PHOENIX RISING

Not only GWS sufferers and their advocates have been alarmed by the British governments intransigence. The War Pensions Tribunal Board itself went out of its way to call attention to the foot dragging exhibited by the Ministry of Defense. In their inimitably understated British way the Board ever so subtly slipped in the knife stating "It is not for this tribunal to ascertain why such a late concession was made, but the kindest comment that can be made is that the lateness of this concession was unfortunate’. To read more about the U.S. government and Gulf war syndrome click here and about the British Government and the same, click here.

CRISP website of Government Grants Updated – CRISP is a government run site that allows you to access biomedical research funded by a variety of agencies including the NIH, CDC etc.. This is supposedly the only place all these government grants can be found together and, as CRISIP is not shy of telling us, it apparently won a prestigious award. Yes, basic information is often missing (abstracts, e-mails, dates, etc.) but at least we have something - and no, not everything is on it; projects funded by the CDC, for example, are not, but this is the only place you can find some of these projects.

We don’t get much of a description of these latest CFS studies and they’re a decidedly mixed bag but of course there is some good stuff in here. Did you know, for instance, a study has begun involving Lyme disease, chemotherapy (?) and cerebrospinal fluid? Click here to visit the CRISP site. (Be sure to click on the phrase tab in the box!) All the grants involving CFS pathophysiology have been incorporated into the EYE on CFS Researchers site on CFS Phoenix.

A – several difference making papers on CFS pathophysiology

B – a difference making paper on CFS pathophysiology plus several important ones

C - several important papers on CFS pathophysiology

F – no important papers on CFS

THE PAPERS – summaries of some of the CFS research papers published this month.

While research into CFS has often been dogged by heterogeneous and sometimes even conflicting findings, the results of studies into the levels of oxidative stress in CFS have consistently found markers of increased oxidative stress in the muscles and blood. Indeed it is notable how many different areas of the body (red blood cells, serum, blood, muscles and indirectly the brain) appear to exhibit evidence of increased oxidative stress in CFS. This study, employing a particularly ironclad methodology, appears to put a cap on the question if oxidative stress is increased in CFS patients.

Why is this study so important? One reason is the high quality of the tests they employed. The measure used in this study, involving isprostane, is more accurate than other more commonly used measures such as TBARS and malondialdehyde. The method used by the Kennedy group to characterize isoprostane levels (mass spectroscopy) while time consuming and expensive is extremely reliable. The results of this study therefore appear to be essentially bulletproof.

The main finding of this study was that CFS patients display significantly higher levels of products of oxidation called F2 isoprostanes than age, sex and smoking matched healthy controls.

Neither isoprostanes nor F2 isoprostanes are free radicals; F2 isoprostanes are byproducts of a type of free radical activity called lipid peroxidation. First uncovered in the early 1990’s, F2 isoprostanes are produced when free radicals peroxidize arachidonic acid (AA) (Morrow et. al. 1998).

Biological Effects of Increased F2 isoprostane levels – When F2 isoprostanes bind to the receptors in the endothelial cells lining the blood vessels they cause the blood vessels to vasoconstrict (narrow) (Roberts and Morrow 2000). They have been shown to reduce blood flow to the kidneys by as much as 45% and can play a role in reduced blood flows to the brain, heart, lungs and eyes. In vitro tests indicate increased F2 isoprostanes are also associated with lung contraction (shortened breath) and promote platelet activation. F2 isoprostane overproduction contributes to the platelet activation in diabetes, decreased renal blood flow in kidney disease, fetal encephalopathies associated with low blood flows and some aspects of the ischemia-reperfusion process (Montuschi et al. 2004).

No one knows exactly what effects F2 isoprostanes play in CFS but the list of possible effects is long. The authors note the increased F2 isoprotane levels in CFS could contribute to several conditions in CFS including postural tachycardia syndrome (POTS) or cardiovascular problems found in some CFS patients. Studies have found evidence of altered blood flows in the legs and pelvic areas of some POTS patients and therefore CFS patients both while supine and during standing. Reduced blood flows in the cerebral artery leading to the brain and in the muscles (McCully et. al. 2004) have also been seen. CFS patients often also display bronchial hyperresponsiveness.

