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on medicine and current thought, including CFS

by John Graham

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Chronic fatigue

 

 

 

 

 

 











 

 

 

 

CHAPTER 18

THE THERAPY OF CHRONIC FATIGUE

.

This chapter is very discursive and warrants some caution as it attempts to cover so much territory.

Feel free to skip to the issues that you want to look at.

How can we evaluate the merit of claims?

Viral factors
Are foods or nutrients useful in viral illnesses and their aftermath?


Stealth viruses

Transfer factors

Mycoplasma

Rickettsiae

Fine tuning or ideal nutrition

Chronic sinus, skin, respiratory and urogenital tract infections


Yeasts and Candida

Nutritional Repair

Mitochondrial Protection


What the consumer needs to know about edible oils in Australia

Abnormalities in the gut

Mineral support


Antioxidants and therapy

Addressing the organic acid changes

Low blood pressure, postural hypotension and dizziness

Electromagnetic fields

Mind or brain fog

Adult Hyperhomocysteinaemia

Other actions of some antibiotics

New aspects of inflammation

The Marshall Protocol

My comments on the Marshall Protocol

Cautions

Spices

Depression

Stress and psychological issues

Genomics and proteomics

 

The therapeutic task in C.F.S. is to understand genetic backgrounds, decrease or eliminate pathogen loads, decrease environmental pollution, optimize immune function, heal any intestinal disorder, optimize nutrition (consider nutrigenomics), counter oxidative stress, and allow restoration of all cellular function and signaling.

All of this is in the setting of the consciousness of the person who is intimately involved in this healing task.

It necessarily involves ongoing conversations that allow each person in her or his own way to co-evolve the healing outcome.
I like to call this “a dance of understanding”

This fits with my idea that evolution whether it be in the changes in the cosmos, in biological systems, or in our thinking, never ceases.
The healing processes could produce a change from an “ill” or “dysfunctional” state of homeostasis to an optimally functioning state.

It should be stated from the outset that in practice this is sometimes a far from satisfactory area.
Hypotheses need much more work on them.

We are accessing the work of many authors, some of whom are laboratory researchers, others clinicians and yet others modelers of molecular biology. Some are readers who like to word and reword the work of others.

How can we evaluate the merit of claims?
( top}
Indeed is it possible at any point in time to put therapies in some sort of order?
Which can be used together?
Taking all these things into consideration some specific therapies have been suggested and some of these are designed to rectify chemical abnormalities and others are to protect and help the cell membrane to improve. I cite some of these therapies.

In what follows there will be a strong emphasis on nutrition.
The quality and nature of nutrients could provide the body with everything it needs for optimal health.
It seems likely that not only are there nutrient deficiencies in the third world, but in the midst of plenty, Western countries have not achieved ideal nutrition. Vitamins C and D should be especially considered.
If impaired ATP production by mitochondria is important, the Sarah Myhill plan is endorsed by cardiologists Stephen Sinatra and James Roberts.

I emphasize that this work needs ongoing research, sifting of evidence and willingness to change ideas.
I encourage readers to beware of claims that are exaggerated or unwilling to rethink the evidence.



Viral factors (top)
Are foods or nutrients useful in viral illnesses and their aftermath?


I am a strong encourager of good nutrition.
Glyconutrients with the less common sugars, mannose, fucose, xylose, N-acetyl glucosamine, N-acetyl galactosamine, and n-acetyl neuraminic acid are crucial parts of functional glycoproteins such as immune cell receptors.

Dr Darryl See claims that glyconutrients from some plants enhance T (NK) (TH1) cell function, (e.g. by acetyl mannans enhancing the receptor response to antigen,) but resulting in decreased viral loads, and decreasing fatigue symptoms.

Helpful glyconutrients occur in aloe vera, garlic, and onion, yams and sweet potato, turnip, parsnip and carrot, cabbage, cauliflower, broccoli and brussel sprouts, tomato, pineapple, paw paw and rice bran. Dr See would recommend plants free from pesticide.
This work has not been adequately evaluated, but there is no risk from these foods in moderate amounts.


Viruses


It will increasingly emerge that we will see the development of effective anti-viral agents.
I would like to emphasize that if viral infection cannot be proven, it may be sensible not to use antiviral agents, especially if they pose risks to the patients.

Antiviral agents
Herpes viruses may be decreased by acyclovir, and famciclovir (HSV1 and 2)
.

These agents are used in acute episodes, and must be started promptly to be effective.
Because of the widespread infection rate, the majority of people have HSV1 antibodies, (also EBV, varicella- zoster virus), but many never manifest clinical disease. It is interesting to map circumstances where these viruses reactivate.

Acyclovir inhibits viral replication but does not eradicate virus. It is converted to active forms by phosphorylation in virus-affected cells, and host cell kinases bring the monophosphate to acyclovir triphosphate, which inhibits virus induced DNA polymerase.

It is effective in HHV1 and 2 in terms of shortening and lessening the severity of attacks.
Clinical trials in EBV infectious mononucleosis have not shown any advantage over placebo treatment.

Ganciclovir is a guanosine analogue that is more active against CMV.
It is converted in cells by a viral phosphotransferase encoded by CMV gene region UL97, and the ganciclovir triphosphate is a selective inhibitor of CMV DNA polymerase.

Most clinical trials have occurred in patients with HIV infections or other immunocompromized states, because CMV infections in patients with AIDS are very serious.
It is not yet clear whether there is a sub group of CFS sufferers who could benefit by IV ganciclovir, but Dr A Martin Lerner claims that there is a mild CMV related cardiomyopathy which presents as a CFS like illness, and that it responds to ganciclovir therapy. Ganciclovir does have some bone marrow toxicity, which should make us cautious in less serious situations.
Ganciclovir has poor oral bioavailability.

Valganciclovir.
An orally available drug called valganciclovir (Valcyte) is available, but is restricted under Australia’s PBS.
It may be the best agent for persistent CMV of HHV6A infection.
At this time I look more closely at myocardial function in CFS sufferers, especially if they report any dyspnoea.
Sarah Myhill certainly thinks the cardiac side of severe CFS has been neglected.
In my searches I am not finding this.


Stealth viruses.
(top)

Although this is a reminder of what we have not yet found, claims have not been verified so far.
The recent virus claim is around XMVR (see below)
A major advocate for anti viral therapies is Dr W John Martin from California, with unfolding evidence about “Stealth viruses”, a variety of mutated CMV.

Unfortunately Dr Martin has seemingly disappeared from the CFS scene.

This subject always needs substantiation, but Martin claimed his data includes cytopathic effects produced by CFS patient’s cells in vitro, induced illness when it is injected into cats, and also extensive PCRs confirming CMV viral sequences on the viral material.

