New rituximab trial results from Norway

Posted on 08/22/2016 by wames

Research abstract:

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology.

We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment.

Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p=0.011).

There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up.

Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab. Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p=0.03).

In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6-9.5 g/L, IgA 1.8-1.5 g/L, and IgM 0.97-0.70 g/L.

Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B-cell regulatory effects on T-cell or NK-cell subsets are not the main mechanisms for the observed improvements in ME/CFS symptoms observed in the two previous trials.

The modest increase in serum BAFF levels at baseline may indicate an activated B-lymphocyte system in a subgroup of ME/CFS patients.

Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome by Sigrid Lunde, Einar K. Kristoffersen, Dipak Sapkota, Kristin Risa, Olav Dahl, Ove Bruland, Olav Mella, Oystein Fluge in PLoS One vol. 11, #8, August 18, 2016

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Reasons given for not releasing PACE trial fitness data

Posted on 08/18/2016 by wames

PACE Trial: Reasons Queen Mary University of London gave for not releasing fitness data

Tom Kindlon reports that retired mathematics teacher, Graham McPhee, requested the numerical values (for the groups, not individuals) used to create this graph of the fitness results in the PACE Trial.

This CFS trial cost £5 million of UK taxpayers’ money.

It was previously announced that this (reasonable) request was turned down.

Graham has now released the submission Queen Mary University of London (i.e. Peter White’s university) made to the Information Commissioner’s Office asking that they not have to release the data.

You can read the reasons here.

You can read a critique of it here.

Ongoing discussion here.

APT = Adaptive Pacing Therapy
CBT = Cognitive Behavioural Therapy
GET = Graded Exercise Therapy
SMC = Specialist Medical Care (the other 3 groups also got this long with their individualised therapy)

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A robot-avatar: easier access to education & reduction in isolation?

Posted on 08/17/2016 by wames

Research abstract:

This paper presents a qualitative study of deployment and use of a robot as a sick child’s avatar at school. Many children and youth suffer from a range of chronic illnesses that make them, often for long stretches of time, deprived of normal education and social life.

The participants in our study are adolescents who have been diagnosed with, and suffered
from, Myalgic Encephalomyelitis (ME/CFS) for at least one year. They attend school typically between 1-3 hours per week, and the robot-avatar is intended as a way for them to extend the time spent in the classroom and to increase their social presence.

The paper discusses tools made to help us understand these young people and their relation to technology (concerning their physical and mental condition) and their connectedness to others (friends, family, teachers and other relevant connections).

Further, the paper reports on experiences with the use of robot-avatars by participants, their parents, and their schoolteachers.

Conclusion

In addition, the first trials in real life show huge potential of the avatar, both in terms of ease of use, and because lessons learned from these two cases most certainly generalize to many of those suffering from ME/CFS. This because the participants had many problems common to ME/CFS, and the feedback from the study is that using the avatar has worsened none of the symptoms. On the contrary, very positive feedback from participants, school and parents were received.

It is still important to adopt strategies for use that are in line with the need for energy modulation related to the ME/CFS illness. Being aware of and sensitive to issues related to the energy modulation is highly important through the whole process of doing research or developing technologies for and with people suffering from ME/CFS.

Our research indicates that the robot-avatar, the added work tasks for teachers and organizational issues still needs more work, but the technology has the potential to support youth suffering from ME to access school and reduce their exposure to social isolation.

A robot-avatar: Easier access to education and reduction in isolation? by Jorun Borsting, Alma Leora Culen in Conference E Health, July 2016

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Selfish mitochondria implicated in a variety of diseases

Posted on 08/17/2016 by wames

Vanderbilt University press release, 12 July 2016: Selfish mitochondria implicated in a variety of diseases

Mitochondrial disorders are a chameleon-like set of diseases that take many different forms and vary widely from individual to individual.

Mitochondria are special organelles found in cells that produce most of  he chemical energy that powers cell operations. Mitochondrial dysfunction has been associated with a wide variety of illnesses, including autism, Alzheimer’s disease, schizophrenia, dementia,
Parkinson’s disease, epilepsy, stroke, cancer, chronic fatigue syndrome and cardiovascular disease.

