PHOENIX RISING

An extensive AP article that ran in over a hundred newspapers chronicled the funding battles CFS advocates have engaged in. You can access the CAA’s response to the article here, or the article itself. http://www.washingtonpost.com/wpdyn/content/article/2007/02/17/AR2007021701006.html 

In "A debilitating condition, an uphill battle," two New Jersey CFS patients tell their story.
http://capwiz.com/cfids/utr/1/ASHZGVGENM/OGGOGVGTTF/1091510946=1

An interview with CFS author (and patient) Katrina Berne and patient Jay Levy. http://capwiz.com/cfids/utr/1/ASHZGVGENM/FUFQGVGTTG/1091510946/(scroll down the page to find the story for March 1)

The International ME/CFS Conference 2007 - An Update on Clinical Diagnosis, Treatments, Support and Research of Myalgic Encephalomyelitis (ME / CFS) - Speakers include Byron Hyde, Jonathan Kerr, Kenny de Meirleir, Vance Spence, Neil Abbot, Basant Puri, Martin Pall, Anne Whittmore and others.

The 2007 Midwestern Fibromyalgia, Chronic Fatigue Syndrome Conference - "Crossing the Chronic Pain and Fatigue Bridge " will take place from Friday May 18 to Sunday May 20, 2007

'We're so excited to finally break ground on this facility,' said Annette Whittemore, 'The design of the building creates a dynamic setting that encourages researchers, clinicians and patients to interact. We have high hopes that in such a setting clinicians will be able to go from bedside to bench and back to bedside to bring better treatments to patients." It should open in late 2008 early 2009. You can read more about this unique and much needed project at  http://www.unr.edu/nevadanews/detail.aspx?id=2049 and watch an interview with Ann, Dr. Peterson, the Institutes medical director, and Dr. Whiting, its research director at http://www.nevadanewsmakers.com/video/nnmstreamb.asp?showID=396 

First CFS/ME Website in India Opens! – This beautiful website "hopes to bring about the awareness of M.E to the very people who suffer from it, as we estimate it to be about 4 million or so in India". It can be found at http://www.meindia.org/

Ground breaking CFS Expose Updated - Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic, the highly acclaimed historical novel about CFIDS/ME, has been updated (ISBN 0595348742). The first 638 pages are the same-but an update of the last ten years has been added to bring the book up to date.

After finding increased mutation rates in a variety of stress response genesthe CDC zeroed in one, the glucocorticoid receptor gene (NR3C1), that determines how rapidly cells respond to the main stress hormone in the body, cortisol. An intensive analysis of this gene – the first of its type done in CFS – found that not only were increased mutation rates present in CFS but they were associated with symptom severity. One mutation found in a subset of CFS patients was associated with particularly high rates of fatigue and disability (Click here for A Key Genetic Anomaly in CFS?). These findings suggest that the cells in CFS patients respond abnormally to cortisol. In this paper, a mathematical model developed by CDC researchers explores how significant a role that mutations in these receptors may play in how main stress response system in the body, the hypothalamic-pituitary-adrenal axis, (HPA axis) functions.

The HPA axis is essential for maintaining the body’s homeostasis in response to stress; that is, it is responsible first for ramping up the body’s activity levels to respond to the stressful event and then bringing them down once the stress has passed. Stressors range from physical stresses such as exercise and temperature changes to infection, fear, etc. Even such a simple act as standing imposes a surprisingly large variety of stressors on the body. At least two things can go wrong with this system; it can fail to ramp up the stress system enough to cope with the stress the body is experiencing or it can fail to turn itself off after the stress is over. The first appears to be happening in CFS.

The hypothalamic-pituitary-adrenal axis (HPA axis) plays an important role in the body and its activities have been modeled before but this model is the first to include glucocorticoid receptor activity. Some researchers believe that simply measuring levels of hormones, cytokines, etc. is too crude to explain CFS; that the problem lies in the interactions between these substances and the cells they are supposed to affect. Dr. De Meirleir, for instance, has proposed that CFS patients are hypothyroid not because thyroid levels are low (they are generally not) but because the receptors for the thyroid hormone have been destroyed. This model takes a similar look at the HPA axis.

In this study Dr. Vernon’s team of data mining specialists, mathematicians, statisticians and molecular biologists analyzed how the cellular response to cortisol affected one aspect of the HPA axis; the pituitary gland.

HPA axis: The HPA axis responds to stress as follows:

• A stressor prompts the hypothalamus to release corticotropin releasing factor (CRF(H)).
• A network of capillaries carries CRF directly to the pituitary gland where it prompts it to release adrenocorticotropic hormone (ACTH).
• ACTH is then carried in the bloodstream to the adrenal glands where it prompts them to produce and release cortisol (hydrocortisone) into the bloodstream.
• When cortisol reaches high enough levels it tells the hypothalamus and pituitary to turn off the stress response; i.e. to reduce CRF and ACTH production. Cortisol also stops immune cells from producing inflammatory cytokines, inhibits the secretion of other hormones and neuropeptides involved in the stress response, and it induces immune cells called lymphocytes to kill themselves.

