ME/CFS Biomedical Research -Report Intern. Conference

[Guest guest]

~~~~~~~~~~~~~~~~~~~~~~~

Send an Email for free membership

~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:

>>> Help ME Circle <<<<

>>>> 23 June 2008 <<<<

Editorship : j.van.roijen

Outgoing mail scanned by AVG AV

~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:

 

 

 

Dear Readers,

 

Because my health is so bad, I can't handle my bulletin at the moment. I

will make an exception for very important messages, like the one below.

 

~jvr

 

````````

 

_http://www.anzmes.org.nz/medical_information.htm_

(http://www.anzmes.org.nz/medical_information.htm)

 

 

For DOCTORS

 

 

Report from the International Conference on ME/CFS Biomedical Research

Cambridge. England 6 May 2008

 

 

 

By Dr Ros Vallings MNZM, MB BS

 

Dr Rosamund Vallings MNZM MB BS (London) reports on both research and

clinical findings from around the world, and believes that this conference gave

a

good overview of the current state of knowledge into ME/CFS

 

 

````````

Index

 

 

A review of the clinical aspects of ME/CFS

 

Intracellular immune dysfunction in ME/CF

 

The development of clinical services for those with ME/CFS

 

Patient centered research and clinical aspects

 

Treatments targeting the methylation cycle

 

The care pathways adopted in clinical practice

 

Clinical studies focussing on autonomic issues

 

A centre of excellence

 

Current research taking place in Nevada

 

Vascular and inflammatory aspects of ME/CFS

 

A review of molecular studies in ME/CFS

 

The Swedish Twin registry--looking for a biomarker

 

Q fever, Rickettsia and CFS

 

 

 

```````````````

 

 

Introduction

 

On 6/5/08 I attended the International conference on ME/CFS Biomedical

Research at Hinxton, Cambridge, UK. 130 people attended and cutting edge

research

was presented from around the globe. The conference was sponsored jointly

by ME Research UK and the Irish ME Trust. Sadly, Vance Spence, who had

organised the conference and was going to give an introductory overview, was

too

ill to attend. The conference was formally opened by one of the patrons Roger

Jefcoate, CBE, and he described ME Research UK as a world leader in Biomedical

Research in ME/CFS, which presented a signal of hope for sufferers and those

taking care of them.

 

 

A review of the clinical aspects of ME/CFS

 

The first presentation was given by Professor Nancy Klimas (Florida, USA)

with an overview on behalf of Vance Spence, followed by her own presentation

reviewing the clinical aspects of ME/CFS. She explained how we needed to get

away from clinical case definitions towards biomedical sub grouping and

described the Canadian definition as more clinical by including autonomic,

neuroendocrine and immune dysfunction. She feels the most important symptom of

all

is post-exertional relapse and stressed the importance now of having a

paediatric case definition. Children can have a diagnosis made after

3 months of illness. Various other symptoms are included, such as rhythm

disturbances of sleep as well as non restoration, more widespread and migratory

pain, and the inclusion of 2 or more neurocognitive manifestations, and

inclusion of symptoms of an autonomic, neuroendocrine or immunological nature.

 

A number of overlapping conditions such as Fibromyalgia, Gulf War Syndrome

and Multiple Chemical Sensitivity were also mentioned. Epidemiologically, this

illness in the USA has an incidence of 522 per 100,000 females and 291 per

100,000 males. This leads to a 50% reduction in household income, and a 9$

billion US loss in productivity. There are probably 1,000,000 sufferers in

the USA of an illness which can be as severe as congestive heart failure. In

the UK, 44% of physicians lack confidence in making the diagnosis and those

that do make the diagnosis more readily usually have had a family member with

the illness. The pathogenesis involves a combination of genetic susceptibility

coupled with a trigger event and/or infection, whence mediators

(immune, endocrine, neuroendocrine, psychological) lead to a health outcome

and persistence.

 

A slide showed the interaction between the various body systems implicated,

to explain the many and varied symptoms. The length of the illness tends to

lead to an overlap and change in symptoms over time, one area affecting

another.

 

In this illness there is an immune cascade leading to chronic immune

activation, with a shift from Th1 to Th2 dominance. The immune activation

leads to

functional defects. The level of severity depends on the pro-inflammatory

cytokines.

 

Viral persistence and reactivation was discussed with references to studies

on HHV6, Enterovirus and EBV. In HHV6 studies, 79% of patients were found to

have HHV6 activity (compared to 22-54% of controls) and 28 out of 144 were

found to have HHV6 in the spinal fluid, and 7 out of 35 in another group.

