells or CD57 that I mentioned other people were having.  She did not put them on the form and by the look on her face I would say she thought it was over the top.  What I saw were just blood tests I have seen done on me over and over but then are ignored anyway even if I do have elevated liver enzymes or something.  However she said I had to have that blood test before I started taking the prednisolone I think it is.  I know from past experience that it will be likely to cause insomnia but hopefully only because I have a false sense of energy which I will have to be careful not to spend until I need it to get to Dr Georgius etc.  I plan on doing as little as possible but I hope I have enough real energy to get groceries and other essentials.  I'd like to dye my hair.  I still have not got my birthday hair cut though so I hacked my own fringe (too short).

My temperature was only 36.1 this morning but it was only 8 degrees C when I went out to post your birthday present Mum.  37.4 last night. 36.8 right now.

Update: June 2nd - All blood test results labelled "No Action Required"