CHAPTER 13

MORE ON METABOLIC CHANGES

In this section, I want to indicate the pivotal role of the intestine in health and disease.

The whole alimentary tract is the place for eating, chewing, swallowing, mixing, digesting, absorbing, fermenting, secreting and/or eliminating the various substances that it encounters.

It is certainly a crucial immune organ, and I place much emphasis on the intestinal flora (the bacteria which inhabit the intestine, particularly the large intestine).

Research is needed to clarify more details of what nutritional physicians and naturopaths call the "leaky gut syndrome". It is supposed that some low-grade inflammatory processes lead to dysfunction of gut cells.

In essence we really need to know whether there are circumstances of decreased synthesis of specific amino acids by gut flora and we need to have objective studies of the degree to which intestinal cells can consume amino acids.

If in addition protein catabolism in C.F.S. exceeds protein availability, the host is compromised.

The Newcastle group claim to identify some of these patterns.

a) Short term protein catabolism involves non-fibrillar or cytoplasmic proteins from muscle broken down to release tyrosine. The amino acid leucine controls non fibrillar proteolysis in muscle and adipose tissue. Thus alteration in leucine metabolism could contribute to this proteolysis in C.F.S.

b) Long term protein catabolism. Here contractible muscle elements (actin and myosin) are broken down releasing 3-methyl histidine.

The Newcastle group measure this in urine, along with many amino acids, serine, alanine, glycine, valine, threonine, leucine and asparagine and find many of these amino acids to be low in C.F.S.

Why they chose to measure urinary amino acids is unclear. It would seem to be more logical to measure blood levels. Some of the amino acids which they report as low in the urine are actually non-essential amino acids (meaning that the body can synthesize them) (e.g. serine, alanine and glycine).

The general principles behind assessing the meaning of any bodily chemical change include the following.

 

DEFICIENCIES.

Low levels of amino acids such as serine in the urine could reflect:

a) A very low protein diet.

b) Under-production by intestinal flora.

c) Consumption by intestinal cells.

d) Impairment of synthesis since serine is normally synthesized from glucose.

e) Excessive conversion to something else.

f) Excessive consumption by some other cellular system. (This might be feasible if other metabolic pathways are blocked or inefficient.)

EXCESSES.

High levels of amino acids might result from:

a) Very high protein intake.

b) Over-production by intestinal flora.

c) Breakdown of cells which contain this amino acid.

d) Blocked conversion to something else.

Some amino acids which appear in high amounts in their tests, might indeed signify muscle catabolism.

Can we distinguish between these and those that are the result of meat/flesh consumption?

What is really needed is clarification of the relationship between blood and tissue levels of amino acid and these urinary levels.

More recently the Newcastle Group have clustered the amino acids according to function.

e.g. High hippurate excretion could indicate a high liver detoxification rate and an increased requirement for glycine. (Could supplements of serine, glycine, glutamine or glutathione help?)

 

ORGANIC ACIDS.

One of the commonest findings is a high urinary citrate level (often ten times higher than in control subjects). High urinary citrate could imply over-production of citrate or blockage in the Krebs cycle (named after Sir Hans Krebs), also called the tricarboxylic acid cycle (TCA)

Paul Cheney writes that blood citrate levels are elevated.

This finding invites a close look at this basic cell energy cycle.

If one crucial part of CFS is inability to replenish adenosine triphosphate(the stored energy source, we could explain post exercise fatigue, as well as poor concentration and thinking.

ATP is the product of the Krebs cycle, or tricarboxylic acid cycle.

 

THE KREBS CYCLE (TCA)

The fundamental pathways of fat, carbohydrate, protein and ketone oxidation result in a 2-carbon acetyl portion of acetyl coenzyme A.

One of the main sources of acetyl CoA for the TCA is pyruvate formed from glucose in the glycolytic pathway.

Pyruvate is oxidized to acetyl CoA by the pyruvate dehydrogenase complex. (PDHase)

This enzyme is in the same family as the alpha ketoglutatarate dehydrogenase complex, but differs by containing additional subunits, one of which is a protein kinase called pyruvate dehydrogenase kinase.