Clearing the spinal fluid led to great improvement in

5 out of 8 people, but the antiviral agents used are potent and toxic.

Enterovirus was found in 13% of muscle biopsies and in 60% of gastric biopsies

in those with gastric symptoms. In EBV the dUTPase is seen as an immune

modulator up-regulating the cytokines.

 

Endocrinologically, there is reduced cortisol output due to various

mechanisms, such as heightened negative feedback, heightened receptor function

and

impaired ACTH and cortisol responses to challenge. There is a possibility of

DHEA abnormality.

 

There are many symptoms of autonomic dysfunction. These occur as a result of

parasympathetic dysfunction with sympathetic over activation. Neurally

mediated hypotension, orthostatic hypotension, slow gastric emptying, heart

rate

variability, haemodynamic instability (shown on tilt table), decline in

cognitive function after treadmill, abnormal perfusion in cerebellum, reduced

perfusion in mid cerebral region, and a drop in BP causing relapse are among

the

many effects

 

In the central nervous system, tryptophan abnormalities in the cerebrospinal

fluid result from abnormalities in levels of serotonin and its precursors.

PET scans have shown that 5HTP binding is reduced. There is pronounced

reduction of serotonic transporters in the anterior cingulate. Reduction of

grey

matter in the more severely affected is evident. There is utilization of more

extensive regions of the brain to process tasks than normal. This has been

shown using fMRI and mPASAT. It has been shown that “practice makes

perfectâ€

and it is in fact possible to rewire the brain. Sleep is usually abnormal

with intrusion of alpha waves, altered hormonal releases and lowering of NK

cell count. There is also a decrease in exercise induced pain threshold.

 

Gene studies are very exciting. 35 genes have been differentially

expressed, which relate to T cell activation, and neuronal and mitochondrial

regulatory abnormalities. Up to 6 subgroups have been identified. ME/CFS is a

complex

illness and the subgroups must be further defined.

 

 

Many treatments were discussed:

 

 

Immunomodulatory:

 

Ampligen.

 

Isoprinosine, thalidomide, antiTNFa, monoclonal antibodies.

 

Autologous lymphocyte study.

 

 

Antimicrobial:

 

Antivirals such as foscanet, valganciclovir.

 

Endocrine:

 

Florinef (failed when used alone).

 

Erythropoietin (very modest benefit).

 

 

Autonomic:

 

Beta-blockers to regulate the pump.

 

HPA drugs (not particularly useful).

 

 

Sleep:

 

Sleep routine.

 

Tricyclics.

 

Sodium oxybate (must have sleep study to eliminate apnoea).

 

Pregabilin.

 

Melatonin (mixed results).

 

 

Cell metabolism

 

 

CNS directed medication

 

 

Nutrition:

 

CoQ10. alipoic acid, NADH etc

 

 

Reconditioning:

 

Short 5 minute spells of upright exercise, followed by

5 minutes of flat flexibility work can be more manageable.

 

Exercises to increase flexibility and muscle bulk should be encouraged.

Studies of gene expression using micro-array techniques will help direct us to

which drugs will be suitable for which sub group, with the eventual aim being a

preventative approach. Quality of life is improved with a multidisciplinary

approach and compassionate care.

 

 

 

Intracellular immune dysfunction in ME/CFS.

 

Dr Jo Nijs (Brussels) gave an overview of intracellular immune dysfunction

in ME/CFS. He described dysregulation of intracellular immunity and up

regulation of the RNaseL pathway (due to proteolytic cleavage of native

RNaseL),

and immune cell apoptosis. The virus in a cell leads to release of interferon,

with change in the activity of the host cell, affecting the enzymes, (PKR,

RNaseL). Apoptotic neutrophils are increased, leading to cell suicide, which is

overactive in ME/CFS.

 

TNFa receptors are increased, RNaseL cleavage is equivalent to caspase

activity and there is G-actin cleavage. There is an interplay between NK cells

and infections. Conflicting data of the functioning of the PKR enzyme in the

blood cells may reflect stages of the illness or distinct subgroups.

 

The clinical importance of this is a reduction in quality of life and a

reduction in exercise capacity, both of which are affected by intracellular

activity. Elastase over- activity maybe an important consideration and

neutrophil

elastase inhibitors may prove useful, as elastase may only be important and

needed when the body is fighting massive infection.