There are a number of different factors that can cause mitochondria to misbehave. However, mutations in mitochondrial DNA (mtDNA) are known to play an outsize role. Now, a team of researchers at Vanderbilt University has discovered that mutant mtDNA may cause diseases by behaving ‘selfishly’ – in a fashion that benefits them while harming
their host.

The Vanderbilt researchers have identified specific molecular mechanisms that selfish mutant mtDNA use to circumvent the molecular control mechanisms that cells have developed to regulate mitochondrial activities. Detailed understanding of these molecular pathways could help researchers develop effective treatments for mitochondrial disorders.

Prevalence of mitochondria disorders

‘About one newborn in every 200 inherits a potentially pathological mitochondrial disease which becomes manifest in about one adult out of 5,000,’ said Assistant Professor of Biological Sciences Maulik Patel, who directed the Vanderbilt researchers.

Their work is described in the paper ‘Homeostatic responses regulate selfish mitochondrial genome dynamics in C. elegans’ published in the July 12 issue of the journal Cell Metabolism.

Team members who contributed to the study were Vanderbilt doctoral students Bryan Gitschlag and Cait Kirby, along with Associate Professor of Molecular Physiology and Biophysics David Samuels, Senior Research Specialists Rama Gangula and Simon Mallal and Major E.B. Shulman, Professor of Infectious Diseases and Inflammation at the Vanderbilt School of Medicine.

‘Once we know the mechanisms that mutant mitochondria use to evade cellular regulation, then we can develop drugs that target these pathways and prevent the mutations from spreading,’ said Patel.

Mitochondria are a unique feature in eukaryotic cells, the types of cells found in plants and animals. The generally accepted theory is that mitochondria were originally independent bacteria that developed an ability to tap highly toxic oxygen molecules as a powerful energy source: an ability that prokaryotic cells lacked. So some prokaryotes found ways to convert the mitochondria into an ‘endosymbiont,’ an organism that lives within the body of another organism. According to one popular theory, this symbiosis was so successful that it provided the eukaryotes with the added energy they needed to begin forming
multi-cellular organisms.

Powerhouse of the cell

Although the self-contained mitochondria are generally known by their role as ‘the powerhouse of the cell’ they are also involved in a number of other cellular operations, including regulation of the cell cycle and cell growth.

One of the things that make mitochondria unique is the fact that they managed to retain their own DNA through the endosymbiosis process. The mitochondrial genome is extremely small compared to the massive human genome and consists of a closed ring of 37 genes inherited solely from the mother.

The number of mtDNA copies in human cells differs widely by cell type. For example, human blood cells don’t carry any at all while human liver cells can house more thousands of copies apiece.

In a normal cell, all the copies of mtDNA are the same. However, cells contain molecular mechanisms that disassemble and destroy unneeded or improperly functioning cell components, including mitochondria. As a result, these organelles can be replicated and destroyed at a very high rate. In the resulting mix, mutant mtDNA can arise. If they reach very high levels they become pathogenic.

Unusual properties of mitochondrial disorders

Mitochondrial disorders have some unusual properties. ‘Unlike bacterial infections that tend to be all or nothing, mitochondrial infections can range from zero to 100 percent,’ said Patel. ‘This makes mitochondrial disorders multi-symptomatic, with a lot of individual differences. One person with a mutant load of 50 percent might be symptom free while another person with 80 percent might have severe symptoms.’ In addition,
mitochondrial diseases are transmitted from mother to child and, except for developmental disorders, tend to develop late in life.

Patel and his colleagues studied the nature of mitochondrial disorders in the transparent roundworm Caenorhabditis elegans (C. elegans for short), a widely used animal model for exploring the basic processes in the development and behavior of multi-cellular  0rganisms, including humans.