This phosphorylates the PDHase into an inactive form.

There may be a subgroup of CFS cases who form lactic acid more readily, because of impaired PDHase.

Another regulatory subunit is a phosphatase which removes the phosphate residue . This is stimulated by increased intracellular Ca++.

Insulin binds to its receptor on the plasma membrane and this somehow activates PDHase.

In the Krebs or tricarboxylic acid cycle, this acetyl fragment is further oxidized to CO2.

This cycle is located in the mitochondria of cells, and accounts for some 80% of cell energy.

The cycle of organic acids Oxaloacetic acid-àcitric acid--àisocitric acid--àalpha ketoglutaric acid-à succinylCoA --àsuccinic acid--àfumaric acid--àmalic acid---àoxaloacetate involves enzymes, electron transfers through electron accepting coenzymes and a way of cells capturing energy for their specific functions, and giving off carbon dioxide (CO2).

The captured energy is in the production of ATP.

Most of the enzymes of the TCA are synthesized in the nucleus and imported into mitochondria by special mechanisms, requiring considerable energy.

We already know that some vitamin deficiencies such as thiamine deficiency result in dysfunctional enzymes such as pyruvate dehydrogenase and alpha keto glutarate dehydrogenase.

Dr Paul Cheney in North Carolina reports that he measures organic acids in both blood and urine, and finds high levels of citrate in subjects with chronic fatigue. This could suggest that the further conversion to isocitrate and alpha keto glutarate is impaired.

The enzyme conversions in these sites are

1) Aconitase, which turns the citric acid into cis aconitic acid and isocitric acid. This enzyme has thiol groups, which could be protected by glutathione and also needs non-haem iron.

It is interesting that aconitase is inhibited by nitric oxide and also by its condensation with superoxide to form peroxynitrite (PON).

Peroxynitrite (PON) also inhibits complexes I, II and V (the ATP synthase) aconitase, creatine kinase, and increases the proton leak in isolated mitochondria in some cultured cell models. We will address other actions of PON in discussing cytokines in more detail.

(2) The next enzyme in the TCA cycle is isocitrate dehydrogenase, which oxidizes the alcohol group on the isocitric acid to a keto group. It is influenced by Ca++, Mn++ and Mg++ and is stimulated by AMP and ADP, and inhibited by NADH.

At this step, the added hydrogen as hydride ( NAD+to NADH), allows the NADH to donate an electron to the electron transport chain.

(3) Of interest is the next step from a ketoglutaric acid to succinyl CoA.

The a ketoglutaric dehydrogenase complex (a triple enzyme complex) consists of a ketoglutarate dehydrogenase (decarboxylase), transsuccinylase and lipoamide dehydrogenase.

It uses thiamine pyrophosphate, lipoate and FAD. Again NAD+ is reduced to NADH.

(FAD and NAD+ are the electron acceptors in the Krebs cycle.)

This complex has similar susceptibilities to peroxynitrite as do aconitase and pyruvate dehydrogenase.

The energy of the succinyl CoA thioester bond is used to generate GTP from GDP and Pi in the reaction catalysed by succinate thiokinase, also called succinyl CoA synthetase.

The exact details of the production of available energy stores for the cell are fascinating and the electron acceptors donate their electrons to co-enzyme Q10 located in the inner mitochondrial membrane.

The electron transport chain gives rise to the phosphorylation of ADP to ATP.

The electron transport system is organized into 3 main membrane-spanning complexes,

Complex I, NADH dehydrogenase, (with Co-enzyme Q10 as electron acceptor then donor)

Complex III, the cytochrome b-c1 which accepts the electrons from the CoE Q10, and

Complex IV, cytochrome oxidase, which contains the binding, site for oxygen.

Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN,
FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper).

In more detail, these enzymes are designated
(1) complex I (NADH:ubiquinone oxidoreductase,),
(2) complex II (succinate:ubiquinone oxidoreductase,),
(3) complex III (ubiquinol:ferrocytochrome c oxidoreductase,)

(4) complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase,), and
(5) complex V (ATP synthase,).