 

 

Drug trials are needed in combination with exercise intervention, as drugs

may diminish the side effects of exercise intervention, leading to improved

effectiveness. Drugs to fight exercise-induced oxidative stress and subsequent

post-exertional malaise may prove useful. Drugs targeting the 2.5A

synthetase/RNaseL pathway in combination with careful exercise intervention may

also

be of future interest.

 

 

The development of clinical services for those with ME/CFS.

 

Dr Gregor Purdie (Scotland) as a GP advisor to the UK NHS looked at the

development of clinical services for those with ME/CFS. He stressed that

knowledge comes from patient contact. There has been some positive progress

this

year. There is still a great need for clinical services, education and

training. Research should be supported and translated into clinical tools. We

need

to ask ourselves who is to do this, when and how?

 

In the current “pyramid of careâ€, with primary care at the bottom and

specialist tertiary care at the top, most effort is currently seen at the

bottom

rung, with much of the work being done by voluntary organizations. Work needs

to be done at all levels: local, regional, national and international. The

personnel involved should include a multidisciplinary approach with

specialist consultants, GPs, nurses, physios, OTs etc. All have a niche role

and the

eventual aim should be for specialist Centres of Excellence for this

perplexing and difficult illness

 

 

 

 

Patient-centred research and clinical aspects.

 

Dr Byron Hyde (Ottawa, Canada) looked at various patient-centred research

and clinical aspects and presented his view that ME and CFS are not the same

thing. He described ME as resulting from chronic brain injury, usually as a

result of infection, often during an epidemic. The injury is measurable and

most often in the limbic area. He demonstrated with a number of brain scans.

 

The long viral phase of herpes and EBV has been studied and he feels these

are not likely to be the primary cause of the illness. Echo viruses maybe

more important. Echo viruses have been recovered in some patients up to 3

years

after falling ill. In another study in 2008, he found that Hepatitis B

vaccination led to 22% of cases of ME. Mention was made of the high incidence

of

enteroviruses in China now. In another study, he found that mercury, lead,

zinc; copper and aluminium were elevated in 11 out of 53 patients.

 

Generally patients suffered poor sleep, which led to poor short term memory

and inadequate production of human growth hormone. Only 1 out of 53 of

patients had a normal sleep pattern with resultant normal brain scan. Brain

oxygen saturation was generally low at 88% or less. He concluded with a case

study

of an Olympic athlete who seemed to have classical ME, and was eventually

found to have a tumour in the atrium. He used this as an illustration of the

importance of thorough investigation.

 

 

 

Treatments targeting the methylation cycle

 

 

Dr Derek Englander (New York) looked at treatments targeting the methylation

cycle. The methylation cycle is complex and a part of general metabolism. He

presented a most complicated slide to demonstrate to us just how complex is

the biochemistry associated with this illness. His team has developed a

protocol over the past 15 years after treating 800 patients, 65% of whom have

benefited. Initially weekly IM injections of kutapressin were used. It was

subsequently theorized that there was a defect in the methylation cycle, which

maybe due to a genome defect. A wider protocol has now been developed using

glutathione, B vitamins, zinc, magnesium, and a number of amino acids.

 

 

 

 

The care pathways adopted in clinical practice

 

Dr Gavin Spickett (Newcastle upon Tyne) discussed the care pathways adopted

in clinical practice in the North of England.

 

This is based on medical assessment and therapeutic intervention. The NICE

guidelines are used for referral, but there is no preferred treatment model,

which is to be regularly reviewed. The diagnosis is one of exclusion, looking

at other causes of fatigue, such as infection, connective tissue disease,

auto-immune disease, sleep problems and organic brain disease. There is overlap

with IBS, POTS, FM, overtraining etc. Everything is being stored on a

database.

 

Medically experienced physicians are needed as are specific treatment

protocols. There is a referral pathway for GPs and there is encouragement to

refer

children early (at 6 weeks). Pre-screening blood tests are recommended to

eliminate other causes, such as coeliac disease, which has been found to be

common. Despite this, 17% patients are still found to have other conditions.

Older, retired patients need more intensive investigation looking for other

conditions.

 

To increase awareness a number of GP training days were set up and there was

no uptake initially, but now these are heavily d. Of note, 57% of

patients relapsed with graded exercise.

 

 

 

 

Clinical studies focusing on autonomic issues

 

 

Dr Julia Newton (Newcastle) discussed clinical studies focusing on autonomic

issues, with particular reference to heart rate and BP regulation. Autonomic

dysfunction is strongly associated with fatigue in many ME/CFS patients.