How mutant mtDNA evade a cell’s regulatory control mechanism

The researchers found that cells activate two specific responses to deal with the mitochondrial dysfunction that ensues due to the presence of mutant mtDNA. Paradoxically however, these very responses inadvertently allow the mutant mtDNA to further propagate and proliferate.

‘Viewed from this perspective, mutant mtDNA can be thought of as selfish entities that exploit cell’s regulatory control mechanisms for their own
evolutionary interests,’ said Patel.

Mitochondrial genome copy number

Cells possess a way to count the number of normal mitochondrial genomes they have. This allows them to make more mitochondrial genomes when they need more energy. The researchers found evidence supporting co-author Samuels’ prediction that some mutant mitochondrial genomes are invisible to the cell’s counting machinery. As a result, the cells make more copies of the mutant genomes in a futile quest to reach optimal energy levels. The end result is the harmful over-production of mutant copies.

Mitochondrial unfolded protein response

Cells continuously monitor the health status of their mitochondria. When they detect mitochondrial dysfunction, the cells attempt to repair the problem with a procedure called the mitochondrial unfolded protein response. In addition to alleviating the dysfunction inside mitochondria, the procedure protects them from being destroyed by the cell’s disassembly mechanisms. The researchers found evidence that some mutant mitochondria can activate this response, which causes the cell to tolerate their presence and allows the mutant mtDNA to proliferate.

‘These are both cases where the mutant mitochondrial genomes exploit cellular defenses for their own ‘selfish’ interests,’ said Patel.

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Roles of the right dorsolateral prefrontal cortex during physical fatigue: a magnetoencephalographic study

Posted on 08/16/2016 by wames

Research abstract:

Background: A regulation system in the central nervous system plays an important role in controlling physical performance during physical fatigue.

Purpose: To clarify the neural mechanisms of this regulation system during physical fatigue using magnetoencephalography (MEG) and a classical conditioning technique.

Methods: Eleven right-handed, healthy volunteers participated in this study. On the first experimental day, subjects performed fatigue-inducing maximum handgrips with their left hand for 10 min. Metronome sounds were started 5 min after beginning handgrip trials. The metronome sounds were used as conditioned stimuli and the maximum handgrip trials as unconditioned stimuli. The next day, subjects were randomly assigned to six groups in a single-blinded, three-crossover fashion to undergo three types of MEG recordings; that is, for control, inhibition, and facilitation sessions, while imagining maximum grip exercise by the left hand guided by the metronome sounds for 10 min.

Results: Decreased oscillatory power for the alpha-frequency band (8–13 Hz) in the right dorsolateral prefrontal cortex (DLPFC) was observed during the facilitation session relative to the control session within 300–400 ms after the onset of handgrip cue sounds. In addition, increased oscillatory power for the alpha-frequency band was identified in the right DLPFC during the inhibition session relative to the control session within the time window of 400–500 ms.

Conclusions: These results show that the right DLPFC is involved in the neural substrates of the regulation system during physical fatigue.

Roles of the right dorsolateral prefrontal cortex during physical fatigue: a magnetoencephalographic study, by Masaaki Tanaka, Akira Ishii & Yasuyoshi Watanabe in Fatigue: Biomedicine, Health & Behavior, Vol 4, no. 3, 2016 pp 146-157 [Published online: 04 May 2016]

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Recovering from CFS & FM – The Lerner Way

Posted on 08/16/2016 by wames

Health rising blog post, by Cort Johnson, Aug 12, 2016: Recovering from Chronic Fatigue Syndrome and Fibromyalgia – The Lerner Way

Recovery

Recoveries or near recoveries from chronic fatigue syndrome (ME/CFS) and/or fibromyalgia don’t happen often but they do occur.  For some, recovery stories bring hope and new ideas, but for others they bring up feelings of sadness or frustration.  They remind some of an outcome they don’t see as possible anymore, and are not an occasion for hope, but a reminder of all that has been lost.