He has further identified a simian (green monkey) CMV in some of his CFS patients.
These materials are infective and cause illness in cats that are injected with this material.
Unfortunately, his work has not been verified and he is no longer working in this field.
This is more a reminder that the persistence of viruses may turn out to be important in particular diseases.
Foscamet has an antiviral spectrum against all of the herpes virus group, and can be active against CMV infections that are resistant to ganciclovir. It also has some antiretroviral activity, and inhibits the viral DNA polymerases from hepatitis B.
Foscamet does not require activation by thymidine kinase (TK) or other kinases. (Theoretically it might be active against herpes virus mutants which are deficient in TK, and in vitro this has been demonstrated.)
It is not an agent to be used lightly. It appears to be ineffective in HHV6 infections and reactivations.

As mentioned above nutritional substances such as some fatty acids such as lauric, capric and caprylic acids, and derivatives such as monolaurin, milk ingredients (lactoferrin), plant antioxidants (kaempferol) and vitamin A have activity against CMV.
It is notable that prostaglandin E2 increases CMV activity.
Lysine at doses of 2 gms/day may enhance reduction of herpes viruses.
St Johns Wort (hypericum) also has activity against herpes viruses, EBV and oral stomatitis virus. The Newcastle group suggest that some viruses are favoured by certain lipid profiles and one might attempt to change lipid patterns.

It should be noted that St.John’s Wort is an inducer of the cytochrome P450 enzyme CYP3A4 and decreases the efficacy of the oral contraceptive pill.
It can also decrease the levels and antiviral effects of HIV protease inhibitors such as indinavir, and the anti-rejection drug cyclosporin.
This reminds us that we need to know more about interactions between drugs and herbal medicines.
Piperine in pepper has quite potent effects upon the absorption and metabolism of some drugs and heral substances.


Transfer factors.
(top)

These are peptides of some 40 amino acid lengths, which enhance antimicrobial activity and also greatly increase T natural killer cell functions. They appear to down regulate auto-immune activity.
Bovine and human transfer factors seem to be identical.
The natural situation leads to the offspring getting immunity to infections
encountered by the mother, but the pathogens of the cow differ significantly from human pathogens.
They appear to be very safe.
Darryl See has tested transfer factor and shows that it has a marked effect in increasing natural killer cell activity.
He strongly favours its use in CFS.

There is very little literature on transfer factors.
Finally, some claim that IV vitamin C 30 Gms infusion may help to deal with any acute viral illness or flare-up. (Lack of controlled trials here, but it should be considered in all serious infections and with burns)
Vitamin C is in highest amounts in all immune cells, adrenal cortex and brain.

Every person is intensive care and heart units, and indeed in every hospital should be replete in Vitamins C and D.
Higher than RDA doses of vitamin C are needed during illness.
I suggest at least 500 mg tds.
I have wondered about the pretreatment of some patients before embarking on the other therapies, and this is where Sarah Myhill’s background therapies are likely to be protective.


Mycoplasma(top)

Mycoplasma infection can be treated acutely with tetracyclines, macrolides or ciprofloxacin.
With chronic persistence of mycoplasmas, we are not usually able to prove whether they are pathogens or not.

If Trevor Marshall PhD is correct then with all chronic bacterial infections we should consider that killing the organisms can result in cytokine release and in some persons this may make them feel ill. This could suggest starting with much lower doses than those mentioned below!)

Doxycycline doses of 200 mgm/day at first (6 weeks) then 100 mgm/day (further 6 weeks). It is uncertain as to what is the optimum duration of these therapies.

Minocycline has better intracellular penetration than doxycycline.
Doses are possibly 50 mg alternate days, increasing as tolerated to 50 mg daily, then and 100 mg daily.
The prescriber will need to be aware of side effects such as benign intracranial hypertension with ongoing minocycline therapy.

If used supplements of minerals, (Fe, Ca, Mg, Mn, Mo, Se and Zn etc) should be delayed to at least 4 hours after the tetracycline dose, since these minerals may impair doxycycline bioavailability and effects.

A difficulty exists in discerning whether resident mycoplasmas are, non pathogenic or pathogenic
Azithromycin, clarithromycin, josamycin and also ciprofloxacin have also been used widely to eradicate mycoplasmas that are pathogens.
The ketolide, telithromycin will emerge as useful for some of these organisms that are resistant to macrolides.

Macrolides (except azithromycin) must not be given with statins (azithromycin is not metabolized by CYP 3A4), and the antihistamines, astemizole, terfenadine and chlorpheniramine, since they are potent inhibitors of CP450 3A4 isoforms.

Azithromycin achieves higher tissue concentrations and intra cellular levels than other macrolides. It has a much longer life in the body.


Rickettsiae(top)

As stated earlier in regards to Rickettsiae, Cecile Jadin recommends one week on and three weeks off with these antibiotic courses.

It is likely that chronic infection requires more courses because the organism can persist inside cells in a dormant state. I would consider continuing these courses for many months, and possibly changing from doxycycline to either a macrolide or ciprofloxacin in resistant cases.
Jadin suggest that in chronic rickettsial disease, the mean time to achieve recovery is about 8 months.
The quinolines are potentially more toxic that some other classes.

There is little published data to help us here!

Classical and established doses appear to be doxycycline 100mg bd in adults, but children where teeth and bones are still growing should avoid this.

My previous plan was to use doxycycline 100mg twice daily for cycles of 7-10 days on 10 days off. (There may be a need to vary the cycle length)

If the situation is of some standing, minocycline with better intracellular penetration may be preferred.
If I use minocycline, I am wary of long courses and as mentioned, we need to consider the risk of benign intracranial hypertension as a side effect.

In the past, if 2 cycles hadn’t helped, I use clarithromycin 500mg bd for 7 days (15mg/kg/day) or azithromycin 500mg one twice per day for 2 or 3 days (10mg/kg/day) can given before the next doxycycline cycle.

I now tend to follow Marshall’s protocol for most suitable persons, but I am very careful how I choose this. I never let vitamin 25 D3 levels become too low!

This is also a situation where persons with CFS may be more prone to the reaction that Marshall thinks is a Herxheimer reaction. This may be more likely with treponemes and borrelia(Lyme disease).

He strongly recommends much lower doses such as 250 mg every third day. He writes and lectures that each molecule entering the germ weakens it.
Azithromycin has high intracellular concentration and a long 1/2 life.

.
Ciprofloxacin 750mg bd for weekly cycles can also be considered, as can clindamycin (A lincoside) at 250 mg bd.
Jadin has case numbers in the thousands and reports 84-96% success rates in the chronic rickettsial group.
She needs to publish the sero-positivity rate of South Africans who are well, and co morbidity data.

Now we can note Prof Kenny De Meir Leir’s findings and the interesting work of Trevor Marshall.

In recent presentations (2006), Marshall reports 40/77 CFS cases and 20/34 FMS cases responding to his protocol, usually taking well over a year to achieve this!
I will later address the Marshall protocol more fully!

A task is damp down any reaction to killing bacteria, as well as to shift things to decrease microbial survival.