The first part of point four is the most important part; the cell responds to cortisol only when cortisol reaches a certain level. What determines this point? The number of glucocorticoid receptors present in the cell. Cortisol cannot affect a cell unless it binds with a glucocorticoid (i.e. cortisol) receptor (GR). Once it does this it changes the shape of that receptor in such a way that it is able to slip into the nucleus and alter gene activity. It is only at that point that cortisol begins to effect the cell.

People with high numbers of glucocorticoid receptors in their cells will react very quickly to cortisol and consequently will shut the stress response down very quickly. People with low numbers of glucocorticoid receptors, on the other hand, will allow cortisol levels to build – and the stress response to proceed – for much longer before the cell shuts it down.

•  High GR levels = a quick shut down of the stress response
•  Low GR levels = a vigorous stress response

Of course it’s more complicated than that – it always is. One of the things the GR's do is to create negative feedback systems by triggering the production of more GR's and more cortisol. By increasing GR production the cell becomes more receptive to cortisol and this should make it easier and easier for the body to shut down the stress response as it proceeds. Chronically high cortisol levels (i.e. a chronic stress response) are associated with depression, sympathetic nervous system damage and an under active immune response.

On the other hand, because the body does not want to get stuck in a situation where it cannot respond to stress, it also uses cortisol to turn off the turn off switch quickly. Since cortisol suppresses its two upstream factors, CRH and ACTH, cortisol production actually inhibits further cortisol (and therefore GR) production in order to return the stress response system to a state of watchful readiness. The body should be able to ramp up the stress response quickly and turn it off quickly and the interaction between cortisol and GR's should allow it to do this.

Unless, of course, there are problems. What kinds of problems? Mutations in the gene that codes for the GRs - the same mutations commonly found in CFS patients. Some mutations will code for low glucocorticoid receptor levels - these presumably have a protective function; others will code for higher than normal glucocorticoid receptor levels – these presumably can lead to poor health – and these appear to be the ones more commonly found in CFS patients. These researchers attempted to determine what effect these mutations have on HPA axis activity. They did this by incorporating them into a model of HPA axis functioning focused on the pituitary gland.

The Model: This group first examined the effects GR mutations have on the stress response by varying the rates at which GR’s are produced and degraded. They found that in people who tend to produce lower numbers of GR receptors, their GR levels return quickly to normal after stressful events. The authors called these people ‘constitutively healthy¼ i.e., (they were) impervious to a dysregulated HPA axis no matter how much they are stressed.’ Another group had GR levels fluctuate between low and high, and a third group – which they called the ‘constitutively unhealthy’ group - was characterized by chronically high GR numbers and chronically low cortisol levels.

They then examined how different kinds of stress (short-lived stress, a series of longer, repetititve stressors and a chronically stressful state) affected cortisol and GR production.

They found that a single short-lived stress resulted in temporary decreases in cortisol and increases in GR production with quick returns to normal. If the stressors occurred too close together (2 hours of stress every 8 hours for 24 hours), however, the system was unable to quickly return to baseline and cortisol and ACTH levels fell and GR levels became chronically high. Remember that GR binding with cortisol results in increased GR production. Under chronic stress (10 hours of unremitting stress) the system essentially went haywire; cortisol and ACTH levels fell and GR levels increased but remained high long after the stress was turned off. Even 50 hours later – the limit of the test - the GR receptor levels still had not come down; this scenario appeared to push the stress response into a chronically unhealthy state in which the stress response was greatly inhibited. As soon as cortisol makes its appearance, it signals the cells to turn off the stress response; i.e. to stop increasing energy availability, to stop fighting infection, etc.

This was an outcome not found by previous modeling studies. This suggests that in people with mutations that increase GR production (e.g. some CFS patients) repeated or chronic stresses can push the cortisol/HPA axis interaction into a new unhealthy stable state characterized by hypocortisolism and a hypersensitivity to cortisol. They noted that this scenario fits what we know about HPA axis functioning in CFS – that as a whole it is slow to recover from stresses.

In order to answer this question we need a study to examine HPA axis activity as people become afflicted with CFS and surprisingly enough we have one. An NIH funded study under Dr. Taylor’s direction is examining, among other things, salivary cortisol and ACTH levels in infectious mononucleosis/glandular fever patients as a subset of them come down with CFS.

The Research Gods smiled on the CDC researchers when a study appeared just after their model that appeared to validate it.

About half of the many studies examining cortisol levels in CFS have found evidence of mild to moderate reductions in this major stress hormone. As we saw above, however, simply measuring cortisol levels doesn’t tell us anything about how our cells respond to it. The CDC model presented above suggests that CFS studies should examine HPA axis responses rather than just hormone levels and that is just what this study did.

These researchers used a cortisol analogue called prednisolone to examine HPA axis functioning in CFS patients (without psychiatric disorders) and healthy controls. They measured salivary cortisol and urinary cortisol metabolites before, shortly following, and 24 hours after prednisolone administration.