CFS patients also had low levels of HDL cholesterol relative to healthy controls. This finding was particularly significant (P<.005). In contrast to the negative effects of LDL cholesterol particles, high density lipoprotein particles (HDL’s) have protective effects on the heart. High density lipoproteins transport cholesterol from the tissues to the liver it is degraded and then excreted in the bile. HDL cholesterol intriguingly also has antiviral properties (!).Thus high levels of HDL particles can reduce cholesterol levels and vice versa. HDL cholesterol levels below 35 mg/dL (0.90 mmol/L) and LDL cholesterol levels above 160 mg/dL (4.15 mmol/L) are all independent risk factors for coronary artery disease. Note that neither group of CFS patients had HDL levels anywhere near this level. (LDL levels were not measured in this study.

CFS patients then have something of a double whammy! While their HDL cholesterol levels are not near the levels associated with atherosclerosis they are still significantly lower than healthy, age and sex matched controls. They have lower levels of the compound (HDL) used to transport cholesterol levels away from the tissues but higher levels of the toxic form of LDL that transports cholesterol to the tissues. Thus they appear to be at risk for oxidative processes that damage the blood vessels.

About 1/3^rd of the patients in this study were obese and had high blood pressure. In contrast to the non-obese, non-hypertensive patients and controls these patients have significantly reduced GSH levels as well as much higher isprostane levels. Because obesity and high blood pressure are associated with increased free radical production the authors believed the low glutathione levels these patients evidenced were probably due to these factors and were not reflective of an underlying pathology effecting antioxidant levels in CFS. They suggested CFS was a disease of increased oxidative stress not reduced antioxidant levels.

Finally in an indication that oxidative status was correlated with disease severity the CFS patients exhibiting the most severe post-exertional malaise had significantly higher isoprostanes levels than those with impairment after exercise. A similar finding was found regarding joint pain. Correlating symptom expression and intensity with laboratory measures is critical in determining the importance of a finding.

The Cause of the Increased Oxidative Stress in CFS – The big question is what is the source of the increased free radical production in CFS Unfortunately simply a finding of increased oxidative stress gives us little indication of its source. CFS joins a long list of often disparate diseases and conditions characterized by increased oxidative stress including Alzheimer’s disease, asthma, COPD, diabetes, heart failure, ischemia-reperfusion, liver disease, multiple sclerosis, organophosphate poisoning, rhabdomyolysis, etc.

Kennedy et. al. suggest three factors are the most likely source of the increased oxidative stress seen in CFS. They stress that since CFS is a heterogeneous disorders; any of the three may be present in a particular CFS patient. These are:

Muscle pathology – The authors note that free radical production is increased in exercising muscle even in healthy people. Several studies suggest oxidative stress during exercise is particularly high in CFS patients. A recent study found altered muscle excitability and increased oxidative stress in CFS patients vs. controls (Jammes et. al. 2005) An examination of muscle tissue in CFS patients found evidence of increased oxidative damage (Fulle et. al. 2000). Other studies have found reduced oxygen flows to the muscle but no other signs of metabolic abnormalities (McCully et. al. 2004)

Immune activation – The immune system produces high levels of free radicals during infection and when cells are undergoing apoptosis (cell suicide) or necrosis (death). Researchers associated with MERGE recently completed a study showing increased levels of neutrophil apoptosis in CFS (Kennedy et. al. 2004). DeMeirleir et. al. also found high rates of apoptosis in CFS patients with high levels of RNase L fragmentation (See CFS ABA Chap 6). The authors note that similarly high levels of F2 isprostanes in several inflammatory diseases suggest CFS may be an inflammatory disease.

Environmental toxins - Since environmental toxins can trigger immune activation or be a cause of oxidative stress in their own right, high levels of environmental toxins could result in increased oxidative stress in CFS.

The authors noted that CFS patients’ have a lipid profile and oxidant biology that is consistent with cardiovascular risk’ and suggest antioxidants may be helpful. In something of a warning to obese CFS patients they indicate obesity presents ‘a potential additional burden to free radical formation and CFS pathology.

Ongoing Studies – No studies targeting oxidative stress are known to CFS Phoenix. The group funding this study, MERGE, is currently funding several studies examining the vascular system in CFS.

__________________________________

Jammes, Y. Steinberg, J., Mambrini, O., Bregon, F., Delliaux, F. 2005. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. J Intern Med. 257(3):299-310.