For the TH1 state he suggests that we may have the task to decrease the high 1,25 dihydroxy D3 in the Th1 set immune set patient, but he says the marker may well be the 25 D3 level, as this may be a blocker on the 1,25 D3 receptor (VDR) interfering with efficiency of innate immunity.
We are still not privy to what is happening in the intranuclear sites of the VDR or indeed on other intranuclear family receptors!
I have not been able to support Marshall’s ideas of reducing vitamin D by either less daylight or avoidance of D containing foods.

Decreasing vitamin D3 intake along with avoiding sunlight could make sense only in some cases of sarcoidosis or sensitivity to excessive daylight. So despite Marshall’s claims, we need to be wary of inducing vitamin D deficiency.

I always follow up 25 D3 and 1,25 D3 levels at 2-3 months intervals.

I am much stricter than Marshall in ensuring that persons do not become D deficient!! I like to keep 25 D3 at 80 nmol/L or higher.
If low I check parathyroid hormone and calcium levels.

Olmesartan appears to rapidly reduce 1,25 dihydroxy D3 levels, but not to subnormal levels.
The dose is 20- 40 mg 3-4 times per day.

Minocycline and azithromycin are better than doxycycline, in dealing with cell wall deficient bacteria, because of better intra cellular penetration.

In this situation dosing could follow Marshall’s recommendations, at least as far as a cautious beginning!

A suggested dose is minocycline 12.5 - 25mg on alternate days for 30 days, then azithromycin 250mg every 3 days for 21 days.
The dose is remarkably low, but it may need to be repeated.

Each of these medications has capacity to decrease inflammation directly as they decrease matrix metalloproteinases such as MMP9.

I need to state my clinical experience that many CFS and fibromyalgia patients appear to have adverse reactions when given antibiotics.

These responses may include worsening of fatigue, aches, nausea, headache and just feeling really ill.

My search of the literature has failed to reveal the reasons for these reactions though many explanations have been offered.
The commonest explanations including Marshall’s ideas seem to be a “Herxheimer type reaction”, and/or release of cytokines, secondary to microbial death.


Since I am committed to holistic approaches, I restate my use of the following supportive therapies to the above antibiotic protocols.

It is apparent that many doctors do not pay much attention to fine tuning or ideal nutrition to each person. (This may be quite different from person A to person B.)


(1) Fresh pineapple.(top)
This contains bromelain a protease which increases the absorption of any quercetin in the diet, and is 40% absorbed itself. It is fibrinolytic and the intention is to decrease fibrin deposition at vascular and other locations.

(2) Quercetin.
This plant flavonoid and antioxidant is an inhibitor of phospholipaseA2, and its antiinflammatory effects include vessel protection.

A bonus is its cancer preventing and antioxidant effect of LDL cholesterol.
Effective doses may be 600-1,000 mg per day in divided doses.
It may also quell some of the Herxheimer type reactions.


Details on Quercetin.


Glycosides are compounds that yield one or more sugars among the products of hydrolysis. Glycosides may be considered sugar ethers.
The non-sugar component is known as the aglycone, and the sugar component is called glycone. The flavonoid glycosides and their aglycones are generally termed flavonoids.


Rutin, quercitrin, and the citrus bioflavonoids, including hesperidin, hesperetin, diosmin, and naringen, are among the best known flavonoid constituents.

Quercetin is the aglycone of quercitrin, rutin and other flavonoids.

Quercetin (3,5,7,3’,4’-pentahydroxyflavone) may delay oxidant injury and cell death by: scavenging oxygen radicals; protecting against lipid peroxidation, and thereby terminating the chain-radical reaction; chelating metal ions, to form inert complexes that cannot take part in the conversion of superoxide radicals and hydrogen peroxide into hydroxyl radicals.

Plants/Food Which Contain Quercetin:
Apple
Asparagus
Bearberry (Arctostaphylos uva-ursi)
Bell Peppers
Black Catechu (Acacia catechu)
Boneset (Eupatorium perfoliatum
Brussel Sprouts
Dill
Elder flowers (Sambucus canadensis)
Eucalyptus (Eucalyptus globulus)
Euphorbia (Euphorbis piluifera)
Fenugreek (Trigonella foenum-graecum)
Hydrangea (Hydrangea arborescens)
Kale
Pale catechu (Uncaria gambir)
Passionflower (Passiflora incarnata)
Pear
Podophyllum (Podophyllum peltatum)
Onion
Squill (Urginea maritima)
Tarragon
Tea ( bioavailability is about half that of quercetin from onion.)
Witch hazel (Hamamelis virginica)

Actions:

Is a potent antioxidant.

Is a PPAR agonist, down regulating inflammatory cytokines.

Inhibits the following enzyme systems:

Aldose reductase (an enzyme which promotes the synthesis and intracellular
Accumulation of sorbitol)
AR is a critical regulator of TNF-alpha-induced apoptotic signaling in endothelial cells.
The inhibition of aldose reductase (AR) provides an interesting strategy to prevent the complications of chronic diabetes.
Catechol-O-methyl transferase
Cyclic nucleotide phosphodiesterases
Cyclo-oxygenase
Oestrogen synthetase
Histidine decarboxylase
This may decrease histamine induced inflammatory injury.
Hyaluronidase
Several lipoxygenases
Matrix metalloproteinase 9
Phospholipase A2
Protein kinases
Transport ATPases
Xanthine oxidase
Thus effects are
Anti-inflammatory - prevents mast cell and basophil degranulation
Anti-oxidant
Helps reduce the formation of leukotrienes of the 4 series
Increases cyclic AMP
Inhibits phospholipase A 2
Inhibits platelet aggregation
Prevents breakdown of collagen matrix of connective tissue and ground substance


*Protects pancreatic beta cells from damaging effects of free radicals
*Sparing effect on epinephrine
*Stabilizes membranes
*Inhibits apolipoprotein B secretion by liver and intestinal cells.
*Decreases diacylglycerol acyl transferase activity.
*Has inhibitory effects on glycation of proteins


Clinical Indications:


Allergies
Antiviral - herpes virus I, para-influenzae 3, polio virus I,
Respiratory syncytial virus
Aphthous stomatitis
Asthma
Benign prostatic hypertrophy (BPH)
Bronchitis
Candidiasis
Cataract prevention- if diabetic
Crohn’s disease
Diabetes mellitus
Eczema
Fibrocystic breast disease
Fibromyalgia
Gout
Headaches
Haemorrhoids
Irritable bowel syndrome
Otitis media
Ovarian cancer - inhibition of tumour promotion (squamous cell carcinoma, ovarian carcinoma and oestrogen receptor negative breast cancer)
Psoriasis
Rheumatoid arthritis
Ulcerative colitis
Atopic dermatitis
Diabetic cataracts, neuropathy, retinopathy
Inflammatory conditions

Dosage:
400 mg. 20 minutes before meals, TID

Drug/Nutrient Interactions
Bromelain may enhance quercetin absorption


Cautions


Quercetin is an inhibitor of CYP450 3A4 isoforms and may increase the blood levels of 3A4 metabolized drugs and hormones.
A major caution is interaction with common HMG CoA reductase inhibitors (except pravastatin)


(3) Be sure that the patient is taking adequate zinc and vitamin C, and lots of coloured plant products.