 

There is a problem of synchronicity between the sympathetic and

parasympathetic systems. 90% ME/CFS patients have Orthostatic Intolerance

(OI). The

higher the OI score, the greater is the fatigue.

52% patients experience a drop in BP on tilt table. MRI scans have shown

that there is impaired proton removal from muscle during exercise in patients,

so it is hypothesized that the fatigue arises due to impaired pH run-off from

muscle during exercise., which maybe influenced by the autonomic dysfunction.

 

 

Research is now focusing on how to help patients reset the

parasympathetic/sympathetic balance.

 

 

 

A centre of excellence

 

 

Annette Whittemore, (Nevada,USA) who is president of the Whittemore-Petersen

Institute for Neuro-immune Disease was unable to be present, so her address

was given on her behalf by Dr Dan Petersen (Nevada,USA). This exciting

development is to be a centre of excellence comprising 80,000 sq ft at a cost

of

$US 78 million. It will be a comprehensive patient-friendly research facility

devoted to patients with neuro-immune diseases such as ME/CFS, FM, atypical

MS and other similar presenting illnesses. Location is within the Centre for

Molecular Medicine, University of Nevada. Research is already being

established and currently looking for bio-immune markers which could lead to

more

effective treatments , and also looking at those ME/CFS patients who go on to

develop cancer.

 

 

 

Current research taking place in Nevada

 

Dr Dan Petersen then gave an overview of the current research taking place

in Nevada. He began by stating that in the US 10% of the patients consume 70%

of the healthcare dollars, and chronic disease diagnosis and management

accounts for a significant proportion. Patient-centred, cost effective

approaches are being designed and implemented.

 

Oxidative impairment is evident in ME/CFS and there is a need to demonstrate

this to insurers. Exercise tolerance testing with expired gas exchange is

widely recommended, but paired tests are needed as performance is significantly

decreased on the second test over a 2-day interval. Other research to be

furthered will be identifying subsets, looking at the role of viruses in the

development of neoplasia in chronically affected patients, looking at bone

marrow as a reservoir for HHV6 as PBMCs rarely show HHV6, and collaborative

studies utilizing viral array to identify potential patients who may be

amenable

to specific antiviral therapy will be undertaken.

 

One study presented analysed cytokines and chemokines in a controlled trial

and found chemokines dramatically high with Th1/Th2 dysregulation. These

patterns may prove useful diagnostically and potentially therapeutically. The

specialized field of Informantics is being utilized to analyse and manage

complex inter-relationships involving multiple variables longitudinally.

 

 

 

Vascular and inflammatory aspects of ME/CFS

 

Vascular and inflammatory aspects of ME/CFS were presented by Dr Faisel Khan

(Dundee). There is increasing evidence that ME/CFS patients have associated

cardiovascular symptoms. Endothelial function is an important regulator of

vascular function and a well established marker of cardiovascular events.

ME/CFS patients have significantly enhanced vascular responses to acetylcholine

(ACh) compared with control subjects. This may be a consequence of free

radical attack on acetylcholinesterase expression on the vascular endothelium,

giving rise to a reduced expression of the enzyme, resulting in the

prolongation

of the ACh response.

 

Arterial stiffness is also significantly elevated in ME/CFS compared to

controls, and this is associated with elevation of CRP, pointing to low grade

inflammation and oxidative stress. All this may result in unfavourable

haemodynamics and increased risks of cardiovascular events in ME/CFS patients.

Increased arterial stiffness and inflammation maybe regulated by levels of

Vitamin

D. Other risk factors for ME/CFS patients may be a tendency to lower HDL

cholesterol and higher LDL. Isoprostane is a marker for oxidative stress, and

in

ME/CFS this goes up with exercise intolerance. Oxidative stress can lead to

endothelial damage.

 

 

A review of molecular studies in ME/CFS

 

Dr Jonathon Kerr (London) gave a review of the molecular studies in ME/CFS

at his centre. 88 genes have been identified of which only 3 were

down-regulated – the others were all up-regulated. The highly represented

functions were

haematological disease and function, immunological disease and function,

cancer, cell death, immune response and infection. 13 transcription factors

were over-represented. Data from ME/CFS patients revealed 7 subtypes with

distinct differences in SF-36 scores, clinical phenotypes and severity. 12

genes

have been linked with EBV. It is now important to determine what these

subtypes represent as they appear to be biologically meaningful. Possibilities

for treatment with 5 potential drugs to target these genes should provide

rationale for treatment. The study needs to be confirmed and replicated, and

specificity of the genes needs to be tested. Eventual diagnostic test sub

typing

should be possible.