Study Findings – The CDC’s model was correct. Prednisolone administration reduced both the salivary cortisol levels and the urinary cortisol metabolite levels far more in the CFS patients than it did in the healthy controls. The hypocortisolism observed in CFS is usually described as ‘mild’ but judging by their significance levels (p<.005, p< .0001) these differences were anything but mild; the CFS patients ramped down their stress response to a far greater extent than did the healthy control.

What did they posit caused this increased in negative feedback activity in CFS? Increased glucocorticoid receptor activity. This isn’t the first time this group has come to such a conclusion. An earlier study found that a subset of CFS patients with higher GR sensitivity responded better a treatment (hydrocortisone) designed to increase cortisol levels.

These are powerful studies. They consist of sets of twins, one with CFS and one without, that undergo a week of intensive testing. Since these types of studies can control for all sorts of factors (age, sex, genetics, upbringing, etc.) that can confound other studies I imagine they really get a lot of attention from researchers.

This is the second round of intensive twin studies from the Dedra Buchwald group. The results of the first round were not particularly exciting; it found no evidence of increased infection, no evidence of one type of orthostatic intolerance, no substantial brain imaging alterations, no substantial evidence of disordered sleep, some neuropsychological deficits and poor cardiovascular performance in both twins (!) and some evidence of altered immune problems.

The second round, however, is starting off with a bang. This study used a type of brain scan – LORETA – I have not seen before. In their earlier study these researchers noticed that the twins with CFS had higher delta and theta band magnitudes at certain points. The delta and theta bands refer to two frequencies of brain waves (1.5-4, 4-7 Hz) measured by electroencephalographs (EEGs) . EEGs measure the electric potentials; i.e. the electrical activity in the brain. In contrast to EEG scans LORETA scans give a true 3 dimensional representation of deeper brain structures and are apparently particularly useful in accessing higher brain functions – a region of special interest in CFS.

Study findings - This study found that CFS patients has significantly lower levels of activity in four very closely related areas of the brain; the left uncus, the parahippocampal gyrus, cingulate gyrus and precentral gyrus of the frontal lobe (Broadman Areas 6, 8, 20, 24, 32, 36, 38).

Theta bands

The limbic system is a collective term that denotes an array of interconnected brain structures (hippocampus, amygdale, fornicate gyrus) at or near the edge (limbus) of the cerebral hemisphere where it connects with the hypothalamus. This part of the brain governs behavior, mood, sympathetic nervous system activity, apathy, concentration and motivation and the effective management of both mental and physical energy.

INCREASED OXIDATIVE STRESS IN CFS - WHAT A SHOCK!

Changes in the shapes of the red blood cells found in CFS patients are believed by some researchers to reduce oxygen delivery to the tissues. This subject got a flurry of attention early in the history of CFS (1987-1991) but now seems to be something of a fringe topic. Richards has proposed that besides their role in oxygen delivery red blood cells play an important role in scavenging free radicals as well.

Dr. Richards proposes that the red blood cells in CFS patients are just not up to the task of fighting free radicals in CFS: that either their antioxidant capacity is limited or they are simply overwhelmed by the high free radical levels found in the blood. He believes free radicals change red blood cell shapes by attacking their membranes and (cyto)skeleton.

The Study: This Australian team asked whether low antioxidant levels (glutathione) and/or markers of oxidative damage (malondialdehyde, methemoglobin) were associated with these strange cell shapes. It also examined 2.3-DPG levels.

They found normal glutathione levels, increased methemoglobin and malondialdedehyde levels and increased levels of red blood cells called stomatocytes.

Both methemoglobin and malondialdehyde are by-products of oxidative stress. Methemoglobin is produced when free radicals render hemoglobin useless as an oxygen carrier by snatching an electron from its iron group. Malondialdehyde is produced when free radicals snatch electrons from the fatty membranes that cover cells and the organs (organelles) found within cells. This leaves these molecules unbalanced and they attempt to rebalance themselves by gloaming onto oxygen, a process called peroxidation.

This study, then, once again confirms that increased oxidative stress levels are present in CFS. Increased oxidative stress is probably the most consistently observed abnormality in CFS but it is not unique to it as many conditions and diseases are characterized by high oxidative stress levels.

These authors are, however, not convinced that problems with the antioxidant system are not to blame and they are continuing their examination of that complex system. Hopefully other researchers will also begin to examine the cause of this problem.

WEBSITE UPDATES: Phoenix Rising readers will be aware of the seven part series that covered the IACFS conference but may not know that CFS Phoenix Conference webpage contains summaries from the conferences of the past 8 years plus Dr. Lappes and Dr. Vallings summaries of the latest one. Click here for all the conference reports.

 CFS Phoenix also has three more papers from Rich Von Konynenburg, two of which were presented at the IACFS conference.

•   Glutathione Depletion-Methylation Cycle Block: A Hypothesis for the Pathogenesis of  Chronic Fatigue Syndrome - Rich proposes what he believes is the underlying cause of glutathione depletion in CFS.

• Treating Glutathione Depletion-Methylation Blockades in CFS - A simplified treatment guide from Rich Von Konynenburg

• Why is the prevalence of Chronic Fatigue Syndrome Higher in Women Than in Men?