Some people are able to find the key to their ME/CFS or FM. Dr. Lerner found it for some.
Chronic fatigue syndrome (ME’/CFS) and fibromyalgia are frustrating in their variability and uncertainty. I see them as being “big-tent” diseases that are so riddled with subsets as to make any discussion of personal recovery problematic. Until we know which subset we belong to, and the appropriate way to treat it, the recovery story situation and treatment in general is going to be confusing.

It’s possible and, perhaps likely that the treatment approach that returns you or I to health has not have been created yet. Or – perhaps more agonizingly  given the plethora of choices and most people’s limited resources – your treatment has been created and you just haven’t tried it yet. Unfortunately, there’s absolutely no way to determine which applies. Recovery is a puzzle we haven’t begin to put the pieces together in a coherent way yet.

It’s good to know in the meantime, though, that some people do recover and do recover fully – sometimes even after decades with these illnesses. If Dr. Lerner didn’t produce recoveries in most of his patients, the evidence suggests that many of his patients did improve significantly, and some did recover.

Dr. Martin Lerner

Dr. Martin Lerner was an infectious disease specialist who became disabled with ME/CFS in the 1970s.  Ten years later after he recovered, he devoted himself to ME/CFS and engaged in research and developed treatment protocols.

A couple of years ago I passed around a request to ME/CFS doctors to have patients who had recovered send their recovery stories to me.  Dr. Lerner was the only doctor who replied. Over the next month or so he provided my request to patients he was seeing. During that time  I received thirteen recovery/recovering stories from Dr. Lerner’s patients.

Antivirals have been an obvious treatment of interest given a viral trigger and findings of activated herpesviruses. It’s not clear how many ME/CFS/FM doctors embrace antivirals but it’s probably safe to say that few have done so with greater enthusiasm than the late Dr. Lerner.

Lerner believed that a smoldering or reactivated herpesvirus or other infections including Lyme disease were present in many people with ME/CFS. His aggressive, high dose antiviral protocols – sometimes lasting longer than a year – could be hard on the pocketbook but clearly could be very effective.

Not all of his patients did so well – his own research bore that out – but many, many people benefited.  In a 2010 interview he stated:

 I’ve got people who are up to 8 or 9 or 10% fully recovered, able to exercise and participate fully in life. I have all kinds of people who are not as well but are living normal lives now, marrying when they couldn’t marry before, working when they couldn’t work before. It’s been extraordinarily satisfying.

His antiviral protocols could be long and at $1,000 or more a month expensive. Lerner found that, in general, the longer one had been ill the higher their viral loads were. Given enough time, though, he felt that many long term patients could be treated successfully.

If somebody had been ill for three years or less they generally  responded to six months of starting antiviral therapy. Anyone with ME/CFS/FM, though, needed to be treated for at least a year before they could really assess how effective treatment is. A look at some of the Lerner recovery stories indicates that if Valtrex wasn’t working Lerner would sometimes add Valcyte to the mix.

Lerner also asserted that when his patients got well they generally stayed well. He  noted that he, himself, was on Valtrex for about six years and when he went off it he maintained his health.  He believed that about 30% of his patients got up to about 8/9 on a ten point functional scale, and stayed there.

Antivirals weren’t the only treatment Dr. Lerner advocated. He used beta blockers, blood volume enhancers and others and made it very clear to his patients that stress – known to be a potent activator of herpesviruses – was to be avoided and proper pacing was critical to give the protocol a chance to work. Exercise had to be extremely limited in the beginning. The body, Lerner felt, needed to reserve all its resources to fight off the infection.

Dr. Lerner’s Protocol

Some general aspects of his protocol are below. Check out Dr. Lerner’s Diagnostic and Treatment Protocols

  1. Any new infection (such as the common cold or bronchitis, or sinusitis, or a urinary tract infection) will worsen the symptoms of CFS.  These common infections must be treated vigorously.
  2. Exercise must be avoided, but living within the parameters of doing what you can do without ensuing exhaustion is encouraged.  In other words, activities that increase your heart rate must be avoided.
  3. Alcohol may be a cardiac toxin.  I ask that CFS patients not drink alcohol.
  4. Other conditions also may be chronic and may worsen or accompany CFS, for instance, chronic Lyme disease.  Other co-existing conditions must be found and treated (e.g. high blood pressure, diabetes mellitus).
  5. Of course, we want CFS patients to be well; we want CFS patients to live normally.  We want CFS patients to be able to exercise, but I ask our patients not to exercise until her/his Energy Index Point Score® (EIPS®) improves to 8.  A CFS patient has an EIPS® of zero if bedridden.  An EIPS® of 5 allows a CFS patient to keep a sedentary job, but do little else.  A CFS patient with an EIPS® point score 7 does not need to nap during the day.