(4) Lactobacilli of the acidophilus and bifidus groups, and perhaps the yeast, Saccharomyces boulardii (these can also decrease antibiotic induced diarrhoea)

It is very desirable to actually assess gut flora in order to find and correct any dysbiosis.
In some cases the above lactobacilli should not be used!
If irritable bowel symptoms are present, the special use of E coli Nissle.

Adequate dietary intake of fructo-oligosaccharide (inulin) as in artichoke, pear, asparagus and similar plants, supports healthy colonic flora.
Probiotics are usually very well tolerated. (See more details below)


(5) Other microbicidal agents.

(a) Antimicrobial substances in colostrum and milk may emerge as having a role in dealing with some infections, while protecting normal gut flora.


Lactoferrin


This consists of a series of glycoproteins with activity against staphylococci, gut bacterial pathogens, candida, and viruses such as hepatitis C. As well it has been shown to heal experimentally induced colitis.
Actions include depriving some bacteria of needed iron, breaking up biofilm which colonies of bacteria use to be less susceptible to body chemicals, and also enhancing of neutrophil phagocytic activity.
There are species differences in these molecules, and most commercial products are of bovine origin.

(b) Derivatives from coconut or coconut milk 300 ml per day.
This contains lauric acid, which can be converted into monolaurin in the intestine, and has anti microbial actions, particularly against staphylococci (see later) but including CMV and allied viruses.
Other fatty acids, capric acid especially as its monoglyceride, monocaprin and caprylic acid have antimicrobial activity. Monocaprin can inhibit chlamydia.

Monolaurin can be obtained from the USA www.lauricidin.com

This form is better tolerated than coconut milk and is probably more effective.
I so far remain unconvinced by this work.



Other Bacteria(top)

Chronic sinus, skin, respiratory and urogenital tract infections should be treated with appropriate antibiotics. At the same time attention needs to be paid to keeping the gut flora as healthy as possible. Some plants exhibit a capacity to inhibit bacterial proliferation. For example cinnamon, garlic, ginger, olive leaf, turmeric and St John’s Wort.

The use of a nasal cream containing mupirocin, neomycin or bacitracin could kill bacteria in the anterior nares. Cleansing lotions and soaps containing chlorhexidine or similar might help cleanse the skin in general and the perineum in particular.

Dental hygiene and particularly healing gingivitis is also likely to be important.
Herbalists may like to use locally placed and diluted tea tree oil or lavender oil as these have been shown to have anti-staphylococcal activity. Systemic antibiotic to eradicate coagulase negative staphylococci is probably not justified (or possible)
Further research is needed in this area.

Other antimicrobial therapies should be explored especially in the light of resistance to antibiotics.
If studies in Hungary on olive leaf extracts are true, (Robert Lyons in Budapest) doses of 750mg (standardized to contain12.5mg oleuropein) 2-4 times per day could be tried. None of the patients that I have seen seem to respond to this.
Olive leaf seems to be more helpful when used in combination with hops and rosemary.


Gut Flora


Newcastle research suggests that in some chronic fatigue sufferers the total count of intestinal flora is lower than normal and that there may be in particular sub normal levels of aerobes such as E coli or anaerobes such as bacteroides. (Note the previous data on bacteriophages that attack E Coli.)

E coli appear to provide synthesis of amino acids, tyrosine, phenyl alanine, and trytptophan as well as coenzyme Q10, folic acid and B12.

There is commonly an overgrowth of alpha haemolytic and non haemolytic streptococci and enterococci, all of which cam make D and R Lactic acid.
The D lactatye appears to contribute to mitochondrial dysfunction, hence low enery and brain fog!

These organisms can be reduced with low doses of erythromycin, ampicillin (made into a slow release form), or cephalexin such as 250 mg bd for 1-2 days.

There may also be a lack of lacto bacilli. Lactobacilli of the acidophilus group appear to be protective in the upper intestine and the bifidus group protective to the lower bowel.

There is a strong case to treat other all chronic fatigue sufferers with lactobacilli (acidophilus and bifidus) together with fructooligosaccharides from onion, artichoke, asparagus and pear) but this is particularly important when antibiotics are used.

We need to evaluate which forms of probiotics are best.
In the future we may find non-pathogenic strains of E coli can be reintroduced into the intestine in much the same way that we use lacto bacilli today.
Recent data suggests that E coli Nissle may be helpful especially in irritable bowel syndromes. (Check through Google search)

Further research is needed on the subject of optimum probiotics in human intestinal disorders, e.g. irritable bowel syndrome and chronic fatigue.
At present I strongly avoid the use of the drug tegaserod (Zelmac).



Yeasts and Candida(top)

Anticandidal therapies and avoidance of dietary ingestion of yeasts (saccharomyces), which might have common antigens, may be one component of lessening inflammatory changes in small intestinal epithelial structures.

Lactoferrin found in fresh milks has potent anticandidal activity; principally through it’s iron-binding effects.
If the claims of yeast over-proliferation in the intestine are true it is astonishing that gastroenterologists doing endoscopic examinations have not identified candida more often. (These claims are common in naturopathic circles, but my perusal of the literature has failed to find support for the claims.)

Even if there is no clear link between chronic fatigue syndromes and candida it is important to protect the body from any low grade inflammation in the functional inner surfaces of the intestine.

I support the use of lactoferrin in these situations.

Perhaps there should be more dialogue between gastroenterologists and microbiologists and those who claim that yeasts do cause other effects than those documented in medical texts.
One area that needs a truly scientific study is that of “live blood analysis”
This involves the use of very high magnification (8.000-18000x) of live blood samples, combined with the ease of changing from direct viewing to phase contrast and dark field illumination.

This was presented at the Chicago conference about Marshall’s work.

There is also facility to obtain photographic and video records of these views.
It would be possible to comprehensively compare this data with the biochemical, microbiological, and immunological data that I have mentioned in this paper.
A formal adequate study on this subject is long overdue and would include special stains, special culture media, immunofluorescent studies and PCR testing for microbial DNA.



Protozoa


Amoebae are very common throughout the world. It is estimated that they are present in one third of the world’s people.
People are vulnerable to pathogenic amoebae, especially in places that lack high quality water reticulation or sewerage.
Dr Peter Snow in New Zealand feels that amoebae (principally Giardia Lamblia) may be important in some cases of C.F.S.
He favours an acute amoebicidal agent (e.g. tinidazole 2 Gm) followed by some 3 weeks of daily metronidazole 400 mgm bd (or similar) to eradicate encysted forms of the protozoa.

These agents have activity against gut anaerobes such as bacteroides.

Herbalists use Artemisia (wormwood) and one drop of pure oil of cloves to kill intestinal parasites. (Both are given orally.)
Artemisinin has been used in Malaria.