These Swedish researchers have been busy. Taking advantage of the largest twin registry in the world they have recently completed the biggest epidemiological study involving twins and CFS yet done. (The Swedish Twin Registry has data on 99% of the 100,000 twins found there!) Twin studies, of course, are particularly intriguing because they allow researchers to parse out how much ones genetic inheritance plays a role in putting one at risk for a particular disease.

From 1998-2002 these researchers screened 31,405(!) twins born between 1935 and 1959. If during the questioning a subject revealed they had fatigue of duration lasting longer than six months they were queried regarding their symptoms, fatigue severity, duration and age, sex, education level and workplace. A long list of exclusionary factors were used to winnow the sample set down.

Findings - The first thing to note from this study is that fatigue is fairly common in the population. About 20% of people are fatigued and about 9% of people visiting their primary care physician site fatigue as a problem.

A central question of this study involved how effective the symptoms in the CDC definition were in differentiating the fatigue found in CFS from fatigue due to other causes. The CDC definition states that along with unremitting fatigue of six months or more that people must display four of following eight symptoms to be diagnosed with CFS; unrefreshing sleep, memory/concentration impairment, muscle pain, joint pain, tender lymph nodes, headaches of a new type, sore throat, post-exertional malaise. This suggests that there is something markedly different about people having four symptoms opposed to only three.

This study found that people with there was no natural cutoff point with regards to the number of symptoms one had in reference to illness. People with three symptoms were a bit less ill than those with four, and people with four symptoms were a bit less ill than those with five, etc. but there was really no point at which signaled a distinct increased level of unwellness. This suggests that the symptom cutoff point is, not surprisingly, basically an arbitrary one and the authors suggest dropping this part of the criteria

The CDC definition also assumes that it doesn’t matter which of the four symptoms you have so long as you have four of them. This study, however, found three of the eight symptoms (sore throat, tender lymph nodes, headaches) had little predictive value with regard to fatigue severity (i.e. people with both low and high levels of fatigue commonly had these symptoms). Two symptoms (post-exercise malaise, unrefreshing sleep) on the other hand performed adequately in predicting fatigue severity and three (memory deterioration, muscle pain and multi-joint pain) performed well.

Finally and most importantly the researchers were able to group their subjects into discrete categories based on the level of fatigue and symptoms they displayed. One group characterized by muscle pain, sore throat, lymph node enlargement and long duration was reminiscent of symptoms produced during the acute phase of a viral illness and was suggestive of post-viral syndrome. This was the smallest group (5%) and these individuals rarely met, interestingly enough, the CDC definition of CFS. Another termed ‘rheumatic’ had high muscle and joint pain of a longer duration but also rarely met the CDC definition of CFS. The authors believed these individuals probably had a variety of ailments including arthritis and fibromyalgia. A third class called ‘depressive’ had high rates of lifetime major depression, memory impairment and deterioration. This was a large group (35%) but people in this group rarely met (1%) the CDC definition of CFS.

Finally, one category composed mostly of women with high numbers of symptoms (5/8), who had very long term fatigue and significant impairment, was reminiscent of CFS patients and suggests a discrete CFS-like state was found in the population. The average duration of fatigue in this group (5 years) was over twice that in most of other groups. Less than 25% of these individuals had sore throat or tender lymph nodes. Most of the people in this group met the CDC definition of CFS (86%).

This is an important validator of CFS as a distinct disease state. Wessely in the U.K. has long argued that because both Gulf War Syndrome (GWS) and CFS are characterized by a set of symptoms including fatigue that are commonly found in the population that they do not  constitute discrete diseases. Instead  these patients simply represent a portion of the population that is unable, for one reason or another, to cope well with illness. It is this poor coping rather than a specific illness that leads to the chronic nature of their illness. As researchers have examined GWS and CFS patients in greater detail, however, Wessely's theory has begun to break down.  A recent GWS study found that while GWS patients may suffer from fairly commonly found symptoms the set of symptoms they display is unique. Another recent study examining the symptom set of CFS and patients with major depression found they displayed markedly different symptom sets (click here) and now this study indicates that an unusual fatigue condition characterized by a unique symptom set (CFS) does occur in a small subset of the population. 

By Cort Johnson

I have both CFS and MCS. I’ve had CFS for 25 years and MC for about 10. Compared to many my CFS is relatively mild - only for the second year or so was I almost bedridden by CFS. Since then I have always been able to work at least part-time or go to school. My MCS, however, is pretty severe and has kept me from working for almost five years now.