Doctor Lerner died last year and his practice is closed. The tenacity with which Dr. Lerner pursued pathogens – and the long antiviral treatment regimens he used – may have been unique. Did these long regimens improve success rate significantly? It would be good to hear how other patients did on his protocol.

Read the full article with the Martin Lerner Recovery Stories

 

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Experience what it’s like to suffer from CFS in video game ‘Robin’

Posted on 08/15/2016 by wames

Daily Mirror news report, 13 August 2016, by Ryan Brown: Experience what it’s like to suffer from chronic fatigue syndrome in this free video game ‘Robin’

Robin game

Chronic fatigue syndrome (also known as ME) is a largely misunderstood condition that seriously affects sufferers’ day-to-day lives, and this free video game hopes to visualise that.

Chronic fatigue syndrome, otherwise known as ME (myalgic encephalomyelitis) is a largely misunderstood and invisible condition that roughly 250,000 Britons currently suffer from. The symptoms of this illness tend to include debilitating fatigue that affects everyday life regardless of sleep or rest, as well as causing painful muscles or poor
memory for some.

For sufferers, it can mean that even the most menial of day-to-day tasks are excruciatingly difficult. For those of us lucky enough to not suffer from the condition, it can be easy to not
understand the struggles of those that do.

A new video game created by a group of game design students at Media Design School aim to fix that, thanks to an interactive experience that may help players better understand the debilitating nature of the illness. In the game, free to download for PC via GameJolt, you play as sufferer Robin in an attempt to get through day-to-day life with chronic
fatigue syndrome.

It’s up to you what you do over the course of the 3 days in-game, but although there are 3 possible endings, the developers explain that ‘there is no such thing as a perfect ending’ – accentuating the troubles of dealing with the illness.

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Post Lyme Disease & ME/CFS – are they the same?

Posted on 08/15/2016 by wames

Simmaron research blog post, by Cort Johnson, August 6, 2016: Post Lyme Disease and Chronic Fatigue Syndrome (ME/CFS) – Are They The Same?

Post treatment Lyme disease syndrome (PTLSD) occurs when someone is treated for Lyme disease but never recovers. This mysterious illness has all sorts of possible interconnections with chronic fatigue syndrome (ME/CFS). Symptomatically it’s quite similar, and of course, as so often occurs in ME/CFS, it’s triggered by an infectious event, from which one never recovers.

The list of possible infectious triggers for chronic fatigue syndrome is a long one (Epstein-Barr virus, parvovirus-B, enteroviruses, Giardia, Ross River virus and others). (With the Simmaron Research Foundation involved in a study looking at the incidence of insect borne diseases in ME/CFS more infectious triggers may be added to the list.)

Some think Borrelia burgdorferi – the pathogen causing Lyme disease – should be on that list. Lyme disease is transmitted by a tick carrying theBorrelia burgdorferi bacteria. Early on the bacteria can cause a red spreading rash and fever, muscle aches, headaches, fatigue etc. If untreated it can cause some horrific problems but even if treated it can cause lifelong problems in some.

That suggests that a problem with the immune response may be involved. Like ME/CFS the symptoms of post treatment Lyme disease syndrome (PTLSD) very much look like immune symptoms. Typically when researchers assess immune functioning they measure cytokines and other immune factors but these researchers and others like them are more and more taking a different route.