We need more research on the prevalence of pathogenic amoebae in the human intestine, particularly in countries like Australia.



GLYCONUTRIENTS


It may be useful to take glyconutrients in the form of vegetables, fruits and salads on a daily basis and in some particular cases to use powdered concentrates of these substances. Helpful glyconutrients include those found in aloe vera, garlic, and onion, yams and sweet potato, turnip, parsnip and carrot, cabbage, cauliflower, broccoli and brussel sprouts, tomato, berries, pineapple, paw paw and rice bran.

From a strictly scientific viewpoint, more evidence is needed on this subject, but these plants are good choices anyway.



NUTRITIONAL REPAIR
(top)

Although this summary will include recommendations by others who support these empirical nutrient trials, there is an urgent need for data collection to throw light on any of these claims.

It is well established that many people eat inadequate diets.

If a CFS sufferer comes to believe that food makes her or him ill, there is a serious danger that she or he may end up with mal or subnutrition.
A recent report suggests that some of the people reporting chemical sensitivity are possessed with acute sense of smell and taste.

They appear to have particular smells and tastes, which they dislike and the aversive reaction (via the limbic system.) can be strong.

This area of human thinking connects strongly with control issues, which in turn are strongly connected with fear and experiences of guilt and anger.

The medical professions find it extremely difficult to find ways to help the problem of the person who believes she or he has major food and chemical sensitivities.


MITOCHONDRIAL PROTECTION
(top)

My thinking has paralleled writings from Dr Martin Pall, Paul Cheney, Dr Stephen Sinatra and especially an innovative general practitioner in Wales, Dr Sarah Myhill,
www.drmyhill.co.uk

She is using

Acetyl-l carnitine 500mg 3 times per day,
Vitamin B3 100mg 3-4 x per day,
Co-enzyme Q10 200-300mg per day,(with piperine in black pepper to increase absorption.)
R-alpha lipoic acid 100mg 3-4 times per day,
D-ribose 3-5Gm /day to increase energy availability

The D-ribose is helpful to an alternative energy pathway(hexose monophosphate shunt), as well as being a component of ATP and RNA. It helps muscles including the heart muscle, generate ATP. It is very safe. After oral dosing, there is good availability, and both fibromyalgia improvement and better endurance have been noted.

It is helpful in almost all heart diseases.


FATTY ACID CHOICES

Fatty acids are carboxylic acids.
Human fatty acids are long chain fatty acids.
The overall intention is to minimize the production of inflammatory prostaglandins, which are metabolites of arachidonic acid.

Inflammatory prostaglandins are of the 2 series and inflammatory leukotrienes belong to the 4 series.
An optimum ratio of omega 3 fatty acids, omega 6 fatty acids and omega 9 fatty acids is still being debated.

A diet that is very high in sunflower or safflower oil is very high in the omega 6 fatty acid, linoleic acid.
While linoleic acid is essential, excessive amounts can increase the generation of arachidonic acid metabolites. For this reason some reduction of these oils is important in inflammatory states.

There is evidence that increased secretion of insulin induced by foods with a high glycaemic index, enhances linoleic acid conversion into arachidonic acid. This suggests an advantage in avoiding more than small amounts of such foods.

Cooking in olive oil which contains 80% omega- 9 mono unsaturated fatty acid (oleic acid) will not produce proinflammatory metabolites. It too should not be overheated!

Pure canola oil also has quite a good ratio of omega9, 6 and 3 fatty acids (Also Australian canola oil has less than 1% trans fatty acids). Flaxseed oil has 50-60% alpha linolenic acid (an omega 3 fatty acid) and can be used to supplement olive though it should not be heated at all.

Fish oils (omega 3 fatty acids) are likely to be helpful.
Fish obtain fatty acids from algae and distribution happens up the food chain.

Eicosapentaenoic acid (C20) and docosahexanoic acid (C22) have anti-inflammatory and cell membrane protective properties.

Recent research continues to show brain protection, and even mild antidepressant effects.

Recently Dr Bob Gibson in Adelaide has shown that supplements of flaxseed oil had little effect on EPA and DHA levels.
This does not mean it has risks.
He suggests that the elongases and desaturases are competed for by polyunsaturated fatty acids, leaving the conversion rate low.

If this is the case, I favour giving both flaxseed and fish oils.
If one gave only the EPA and DHA, one should consider giving the fatty acid transporter acetyl-l- carnitine as well. (See below)
(top)
It is pertinent to note that labeling of edible oil products in Australia is inadequate. In Australia, only 2 manufacturers make all margarines.

The consumer needs to know that trans fatty acids are at very low levels (<1%), and that omega 3,6, and 9 unsaturated fatty acids are balanced.

It should state on the product container that the trans level is 0.03 G (or less)/5g serve of the product.

A good rule is to avoid all cheap or inadequately labeled margarines.

It is unacceptable for manufacturers to continue to leave the high trans fatty acid products on the market!
Peanut pastes are now usually labeled in Australia.
I believe we should continue to protest to the Government until other food labeling is adequate!

In Australia, Flora Canola spread, Golden canola, Flora Monosun spread and Meadow Lea Canola spread appear to be safe. (There are others)

Oxidized fatty acids, and trans fats appear to increase the risk of macular degeneration in the eyes.

All polyunsaturate increases in diet need the use of anti-oxidants. (See below)

Butter usually contains about 2% trans fatty acids, but the trans palmito-oleic acid in milk fat does not confer any risks.

I regard butter as safe as long as the cows are pasture fed.

We need governments to enforce adequate food labeling about trans fatty acids.

If inflammation is mediated through leukotrienes of the 4 series (principally LTB4) there is a case for using fatty acids from sea creatures such as the sea cucumber and the New Zealand green lipped mussel.

The preparation called Lyprinol (Lyprinex) is a purified mixture of eicosatetraenoic acids analogous to arachidonic acid and inhibits both 5 and 12 lipoxygenases radically reducing proinflammatory leukotrienes. The dose is 5 mgm per kg of body weight per day.

While in vitro activity has been demonstrated by Dr Henry Betts at The Queen Elizabeth Hospital in Woodville, South Australia, there is a need for proof of activity in human inflammatory states.
Lyprinol might be indicated when neutrophils are implicated in the ongoing pathology, as LTB4 is a potent chemotactic agent for neutrophils.

In these inflammatory states it may also emerge that there is a role for the use of cetyl myristoleate, which is an esterified form of a monounsaturated fatty acid known as myristoleic acid.
This substance exists naturally in small quantities in some animals, (for example mice with natural levels of CMO were resistant to polyarthritis induced with Freund’s adjuvant.)

Subsequently this has been found to apparently turn off inflammation in a range of human inflammatory conditions such as rheumatoid arthritis. The dose is 2.5 grams twice a day for a month.

This is also work that needs validation from other researchers.

It is disappointing that there is so little literature on this.