My latest misadventure with MCS begin in November as we (my sister’s family and I) prepared to leave San Diego for a Thanksgiving/Xmas celebration in Las Vegas with my father. I had been trying to get out of San Diego for five months now but a mysterious problem with my car that often left me ill when I drove it had kept me stuck there.

First some background. My car, my only really substantial possession ($3500!), has played a key role in my health for several years now. It was only 3 years ago that I found a car I could sleep in. This car, a regular cab Toyota pickup, was hardly comfortable given my height (6’6") but I was able to curl up in it and sleep at night. Being able to sleep in it is important because in the winter I stay at my sister’s house in Southern California and housing construction of one type or another over the past two years has made it mostly impossible for me to sleep at the house or on the grounds. Either I have to sleep in the car or on the hillside on a little preserve adjacent to the house. The hillside is mostly fine during the summer but when it rains I have a bad reaction probably because of the mold in the ground and try to stay away from it. Because my site is almost visible from the street there is no place to pitch a tent (a tarp actually) so when it rains I have to simply lay the tarp over me – not a optimal situation given my sensitivities. If it really rains hard the ground will get wet enough that even with the tarp under me I have trouble staying dry and have to lug huge amounts of wet linen (since I can’t tolerate sleeping bags) up and down off the hillside – an arduous procedure. In short living on the hillside in the winter is a mess; it’s exhausting, I get sick often, my sensitivities flare up....its basically on the top of my list of things to avoid.

Unfortunately the pickup I could sleep in burned up in the desert a year and a half ago and I had to get another car. This time I wanted a car I could easily sleep in and in lieu of a full-sized van, which is what I really wanted but which the price of gas prohibited, I got a Nissan Quest Minivan. After tearing virtually everything out of it that I could – the seats, carpeting, side panels, the tar insulation on the floor, etc. - I was able to tolerate driving the car but for some reason still wasn’t able to sleep in it. Doing so would cause me to groggily wake early in the morning with a strange taste in my mouth and a headache. Because of this I spent the last winter I spent on the hill or, when I could, I escaped to the desert when the storms came.

Upon returning to San Diego from Las Vegas in July to complete my bankruptcy and get some dental work done I started getting sick in the car. Over several months various mechanics found several problems including some small leaks in the exhaust system and in the fuel lines leading to the gas tank. The last fix, which had come just days before we planned to leave had actually seemed to make me worse but upon looking under the car I found the mechanics had left a fuel line unattached (!). I fixed it and resolved to leave the next day.

This decision had some interesting consequences though. About 9 months earlier my sister had put in a new driveway, walkway and patio. Even though I’d gotten to San Diego three months after that I’d had a terrible time with the fumes escaping from the concrete and even now, 9 months later, I still wasn’t close to being able to sleep near the house. Since I couldn’t drive, let alone sleep in the car without problems I was back out on the hill but I wasn’t near my sister’s house, I was about a ¼ of a mile away. My sister had unfortunately bought a house about half a block away from and above a golf course. Since the prevailing winds generally blew from coast away from the golf course the fertilizers were generally not a problem but if it was foggy or if the winds blew from the east I got hammered when I slept on the hill. We had frequently experienced both those situations this summer and I had moved to another part of the hill. The problem was getting to it; because the only place flat enough for me to get in there was at a busy, illuminated intersection, I had to drag my stuff in there either very late at night or very early in the morning. The morning I decided to leave I awoke before dawn and carried my stuff out.

That next day, however, I had a terrible time in the van and decided I couldn’t make it to Vegas. That night I brought my linen back up to the hill. The next morning, however, I felt much better driving the car and decided, on the spur of the moment, to attempt to make the trip, and so I left, most of my linen still on the hill....

A Paper called Cracks in the Dike examining a recent study casting some doubt on an aspect of the RNase L fragmentation test and a reply to is found the RNase L portion of the research section.

Amy Proal’s successful experience with Benicar can be accessed by clicking here and scrolling down to where Trevor Marshall is mentioned.

Check out MERGE and if you are able please donate to them. this innovative research group receives no government funding and relies entire upon private sector funding. MERGE makes this process easy by providing a wide variety of donation options (click here). You can register to get MERGE updates or their online newsletter.