Cytokines can help us understand what’s happening in the immune system but they don’t tell us what is causing the problem. Examining the genes that turn on those cytokines (and many other genes) might. At the very least it provides researchers with a much wider inquiry.  The upside to this kind of inquiry is lots of information – and so is the downside; researchers have to filter through that information to figure out what is relevant and what is not – not an easy task.

It is a task, though, that more and more researchers inside and outside the chronic fatigue syndrome field are embracing.  In this case a look at the gene expression of people who came down with Lyme disease and then were treated for it proved to be quite illuminating.

The Study
Using “next-generation” techniques this study examined the gene expression of the PBMC’s in the blood

  1. just after people got Lyme disease
  2. three weeks after they get treated for it
  3. and then six months later.

This same kind of study has been done twice in ME/CFS to mixed results. In this case the results were exciting enough for the Director of the NIH, Francis Collins, to devoted one of his recent blogs to it.

Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease. Jerome Bouqueta, Mark J. Soloskib, Andrea Sweic, Chris Cheadleb, Scot Federmana, Jean-Noel Billaudd, Alison W. Rebmanb, Beniwende Kabrea, Richard Halpertd, Meher Boorgulab. MBio. 2016 Feb 12;7(1):e00100-16. doi: 10.1128/mBio.00100-16.

The Results
The study revealed the startling fact that even after antibiotic treatment almost half the patients (13/29) had lingering effects (new-onset fatigue, widespread musculoskeletal pain involving ≥3 joints, and/or cognitive dysfunction) from the infection six months later. Four met the new criteria for post-treatment Lyme Disease Syndrome (PTLDS). (See the new criteria which is similar to some ME/CFS and FM criteria – here. )

The infection initially caused a massive change in gene expression involving over 1200 genes. Surprisingly three weeks of antibiotic treatment, which presumably had wiped out the bacteria, the gene expression was still greatly altered with over 1,000 genes acting up (or down) in the Lyme disease patients.

A pathway analysis indicated that the types of genes one would expect to get involved with an infection did; the inflammatory, immune cell trafficking, and hematologic system pathways were all upregulated.

Lyme triggered a massive and possibly permanent change in gene expression

The big surprise, though, came in the last blood draw which showed that six months after treatment the gene expression of the Lyme patients (well and ill) and the healthy controls was still quite different.  The researchers clearly expected that six months after the antibiotic treatment, with many former Lyme patients fully recovered, that they would look, once again, like the healthy controls but they didn’t.

Some important immune genes had been turned off; genes associated with the toll-like receptors which alert the body to a pathogen, for instance, were no longer activated. Almost 700 other genes, however, were still significantly upregulated or downregulated in the Lyme disease patients.

This suggests, as we’ve seen before, that significant infectious events can have long term consequences.

The gene expression analysis, unfortunately, provided no clues why some people with Lyme disease recovered after antibiotic treatment while others remained ill. That was probably due to the fact that only four Lyme patients meet the criteria for post treatment Lyme disease syndrome (PTLDS); i.e. the sample size was very small and that small sample size brings up a question.

A Missing Group?
Where to draw the line symptomatically between a disease and non-disease state has dogged ME/CFS researchers since the disease began. A more stringent criteria has the benefit of ensuring that a more ill patient group is identified but it can also cut out those who are still ill. That may have happened with this Lyme study.

In the beginning of the article, the authors asserted that Lyme patients who remained ill after antibiotic treatment were a) a minority and b) unusual. They stated that these patients tended to have more severe symptoms in the beginning, had greater spread of the pathogen through their body, and had had delayed antibiotic treatment. The vast majority of Lyme patients (about 90%) who were treated appropriately with antibiotics, on the other hand, tended to “recover rapidly and completely”.

This study, however, found that almost half (13/29) the Lyme disease patients, all of whom were presumably appropriately treated with antibiotics, said some of their symptoms persisted at six months.  Because they didn’t meet the PTLDS criteria they weren’t included in the analysis between recovered and non-recovered patients. (Apparently they were included in the recovered group.)