Its effect seems to be enhanced by adding digestive enzymes containing lipases and by concomitant use of glucosamine and perhaps Lyprinol.
In summary it appears that there is an optimum ratio of omega 3, omega 6 and omega 9 fatty acids, and we will integrate these with antioxidants such as mixed tocopherols, tocotrienols and coenzyme Q10 which decrease lipid peroxide levels.
Other plant antioxidants such as quercetin also protect against lipid peroxidation.
The full improvement of each person’s diet is the subject of my ongoing commitment to people finding health promoting and protective diets.


GUT (and OTHER CELLS) (top)
Kenny De Meir Leir emphasizes the abnormalities in the gut in many forms of CFS.
Restoration of normal gut flora and optimal health of epithelial and other gut cells might be enhanced by the following methods:

(1) Adequate protein intake and this might well include supplements of specific amino acids such as those reported as low by the Newcastle group (eg serine). Their belief is that protein digestion is incomplete, thus many sufferers are requiring amino acids in the diet.

Specific amino acid supplements ((glutamine, taurine, serine, glycine, glutathione, alpha keto glutarate and carnitine are suggested) and the antioxidant,R alpha lipoic acid could well be important.
This is particularly for intestinal cells but as well to be certain that all other body cells get adequate essential amino acids as well as to overcome putative metabolic blocks.
It seems that there is no evidence that oral glutathione is effective in boosting cellular levels of glutathione.
There is some evidence (as mentioned earlier) that whey proteins from milk may be good way to increase amino acids and increase glutathione production inside cells.

I have not seen success with amino acid supplements, and am presently following Cheney in recommending whey protein devoid of casein and lactose.

(2) Vegan diets are deficient in Vitamin B12, carnitine and taurine.

There is some evidence of carnitine deficiency in CFS.
On days when meat is not consumed, take 2 grams of acetyl-L-carnitine. Vegetarians should supplement their diet with acetyl L-carnitine (best absorbed form) by taking 2 grams daily. (See Website of Dr Sarah Myhill <www.DrMyhill .com>

(3) Eating evenly.

(4) Avoid excessive intake of foods with high glycaemic index (avoiding functional hyperinsulinaemia).

(5) Consider using D-ribose. In order to make new ATP, one needs a sugar, namely D-ribose. Normally the body can manufacture this for itself from glucose, but if energy levels are very low, then it may be unable to synthesize enough of this essential sugar. So when the CFS sufferers push themselves too much, ADP is converted into AMP, which they cannot recycle. It normally takes a few days to make new ATP from D-ribose, but the CFS sufferers may really struggle to make D-ribose.

(6) Avoiding foods which might cause gut “sensitization”, or other injury, (e.g. dairy products, gluten). (Also excluding gluten enteropathy.)

This aspect needs elaboration in light of the possible role of lectins in grain husks promoting some disease states.
At least 3 weeks of exclusion and perhaps more should be considered in refractory CFS.

(7) Adequate folate, B12, B5 and B6 and vitamin A,C and D.

(8) The recent evidence of people avoiding sunlight has led to studies on levels of vitamin D in various populations. This has uncovered many people with low levels.

A recent Australian study (Geelong, Victoria) revealed that about half of psychiatric patients had low levels of vitamin D3
Low vitamin D in childhood gives rise to rickets, and in adulthood to osteomalacia. I check to see that PTH has not risen.
Immune cells need 1,25 D3I am keeping an open mind about this subject.
Now there is further evidence of vitamin D helping immune function.
In multiple sclerosis, rheumatoid arthritis and Sjogren’s syndrome, low vitamin D levels increase the risk of these diseases.

(9) The Newcastle researchers favour pancreatic enzyme supplements to increase the adequacy of digestive processes.

(10) Fish and flaxseed oil also appear to be protective to the gut.

(11) Vitamin C in small repeated doses during each day. I make the comment that whenever we cook foods and destroy vitamin C, it makes sense to take vitamin C to replace that loss.
I always favour taking it with the plants we eat.

(12) In true vitamin D deficiency, cholecholecalciferol (vitamin D3) can be added as 4,000 IU/day until levels are 80-100 nmol/L (Daylight skin exposure is also needed.)


Mineral support
(top)

Magnesium in a highly bioavailable form up to 300 -500 mgm elemental Mg/day can correct any chronic magnesium deficiency, and perhaps act as a functional calcium channel blocker. Magnesium may enhance sleep, decrease irritability, and diminish central nervous system NMDA activation.
Serum magnesium levels are not a good guide to cellular magnesium levels and red cell magnesium is a better measure.

Potassium supplementation (or use of spironolactone or amiloride) could increase total body potassium and this is being studied further by Dr R Burnet, as it appears to only apply to the low potassium group.
I prefer the potassium supplements if I can establish potassium deficiency.
(The potassium and above drugs should not be used with ACE inhibitors or angiotensin 2 receptor blockers.)

It is important for people to be replete in chromium, manganese, molybdenum, selenium and zinc, so that metallo-enzymes using these elements can function optimally.
Molybdenum is only added if hair analysis shows low levels. It is usually adequate in leafy vegetables and legumes.

Suggested daily allowances would be


Zinc (elemental) 15 mg
Manganese (“) 2.5 mg
Molybdenum (“) 50-100mcg
Chromium (“) 200 -600mcg
Selenium (“) 200 mcg


Further research is needed to appraise cations in people who have a high urinary citric acid level.
The subject of mineral ratios is another area that is being explored in human and veterinary medicine.

We probably need to rethink the subject of the correct balance of minerals if further research supports Mark Purdey’s evidence that high manganese and low copper in environments, and in animal and human brains increases the emergence of abnormal prions as in Creutzfeld-Jacob disease and bovine spongiform encephalopathy.

Aside from the ignorance and arrogance, which led to people feeding herbivores with products from animals, and transferring prions in this way, we can have more vigilance about the interplay of causative factors

Possibly exposure to organo-phosphorus pesticides is another risk factor.
I mention this in order to remind ourselves of the need to evaluate care of the environments in which we live.
Persons from rural locations and users of these chemicals are the main ones at risk!
Mineral contamination of human food may include excessive mercury, aluminium, copper, lead, nickel and cadmium.
(Dr Igor Tabrizian from Western Australia writes about this)
High mercury can come from fish high up in the food chain.
Some of the metals can be used by gut flora, but with permeable gut disorders may harm human health.

  • Kenny de Meirleir has a special interest in this area.
    Some protective chelation can be given through coriander, chlorella and free-range organic eggs.
    It is also important to get all minerals in balance, as described by Dr Igor Tabrizian.



    ANTIOXIDANTS (top)

    Drs Ian Brighthope, Robert Buist, Paul Cheney, Henry Osiecki, Sarah Myhill, Jeffrey Bland and Martin Pall are all in favour of multiple anti oxidants to cover a wider range of sites and oxidant situations.

    Oxidation involves electron donation, and antioxidants are electron donors.
    It follows logically that when antioxidants mop up free radicals, they are themselves oxidized.
    The net outcome of this depends on how much the products can still cause cell membrane or other cellular injury.