To summarize,
This is called the electron transport chain, NADH dehydrogenase (complex 1)is the first step, then Coenzyme Q10 which transports electrons, to the cytochrome b-c1(Complex 3), cytochrome c (a small protein) and cytochrome oxidase(Complex 4), and ATP synthase.
Co E Q10 has 2 electrons to donate so can replenish oxidized tocopherols, and shuttles between the ubiquinone and ubiquinol forms,(I have a monograph on CoE Q10) as can alpha lipoic acid.
I should mention that mitochondrial DNA is 10 times as susceptible to free radical injury as intra-nuclear DNA

As electrons are transferred through each of the 3 membrane spanning complexes, protons are pumped from the mitochondrial matrix to the cytosolic side of the inner mitochondrial membrane.

There are chemo-osmotic theories about how the energy from this electron transport is transformed into the high energy phosphate bonds of ATP, but perhaps these can be left to the interested reader to find in modern biochemistry textbooks.

If the CFS sufferer spends energy faster than the mitochondria can supply it, (and most CFS sufferers are doing this most of the time!) ATP is converted to ADP faster than it can be recycled. This means there is a build up of ADP. Some ADP is inevitably shunted into adenosine monophosphate (AMP -1 phosphate). But this creates a real problem, indeed a metabolic disaster, because AMP, largely speaking, cannot be recycled and is lost in urine.

If ATP levels drop as a result of leakage of AMP, the body then has to make brand new ATP. ATP can be made very quickly from a sugar D-ribose, but D-ribose is only slowly made from glucose (via the pentose phosphate.

(Any modern biochemistry text will do, but I am drawing upon Chapter 20 of Basic Medical Biochemistry, Marks, Marks and Smith 1996)

It remains crucial to discover which of these processes are most susceptible to injury.

As mentioned, aconitase and alpha ketoglutarate dehydrogenase, appear to be susceptible to free radical injury.

Isocitrate dehydrogenase and alpha ketoglutarate dehydrogenase are rate limiting in the TCA. Both appear to be activated by calcium ions (Ca++)

Since I draw upon this material for my plan of helping cellular energy, I want the reader to consider the following information.

Glutathione

Dr Cheney suggests that the primary cause of citrate elevation is glutathione deficiency. This would need some substantiation.

In the CFS cases that have the abnormal 37 kDa form of RNAse L, the glutathione system may be damaged

Glutathione (GSH) (Gamma-glutamylcysteinylglycine) is a tripeptide of glutamine, cysteine, and glycine.

There is a gamma glutamyl cycle involving amino acid transport into certain types of cells.

Glutathione reduces free radical damage by reducing compounds such as hydrogen peroxide. It protects the sulphydryl (thiol) groups on the aconitase and also other thiol containing enzymes and cofactors.

The glutathione sulphydryl groups serve as electron donors, and are oxidized to a disulphide form (GSSG).

Once the disulphide is formed it must be reduced back to the sulphydryl form by glutathione reductase, which requires electrons from NADPH (generated from the pentose phosphate pathway)

GSH appears to be involved in recycling vitamins E, C, coenzyme Q10 and alpha lipoic acid.

Whey proteins contain serum albumin. alpha lactalbumin, and lactoferrin, (all rich in cystine) but do not contain lactose or casein.

One brand (Pharmafood) is called” IsoWhey”.

Almost 30% of the Iso Whey proteins contain branch chain amino acids

(Leucine, isoleucine and valine)

The Newcastle group claim that low leucine in the unexercised CFS patient denotes impaired regulation of muscle catabolism.

Leucine can be lost in exercise by increased action of branch chain keto-acid dehydrogenase.

Particular products may have advantages.

Dr Robert Buist says that Pharmafood’s Iso-Whey contains approximately 32% of the 3 cystine rich proteins.

He says that the cystine in whey is more able to avoid hydrolysis in the gut, and inside the cell liberates 2 molecules of L-cysteine, and this drives the synthesis of glutathione.