Nor would they be included as post-Lyme disease patients by a doctor using the PTLDS criteria, and might very well be considered depressed, malingerers or whatever. This not to say the PTLDS criteria is a bad one; it’s designed to produce a group of quite sick post Lyme patients for studies, but that criteria – particularly any criteria based on symptoms – is going to have problems.

Disease Similarities
The study indicated that the gene expression responses to an infection can vary dramatically  and in unexpected ways. The researchers compared their gene expression results to those of five other infections.

Early in the disease, for instance, Lyme disease looks more like viral influenza than other bacterial infections such as Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli. (Even with influenza, though, the response at the gene level is far different with the two infections sharing just 35% of activated/downregulated genes.)

This study indicates that infections can cause surprising results at the gene expression level.

All five of the infections analyzed did trigger the upregulation of two immune pathways (TREM1,TLR) involved with infection but interferon signaling pathways – often believed to be active in viral infections – were upregulated only in Lyme disease and influenza.

Genes identified with activated B-cell pathways were prominently featured in the early phases of all the infectionsexcept for Lyme disease.

Plus, Lyme disease was the onlydisease to exhibit a down-regulated EIF-2a (cellular stress response) pathway. Because that pathway was down-regulated at all three blood draws it could play a major role in Lyme. The fact that the same pathway is down-regulated in lupus suggests Lyme disease could have something in common with autoimmune disorders and the authors suggested a lupus treatment might be helpful in Lyme. )

The takeaway message is that the body’s response to an infection is probably unique to that infection. That suggests that the many infections that trigger ME/CFS may produce very different gene expression responses – and that many different pathways to ME/CFS may exist. Whether they all merge upstream at some point to produce ME/CFS or if a bunch of entirely different pathways to ME/CFS exist is a question that can’t be answered at this time.

The Chronic Fatigue Syndrome (ME/CFS) Connection
At the gene expression levels Lyme disease appears, at this point, anyway, to be little like ME/CFS. While some similar pathways were seen in the two diseases in the end only 18% of the same genes and about a third of the same pathways showed up in both diseases.

At this point Lyme disease looks much more like lupus (60% of pathways in common) than ME/CFS, and the authors suggested that circulating immune complexes might be a tie that binds those two diseases together.

I found two ME/CFS studies with a similar design; each assessed gene expression during an infection and then afterwards and then determined if the results varied between those who recovered and those who got ME/CFS.

An early small Lloyd study (2007)  found significant gene expression differences in those who developed ME/CFS after infectious mononucleosis compared to those who recovered. A 2011 gene expression study (n=36) by the same group, however, that compared ME/CFS patients with infectious onset (EBV, Ross-River, Coxiella virus) and healthy controls over time, found so little difference over time between still sick and recovered patients the papers ended stating that “further investigation of the peripheral blood transcriptome is not warranted.”

Some researchers beg to differ. Five years later with several groups (Ron Davis – Open Medicine Foundation, Derya Unutmaz – Bateman-Horne Center,  Lipkin/Hornig – Center For Infection and Immunity, Nath – Intramural NIH Study and Dr. Montoya – Stanford ME/CFS Initiative) are mounting major efforts to understand the ME/CFS “transcriptome” and other “omes” using better techniques.

Genomics and other “omics” studies will provide new and probably unexpected insights into ME/CFS and other diseases

Unutmaz, for instance, proposes to use gene expression and other technologies to uncover immune subsets that he believes will irrevocably alter how ME/CFS is viewed and studied. Some time ago, he threw some samples from the Solve ME/CFS Biobank into his big immune machine. The data that popped out was enticing enough for him to spend a considerable amount of time working up an NIH grant proposal. That work paid off and he recently scored a major grant from the NIH.

While the Lyme disease study didn’t help researchers understand what goes awry in people who are still sick after getting an infection (and after being treated for it) – which is what we really want to know – a larger study is underway to determine that.  Researchers were also working on identifying 50-100 genes they hoped could finally produce a early diagnostic test for Lyme disease.