    Some evidence is emerging that single antioxidants such as vitamin C or E are not particularly protective and may even become pro-oxidant.
    For example, pure D alpha tocopherol can mop up a free radical and become a free radical itself.
    e.g. EH + R’ -> R’H + E’ E’ is a free radical

    Co enzyme Q10 has been shown to quench the vitamin E free radical and is also better at reducing oxidized LDL cholesterol, than is vitamin E.
    A number of trials with pure D-alpha(RRR-alpha) tocopherol have failed to produce evidence of protection against cardiovascular disease. It is known that gamma tocopherol can mop up the E free radical.

    The Heart Protection Study (HPS) is a recent example of 8 years of D-alpha tocopherol 500IU, vitamin C 500 mg and beta-carotene in combination failing to alter outcomes in people with heart disease.

    We need trials of mixed tocopherols (alpha,beta,gamma and delta,) and tocotrienols (alpha,beta,gamma and delta), particularly because nature tends to have these antioxidants together.

    The richest sources of these substances are edible vegetable oils.

    D alpha tocopherol is high in wheat germ oil,
    gamma tocopherol is high in soybean and corn oil.

    Palm oil is high in alpha and gamma tocopherols and alpha and gamma tocotrienols.

    Thus antioxidant therapy would include:

    1. D alpha tocopherol succinate 500IU orally daily (needs another substance to deal with the generated vitamin E free radicals. (e.g mixed tocopherols, gamma tocopherol, tocotrienols, vitamin C, R-alpha lipoic acid, and coenzyme Q10 could each carry out this function.) (See below)

    2. Co enzyme Q10 100-300 mgm daily (paper in coenzymeQ10 conference, Boston1998) (enhances mitochondrial energetics and mitochondrial DNA repair, and mops up oxidized vitamin E)

    3. Plant flavonoids from many coloured vegetables, salads and fruits (especially beneficial)
    eg.

    anthocyanosides (bilberry)
    astaxanthin (salmon)
    mixed carotenes (carrots, yellow and orange vegetables),
    lutein and zeaxanthin(egg yolks, spinach),
    lycopenes (tomatoes),
    proanthocyanidins (grape seed and pine bark)
    quercetin ( apples, brussel sprouts, ginkgo biloba, onions, pears)
    resveratrol (grapes and peanuts)

    A minimum of seven different vegetables per day is recommended (pesticide free) specifically ensuring many different anti oxidants.(more is better)

    Specific herbal agents are now being tested for anti-inflammatory actions and I note that

    (1) Humulones from hops, and curcumin from turmeric are PPAR agonists

    (2) Nettle stops activation of NF kappa beta by TNF alpha and peroxynitrite.

(3) Boswellic acids from frankincense (boswellia) are potent elastase inhibitors.

(4) Curcumin (from turmeric) is a good elastase inhibitor, but it also needs piperine from black pepper to improve absorption and to prolong its half life)

(The drug Kenny De Meir Leir uses is cefoperazone)
This is the herb that Kenny De Meir Leir uses in cases with abnormal RNAse-L.

Now evidence is emerging that curcuminoids are neuroprotective.
They may also have useful anti-inflammatory actions.

In time, ginger, turmeric, cinnamon and other spices will be further explored for anti-inflammatory actions.
Feverfew has anti-migraine and anti-inflammatory actions and may also be protective to bone.


4. Vitamin C in doses of up to 500 mgm 5-6 times per day.
I rate this as extremely important.

Human beings lack an enzyme needed to synthesize vitamin C.

In other animals that cannot make vitamin C (primates, fruit eating bats, and guinea pigs), there is a turnover equivalent to many grams/day (as much as 10-20 gm/day in a creature weighing 60-70 kg).

It is largely because we cook our food that human beings eat so much less.
Since nature provides antioxidants in combination rather than in isolation, there is a pattern for maximum mopping up of free radicals with less residual damaging products.

Thus I eat a plant with colour with each dose of vitamin C
It is worth considering infusions of vitamin C in people who do not eat well or have gut abnormalities.
The Australian College of Nutritional and Environmental Medicine teach practitioners of the value of IV vitamin C, particularly in any one getting an acute infection and as an adjunct to cases not responding to appropriate antibiotic regimes.


5. R-Alpha lipoic acid 200 mgm twice a day can be used to quench peroxynitrite anions (ONOO-) and gamma tocopherol 300 mgm a day does the same thing.

R Alpha lipoic acid (ALA) converts into dihydrolipoic acid (DHLA) but both are capable of quenching free radicals covering antioxidant effects in both water and fat soluble domains.
DHLA thus neutralises reactive oxygen species such as super oxide radicals, peroxyl and singlet oxygen and is a co factor in acyl transfer reactions regenerating reduced glutathione and ascorbic acid and maybe indirectly helping the recycling of vitamin E.
As lipoamide, ALA/DHLA function as a co factor in oxidative decarboxylation reactions of pyruvate, alpha keto glutarate and branched change keto acids. Both also have metal chelating activity.

It is emerging as one of the best neuro-protectors currently available.
It appears to protect in all neuropathies and neurodegenerative diseases.


6. Gamma tocopherol has more immediate activity than d alpha tocopherol in dealing with already present free radicals and in any event probably needs to be present at above 20% of total tocopherols to lessen damage to the D alpha tocopherol.


7. Hydrogen atoms with an extra electron loosely attached (negative hydrogen ions) are present in glacial water in mountains in the north of Pakistan (Hunzaland) and it is claimed by Dr Patrick Flanagan that this results in water with low surface tension, and effective electron donation with potent antioxidant effects.
Flanagan microclusters are tiny mineral clusters which act as transport vehicles delivering nutrients into cells.

They have a very high negative electrical charge and Flanagan claims that they enhance removal of metabolic products from cells.
They are marketed as MICROHYDRIN.
Electron loss is part of all oxidations and electron donation is part of all antioxidant effect.

Flanagan says that plants produce negative hydrogen in fresh ripened fruit , but the negative hydrogen is lost in cooking or canning.
I cannot find independent validation of Flanagan’s claims.

Claims about colloidal minerals are also worth scientific exploration.
I cannot find a sound basis for these substances, but suspect that they have not been adequately tested.



OTHER SPECIAL ASPECTS
ADDRESSING THE ORGANIC ACID CHANGES
(top)

It may be worth giving supplements of glutathione (e.g. in undenatured whey protein), or glycine, serine, glutamine and cysteine. Dr Paul Cheney favours using oxygen in some of these situations.
Dr Robert Buist claims his ”Isowhey” preparation is ideal for this purpose!

Perhaps extra vitamin B12 increases succinyl CoA levels enhancing succinic acid levels.It is certainly worth bringing B12 levels up to the high end of the therapeutic range.

As stated in chapter 13, injections of hydroxycobalamin 1mg, or oral methyl cobalamin are important.
Methyl cobalamin may allow increased delivery across the blood–brain barrier(BBB).