At least some people with chronic fatigue also have low urinary levels of alpha ketoglutarate, or low succinate levels (further around the Krebs cycle).

So is the glutathione low and if so why is it? At least some may be associated with low glycine, and perhaps some with low glutamine, and now we have evidence of the question of active mechanisms which might deplete it.

Cheney explains that some viruses when activated encode genes for glutathione peroxidase which will deplete selenium, as selenoproteins are needed for viral replication.

These include HIV, E-B virus and presumably other herpes like viruses, as well as hepatitis B and C.

For our cells glutathione peroxidase is one of the body’s principal ways of protecting us from free radical damage.

One of the two glutathione peroxidases requires selenium for its function.

Cheney says that glutathione has antiviral activity.

Cheney says that the elevated citrate level lowers the level of 2,3 diphosphoglycerate (2,3DPG), which in turn makes it harder for haemoglobin (Hb) to give up its oxygen to tissue cells.

It is well established that 2,3 DPG is needed for haemoglobin to release O2 in low O2 tension sites.

The tissue hypoxia would increase the tendency to increase lactic acid.

This could set up intracellular acidosis, and a compensatory blood alkalosis, as well as further compromising the Krebs cycle

He suggests supplements of glutathione as whey protein, and inhalation of oxygen for 20 minutes three times per day. (In specific circumstances)

Newcastle researchers suggest increased urinary loss of cations such as sodium (Na+, potassium (K+) and magnesium (Mg++) would be enhanced by high urinary citrate.

Low sodium might account for some part of the reduced blood volume reported by David Bell and Peter Rowe, and low potassium the 50% of CFS with low total body potassium reported by Dr Richard Burnet.

Burnet also describes a subgroup with high total body potassium.

We need some studies to check whole body magnesium to clarify the comments on the need for magnesium by such people as Dr Paul Cheney.

Roberts and colleagues in Newcastle NSW have discussed the concept of “channelopathy” and Dr Donald Lewis in Victoria reports success by using lamotrigine, which acts on sodium/potassium channels.

If selenium is also lost or deficient, the selenium dependent glutathione peroxidase would not work efficiently, and this could disadvantage the high oxygen sites such as red blood cells.

The Newcastle group suggest very high levels of lysine are found in about 10% of CFS cases and that this correlates with neurally mediated hypotension and perhaps persistent infections and ANA levels.

Mention needs to be made of urine metabolites (UM), which are detected in Newcastle screens but have not been fully characterized.

The researchers say that CFS UM1 correlates with high levels of 3-methyl histidine and also correlates with increased symptom expression such as cognitive changes, musculo-skeletal symptoms, infective symptoms and increased somatization scores in psychological testing.

They associate UM15 with depressive scores and UM's 13, 13A, 15A, 27 and 28 with carriage of toxin producing coagulase negative staphylococci.

We need to have these chemicals identified, and understand their functions.

The Newcastle group is doing this.

As well blood and tissue levels are probably more important than urinary levels, and the work needs independent evaluation.

Kuratsune and colleagues in Osaka, Japan report low levels of acyl carnitine in CFS and hepatitis C.

 

Insulin and hyperinsulinaemia.

There appear to be genes which increase the risk of developing insulin resistance.

With such genes, caloric excess, dietary obesity and particular food eating patterns appear to increase the risk of pancreatic beta cells making too much insulin.

This can drive increased sympathetic activity which can predispose to feeling unwell, and ultimately increase the risk of hypertension.

Insulin has a principal function in promoting and allowing glucose to enter cells, an done part of this is to allow fat cells to receive the glucose.

But excess insulin can increase the amount of fat.

In normal circumstances, a product of fat cells called leptin, signals the hypothalamus to stop the person continuing to feel hungry.

But there can arise leptin resistance, where the person continues to feel like eating.

Recent evidence has suggested that modern man is at high risk to eat too many calories, the wrong kind of food, and at the same time exercise too little.

One adverse effect of food manufacturers adding sucrose (cane sugar), or fructose

(Eg in corn syrup) is the risk that modern man eats too much fructose.