 

 

 

The Swedish Twin registry-- looking for a biomarker

 

Professor Birgitta Evengard presented her team’s work with the Swedish Twin

registry looking for a biomarker. 31.406 individual twins, comprising 12,407

complete pairs, responded to a telephone interview and 1 in 5 claimed to be

tired. 2.36% had fatigue with symptoms suggestive of CFS of at least 6

months duration.

 

33 pairs of monozygotic twins discordant for CFS were identified and 1779

individual twins were identified for ongoing study. There was no sex

difference in symptoms, but the females had more severe symptoms.

 

There was no association with age, education or occupation. The mean number

of symptoms was 2.4. The commonest symptoms were sleep difficulties,

cognitive impairment, myalgia and joint pain. Estrogen may be the key

regulator.

It is a regulator of growth and differentiation in the reproductive tract,

breasts, CNS` and skeletal system.

 

Alpha and beta Estrogen (ERa and ERß) receptors are implicated in several

diseases. There was reduced expression of ERß in patients consistent with

immune mediated pathogenesis in CFS. There was also HPA axis disturbance,

immune

dysfunction

(with abnormal cytokine dynamics), abnormal blood/brain communication and a

background of infection. 75% improved with valganciclovir. Genes were

identified in 20 of the women and 2 more viruses were detected (orphan

viruses).

 

 

 

Q fever, Rickettsia and CFS

 

Q fever, Rickettsia and CFS was the topic discussed by Dr Stephen Graves

(NSW, Australia). Rickettsia are gram negative bacteria transmitted by

arthropod vector. They were named after Ricketts the microbiologist, and are

nothing

to do with rickets due to malnutrition. Patients respond in different ways:

 

Death.

 

Infection, then recovery

 

Auto-immune illness

 

Chronic Fatigue Syndrome. (10-20%)

 

Illness due to Rickettsia honei and Q fever caused by Coxiella burnetii both

has similar sequelae.

 

CFS is largely a post-infectious condition, and Q fever and Rickettsia can

be precipitants. The microbial antigen may persist. These bacteria have an

intracellular lifestyle. Post Q fever the microbial antigen persists in the

bone marrow and PBMCs. The microbe C,burnetii is not viable because a cell

mediated response has killed it, but it may persist as undegraded cells with

some DNA. The antigen is only found in the more virulent form. The

persistence of the microbial antigen appears to cause dysregulation of the

cytokine

cascade leading to ongoing fatigue in a genetically predisposed subpopulation.

The relevance of this could mean that Q` fever vaccination could have a

positive impact on the incidence of CFS in Australia.

 

 

 

 

 

As always when a conference ends, there is a sense of sadness saying goodbye

to old friends again, but inevitably a great sense of excitement and hope at

the progress and new ideas. Thank you to Vance Spence and Neil Abbott, and

their Irish counterparts for the brilliant organization of this wonderful

event, which I felt privileged to attend in such a lovely English setting.

And,

many thanks also to ANZMES for enabling me to participate.

 

 

 

 

Rosamund Vallings

 

MNZM, MB BS

 

 

6 May 2008

 

 

 

~~~~~~

 

This email was cleaned by emailStripper, available for free from

_http://www.papercut.biz/emailStripper.htm_

(http://www.papercut.biz/emailStripper.htm)

 

 

 

 

 

 

 

[Guest guest]

,

bestsurprise2002 wrote:

>

> ~~~~~~~~~~~~~~~~~~~~~~~

> Send an Email for free membership

> ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:

Hi Rosamund

 

Thank you so much for taking the time and energy to pass this info

along. It is very interesting to me as I have FMS/CFS,among a host

of other assorted diagnoses. It is much appreciated.

 

Love, light, peace, and health,

Debbie in NJ

 

> >>> Help ME Circle <<<<

> >>>> 23 June 2008 <<<<

> Editorship : j.van.roijen

> Outgoing mail scanned by AVG AV

> ~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:~:

>

>

>

> Dear Readers,

>

> Because my health is so bad, I can't handle my bulletin at the

moment. I

> will make an exception for very important messages, like the one

below.

>

> ~jvr

>

> ````````

>

> _http://www.anzmes.org.nz/medical_information.htm_

> (http://www.anzmes.org.nz/medical_information.htm)

>

>

>