The study demonstrated the power of this technology to reveal new things about disease. Several things popped out in this study that weren’t expected:

  • Every infection probably triggers a unique response
  • a Lyme infection may irrevocably change how our genes are expressing themselves (even after treatment)
  • Early in the course of the disease Lyme looks more like viral influenza than other bacterial infections
  • Lyme disease has some important similarities to lupus and rheumatoid arthritis that could suggest new treatment possibilities
  • That some commonalities exist between ME/CFS and Lyme disease but the diseases appear more different than similar

Seeing gene expression differences emerging between different infections suggests this work provides a kind of precision that we very much want to see.  That precision, though, requires an enormous amount of data, and with that ironically, can come some muddiness.  Where gene expression has generally let us down in ME/CFS has been the difficulty of  consistently identifying the specific genes on which the disease may turn.

Hopefully the more powerful machines and analytic techniques being used by ME/CFS researchers will help provide the diagnostic biomarkers and new treatment options that other research efforts have not been able to. If this study is any indication, as researchers dig more deeply into the molecular underpinnings of ME/CFS, we’ll probably be in for some surprises.

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Roundup of Severe ME day activity

Posted on 08/12/2016 by wames

Tymes Trust Facebook: Remembering all the severely ill young people whom we know and have known.

Phoenix rising, by Jody Smith: August 8th, 2016: Understanding and Remembrance Day for Severe Myalgic Encephalomyelitis

MEAction: Take Action on Severe ME Day

25% ME Group: In Remembrance: Emily Rose Collingridge, 17th April 1981 – 18th March 2012

 

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The UK ME/CFS Biobank paves the way for bigger & better research

Posted on 08/12/2016 by wames

MEAction blog post, by Simon McGrath, 11 August 2016: The UK ME/CFS biobank paves the way for bigger and better research

Simon McGrath reports that the UK ME/CFS Biobank is open for business, with blood samples available from 300 patients, soon be joined by samples of over 200 controls.

UK ME CFS BiobankArticle excerpt:

New blood for new blood
The Biobank makes it much easier for new researchers to come into ME/CFS research from other fields, as they now have a straightforward way access to patient samples (subject to Biobank approval of proposals). And attracting new talent to ME/CFS, to speed up progress, is a priority for the NIH in the US, the MRC in the UK, and patients too.

The Biobank could also make the tedious work of replication much easier. Any promising finding, such as a potential biomarker, needs replicating on a new group of patients to see if it represents real progress or is a false positive. The Biobank makes finding that new group of patients a great deal easier, paving the way for more replications and therefore more reliable research findings.

Enough blood to launch a wave of large studies
Blood is processed into different sample types, such as plasma and white blood cells.
The Biobank is big enough to potentially power a wave of new, large studies that would significantly change the research landscape.  Size matters in research studies and bigger is better (for rather tedious statistical reasons). Big studies can detect smaller, but important, differences small studies would miss, as well as having the power to find subgroups – something incredibly important in ME research. Also, findings from small studies are also more likely to be false positives, and where they do find a real effect, it’s likely to be smaller than the study finds.

To put the Biobank’s potential to enable bigger studies into perspective, the largest biomedical study in recent times is Dr Mady Hornig and Dr Ian Lipkin‘s cytokine signature study last year, with almost 300 patients. There are 300 patients in the UK ME/CFS Biobank, with 40 samples for each patient (and control) so it could power many studies this size. The Lipkin/Hornig study needed two samples for each person in the study and if that’s typical then the 40 samples for each Biobank subject could power twenty such studies, each with 300 patients. Or it could power 60 studies with 100 patients each, still large by current standards.

The Biobank could power twenty huge studies with 300 patients each, or sixty large studies with 100 patients each. That would be game-changing

Of course, the key work is done by the researchers themselves, but the Biobank provides the all-important infrastructure that suddenly makes large studies much easier to pull off.

Read the full article

The Biobank was set up by the London School of Hygeine & Tropical Medicine’s CURE-ME group, and funded by UK charities Action for ME, The ME Association and ME Research UK with a £1 million grant from the US National Institutes of Health (NIH) for a major expansion.

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