Now fructose can only really be used by the liver, and if given in excess, is toxic to the liver,

It

(1) Increases phosphate depletion in liver cells.

(2) Increases uric acid.

(3) Allows increase in nitric oxide which helps keep BP down.

(4) Initiates de novo lipogenesis, and increases LDL (sometimes called “bad cholesterol”)

(5) Increases c jun terminal kinases which increases inflammation.

A proportion of persons develop fatty liver when this situation prevails.

Thus hyperinsulinaemia, leptin resistance contribute to people feeling unwell, anxious, fatigued and even achy.

One remedy is exercise since this

(1) Increases skeletal muscle insulin sensitivity.

(2) Reduces cortisol levels.

(3) Decreases visceral fat that results from too much cortisol.

(4) Helps detoxify fructose.

This will work even better when calories are decreased to balance energy expenditure ,fructose and sucrose intakes are reduced, fibre intake is increased, and the total glycaemic load is reduced.

In fact most fructose containing fruits are much safer when eaten as whole fruit .Juice intake needs to be minimized.

 

Sleep disorders.

We cannot leave metabolic disorders without paying attention to some of the consequences of disordered sleep.

Impaired sleep is suggested by the presence of any of the following,

(1) Snoring,

(2) Sleep apnoea (breathing stops repeatedly during sleep)

(3) Sleep deprivation,

(4) Shift work and altered sleep rhythms,

(5) Experience that sleep is unrefreshing,

(6) Excessive daytime sleepiness, and tendencies to drop off to sleep in daytime activities.

The metabolic changes include, lack of oxygen during apnoea (hypoxaemia,) with marked sympathetic responses that can generate high blood pressure and increase the risk of cardiac events.

The more severe sleep disorders may increase a hormone called Grhelin, increased insulin release, and resistance to insulin and leptin.

The person may eat more in these states. In some cases there is increased obesity, and an increased risk of diabetes.

This may become a vicious cycle.

There is a risk of increased accident rates while driving or at work.

 

Molybdenum

Molybdenum (Mo) appears to protect people from oesophageal cancer.

It is necessary for the activity of sulphite and xanthine oxidase, and aldehyde oxidase.

In all molybdenum-containing enzymes with the exception of nitrogenase, the molybdenum cofactor (Moco)1 consists of a mononuclear Mo atom coordinated to the cis-dithiolene moiety of molybdopterin (MPT).

The metabolic pathway that shows the likely cause of aldehyde protection is--

Threonine or Ethanol--> aldehyde--> acetic acid--> acetyl coenzyme A.

A toxin, acetaldehyde, can be transformed into a source of energy, acetyl coenzyme A provided there is adequate molybdenum in the diet or through supplement form.

Thus this claim is correct if Mo was low. Can extra Mo protect?

Molybdenum is usually found in milk, lamb, pork, beans, lentils, peas, soybeans and some seeds, including oats and wheat germ.

If a soil was deficient, the plant would have less Mo.

What is the RDA?

Average USA intakes vary from 120-240mcg/day.

I seems to be safe to add 100-200mcg /day as a supplement for a month to assess the response.

Eagle “Tresos B” has 46.6mcg per tablet, and Bioceuticals “Ultramuscleze” powder has 60mcg per teaspoon.

One could suggest that people who are chemically sensitive might find Mo could decrease reactions to formaldehyde in carpets and metabisulphite in dried fruits and wines.

There are some claims that Mo can help chronic fatigue syndromes, fibromyalgia and post polio syndromes at doses of 100mcg 3 times per day.

I consider that at this point of time, this lacks adequate evidence base.

CELL CYBERNETICS AND REGULATORY DYSFUNCTION
Is there a link between immunological and inflammatory changes and metabolic consequences?

Martin Pall, a research biochemist at Washington State University in Pullman, Washington has formed a hypothesis about the generation of a chemical called peroxynitrite (PON), which would result in the chronic homeostasis of chronic fatigue.

In essence the interleukins above induce one form of nitric oxide synthase called inducible nitric oxide synthase (INOS). The nitric oxide which forms reacts with superoxide in mitochondria to produce the peroxynitrite, a more reactive free radical.

Superoxides are also a product of oxidative injury in cells in circumstances of chemical and microbiological damage.

 

PEROXYNITRITE EFFECTS.

(1) The peroxynitrite inactivates superoxide dismutase in mitochondria increasing the levels of superoxide.

(2) But in addition the peroxynitrite activates a transcription factor called nuclear factor kappa beta (NFKb) which stimulates gene transcription for ILI, IL6, TNF alpha and IF gamma, and also gene transcription for inducible nitric oxide synthase. (A self perpetuating cycle)

Thus both superoxide production (and decreased degradation) and nitric oxide production are kept high, perpetuating a higher level of peroxynitrite.

(3) Peroxynitrite contributes to a decrease in ATP pools in the following fashion (a further feed forward effect).

An enzyme called poly adenylate ribose synthase is activated by breaks in DNA. Free radicals produce "nicks" in mitochondrial and nuclear DNA.

The PARS promotes polyribosylation of histones, and the substrate NAD involved in all oxidative and energy metabolism conversion to NADH is depleted.

We have already mentioned the inhibiting effects on aconitase, and other enzymes.

With depleted NAD+/NADH, ATP is also depleted. Hence mitochondrial and perhaps nuclear cell energetics are impaired.

(4) It is likely that increased peroxynitrite contributes to injury in other inflammatory states. The proximity of T cells, and other cells participating in pathological processes, to target cell sites shapes the risk of interleukin over-activity or oxidative injury.

It is clear that a number of factors are involved in the location of these specific injuries.

(5) Chromosomal abnormalities are found in up to 90% of cases of scleroderma where peroxynitrite is likely to be active at endothelial and sub endothelial vascular locations.

(6) Dr Judy Ford has reported increased chromosomal abnormalities in people using pesticides.

(7) I believe that we need to be much more concerned than ever about the high level of environmental pollutants. Sufferers with chronic fatigue may represent a more vulnerable sub group.

(8) PON increases intracellular calcium, which is pertinent to 2 other NO synthases, which are calcium dependent. Increased intracellular calcium could further disadvantage cell function.

(9) NO and PON might also facilitate rapid glutamate release in some neurological injury states but it would be speculative to know whether the" mind-fog" states of CFS are related to this.

 

OTHER ASPECTS OF IMPAIRED ATP FUNCTION

(1) There may be decreased transfer of free fatty acids by carnitine across the mitochondrial membrane.

Acetyl l carnitine is needed to transport long chain fatty acids across mitochondrial membranes.

(2) If magnesium is low, ATPase cellular pumps may not work as well.

 

FURTHER PROBABLE PATHOPHYSIOLOGICAL CHANGES.

There are a proportion of people with chronic fatigue syndromes who have a tendency to low blood pressure and postural hypotension. Some also seem to exhibit a readily provoked tachycardia.

Dr Peter Rowe from Johns Hopkins School of Medicine in Baltimore, Maryland reports the concepts of neurally mediated hypotension and postural orthostatic tachycardia syndromes in chronic fatigue.

Some of these may have a reduced blood volume and others may be prone to orthostatic blood pooling. Perhaps vasomotor tone is altered.

Dr David Bell from New York (also Harvard's Cambridge hospital) reports that in 45 patients with chronic fatigue he evaluated that 68% had a decreased circulating blood volume, 71% a reduced red cell mass, and 67% a decreased plasma volume. There was a trend for the hypovolaemic sufferers to have an increased plasma osmolality above 290 mOsmoles/ml and since some also had reduced fasting urine osmolality an anti diuretic hormone deficiency may be present.

 

OTHER AUSTRALIAN STUDIES.

Dr Richard Burnet, an Adelaide endocrinologist, as mentioned above, has found total body potassium to be low in about 50% of C.F.S. subjects, (despite normal serum levels).

He also finds evidence of delayed gastric emptying in some 60% of CFS subjects.

This could account for bloating reported by many patients.

There is also separate work using SPECT scans on the brain revealing altered (reduced) perfusion in some specific brain regions. (Burnet, Kwiatek and Casse)

Professor Tim Roberts, of the Newcastle group, thinks that intracellular organisms subvert the sterol pathway to use cholesterol to make ergosterol.

We may have to add that toxins evoke injury to cell membranes including specific injury to ion channels, a so called “channelopathy”.

Such injuries have been demonstrated with ciguatera toxin.

Are chronic fatigue and fibromyalgic syndromes inflammatory states?

To address this question I will outline some recent research into something which seems to be emerging as common in such situations as obesity and other mild inflammatory states.

It is becoming evident that there are many patterns of inflammation, and doctors look carefully for evidence of inflammation in the patient’s history, examination findings and by ordering common tests such as measurement of C reactive protein (CRP), erythrocyte sedimentation rate (ESR) and fibrinogen along with a close look at various kinds of white blood cells.

We may observe for example that a patient has some mild gingivitis (or reports that gums bleed a little on cleaning her or his teeth, but the CRP and ESR are normal.

The researchers into premature births around the world have noted the danger of the pregnant woman having vaginal flora containing beta haemolytic streptococci.

Eradication of the vaginal streptococci had marked ly reduced prematurity, but this is not enough.

Now the researchers at the Princess Margaret Hospital in Perth, Western Australia report a further reduction of premature births by special care of gums and mouth in pregnancy.

I believe that we need to be this fastidious in the care of persons with CFS, and fibromyalgia syndromes and indeed in any hard to diagnose chronic disease.

A discovery of another inflammatory association has come with elucidation of PPAR, a family of nuclear receptors.

Nuclear peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. As transcription factors, PPARs regulate the expression of numerous genes and affect glycaemic control, lipid metabolism, vascular tone and inflammation.

Also PPAR agonists inhibit the metalloproteinase activation in macrophage.

There is even evidence that intestinal flora influence PPAR expression in intestinal locations.

 

NON SPECIFIC INFLAMMATORY MECHANISMS.

The non-specific inflammatory pathways may be activated in some forms of chronic fatigue in a lesser degree than in what we call "collagen diseases".

Arachidonic acid (an omega 6 fatty acid) in all cell membranes is released from its membrane bound form by phospholipase A2 (more so in states of cell injury).

Active eicosanoid metabolites generated through cyclo-oxygenase pathways are prostaglandins of the 2 series (PGE2, G2), which increase pain and inflammation. (See diagram)

Leucotrienes of the 4 series, LTA4, B4, C4, D4 and E4 are generated from 5 lipoxygenase. LTB4 increases local oedema, and is chemotactic for neutrophils and eosinophils, while LTC4, D4 and E4 are broncho-spastic.

In some more inflammatory conditions, the above leucocytes release enough proteases to add to target organ damage.

When I address recent advances in treatment of the CFS/FMS and brain fog states, I will draw upon this material.

 

KEY CELL CHANGES IN CHRONIC FATIGUE.

The above information reveals some of the ways that infection, genetic vulnerability, inflammation, the immune system and intricate cell signalling and biochemical pathway alterations could set a chronic homeostasis of illness in chronic fatigue and in auto immune and collagen diseases. In particular some subtle metabolic changes in cells may be crucial to the striking lack of energy and the marked post exercise lassitude that may last for hours or days.

Antinuclear antibodies are often slightly elevated in chronic fatigue.

Peroxynitrite also plays a role in autoimmune diseases (which themselves appear to be responses to exogenous viral and bacterial material). We actually need to be vigilant about these diseases, which may evolve slowly, eluding early diagnosis.

It can be seen that abnormal gut, muscle, and neural function can be evoked with or accompanying immune/inflammatory happenings.

The above hypothesis remains a hypothesis but at least gives an indication of how chronic fatigue syndromes might emerge.

Dr Sarah Myhill <http://www.drmyhill.co.uk/> in Wales has a plan based on correcting cell energy mechanisms. I expand on this in Chapter 18 on the therapy of CFS.

The reader should now be able to see that before we rush into claiming that psychological mechanisms are the reason for symptom bearers, we have a lot or searching to undertake.

 

^