Some clinicians have recommended extra alpha keto glutaric acid.


LOW BLOOD PRESSURE, POSTURAL HYPOTENSION AND DIZZINESS. (top)

Increased intake of salt and fluids are recommended.

Drs Richard Burnet and Peter Rowe (Johns Hopkins) did add fludrocortisone perhaps with potassium supplements if the above failed, and postural hypotension is confirmed. Electrolytes should be monitored if fludrocortisone or liquorice is used.

In a recent article in the Journal of the American Medical Association, the John Hopkins group found that a trial of fludrocortisone was not superior to placebo in this type of CFS.
In the laboratory situation most of these postural changes do not seem to be of significance, and my emphasis is simply that of maintaining adequate blood volume.

I do not support the use of fludrocortisone. I do not use fludrocortisone!



DHEA

It is possible that a sub group of CFS sufferers are low in blood levels of dehydroepiandrosterone (DHEAS). This may relate to low cholesterol levels.
In chronic disease, DHEAS levels may be low, and levels decrease with aging.
By contrast adding DHEA can reduce inflammatory cytokines such as TNF?. (This latter occurs at supraphysiological levels.

Studies continue on its role in immune regulation.
There is some use of this by some doctors, but in general endocrinologists do not support its use in CFS. There are anecdotal examples of improvements in some cases.

I now support its use if blood levels are low.


ELECTROMAGNETIC FIELDS
(top)

There is a Swedish interest group concerned with the increasing use of equipment and lines that generate electromagnetic fields.
It is now clear that by measurement there are many potential areas of human exposure to these significant fields.
It is estimated that 10% of workers are presently exposed to such fields with significant adverse effects in health.
Computers, copying machines, printers, mobile telephones, electric motors, electric blankets, fluorescent lighting and coils of cable all generate electric and magnetic fields.

It seems likely that some people are much more sensitive to these effects and in particular sufferers of chronic fatigue give many accounts of such sensitivities.

One sub group may be getting adverse effects from chemicals sprayed on new electronic circuits for flame resistant protection.
The medical profession at large has not accepted hypersensitivity to these fields as proven, but Don Maisch in Tasmania has visited homes of people with severe chronic fatigue and established that fields from two to ten milligauss are able to produce symptoms. When a person was removed, for example, from sleeping on an electric blanket or their bed was moved so that the pillow was no longer next to the refrigerator motor on the other side of the wall, the patient became normal in four to six weeks.

We are in a strong position to say that people with chronic fatigue syndrome should do their utmost to avoid significant EMF fields and if in doubt they may need to contact experts in the field to test particular locations.



MIND OR BRAIN FOG (top)

Sarah Myhill’s supplements can also help this foggy thinking, and there is now a great deal of evidence that these are neuroprotective.

If specific eradication of pathogens is achieved there is often a return of normal clear thinking.
Treating Rickettsiae adequately seems to clear this mind fog.

Dr Ian Brighthope points out that in chronic fatigue in at least one major subcategory particularly where there are CNS type disabilities ordinary B12, in the form of cyanocobalamin or hydroxy cobalamin do not cross the blood brain barrier. For this reason he believes it is necessary to use methyl cobalamin 1 mgm by injection daily for about a week and thereafter weekly.

Normally there should be no difficulty in converting hydroxy cobalamin into methyl cobalamin or S-adenosyl cobalamin, and this too needs some scientific validation.

Methyl cobalamin is unstable in solution, and needs to be shipped from the manufacturer in a frozen form and thawed overnight in the refrigerator for injection the next morning. Dr Brighthope suggests that this can greatly improve mind or brain fog. It is stable in powder form.

I have tried a product called Methylguard, which contains methyl cobalamin400mcg, folinic acid 400mcg, pyridoxal -5-phosphate 6.8mg and trimethylglycine, 600mg. This would enhance methylation and hopefully enhance brain function in this group of people. It would also increase formation of S –adenosyl methionine.
Methyl cobalamin is also available as oral 1mg lozenges.
S-adenosyl methionine is claimed to be a natural antidepressant and may have a place in treating depression or brain fog in CFS.

It is crucial that people get adequate folic acid which should be redefined to at least 400 mcg per day (E coli in the gut may contribute a substantial amount of folic acid in the normal person).
More (up to 1mg) is needed in people who have elevated levels of homocysteine. This subgroup has now been characterized. (Modern Nutrition Textbook)


ADULT HYPERHOMOCYSTEINAEMIA
(top)

About 15-20% of Caucasians have a point mutation(double T configuration) in the gene which is responsible for the enzyme 5,10 methylene tetrahydrofolate reductase that converts homocysteine into methionine by adding a methyl group. These individuals have about 50% of the enzyme activity of the normal population.

If we add the heterozygotes at C677T and A1298C, up to 35% of person have raised fasting homocysteine levels)
It is suggested that folate is given in increasing doses until the homocysteine drops well into the normal range. I suggest a target of 7-8 micromols/L.
Trimethylglycine can be added if this is not successful.

If the levels do not drop, there may be a deficiency in dihydrofolate reductase so that they cannot turn folate into dihydrofolate and tetrahydrofolate.This can be overcome with either folinic acid or methylene tetra hydrofolate.

High homocysteine is also associated with more rapid shortening of telomeres as we age. It is also associated with increased risks of vascular disease ,and if persons are developing Alzheimer’s disease, correcting the raised homocysteine by the above steps is protective.(Dr David Smith, Oxford)

Dr Brighthope is a strong supporter of high amounts of vitamin C spread out over the day (equivalent 2-10 Gms) and niacin (mixture of nicotinic acid and nicotinamide) to a total of at least 500 mgm a day (a supraphysiological dose), in this” brain fog” group.

All of this makes sense since NIACIN is also a precursor to the NAD/NADH reactions. NADH can be purchased in the USA, and there are claims that it helps in CFS.

Tim Roberts also mentions amino acids as being helpful in this group, but I have not been impressed with this therapy.



OTHER ACTIONS OF SOME ANTIBIOTICS.
(top)

Tetracyclines inhibit intracellular protein synthesis in organisms, but also inhibit mammalian proteins such as metallo-proteinases including collagenases and elastases.

Every molecule of these antibiotics weakens intracellular, cell wall deficient bacteria.
The MMP9 inhibition may be important in inflammations such as gingivitis, synovitis and arthropathies.

These agents also affect T cells and cytokines.

Azithromycin also inhibits MMP9.

Clarithromycin has been shown to modify T cells and cytokines in many situations. It can inhibit T cytotoxic cells and decrease TNFalpha.


NEW ASPECTS OF INFLAMMATION
(top)

We need to find all persons with insulin resistance and hyperinsulinaemia, and this will include persons with fatty liver and metabolic syndrome (Syndrome X)

For the scientist I elaborate on this research.
Peroxisome proliferator activated receptors (PPAR)
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.

This subfamily consists of three isotypes, alpha (NR1C1), gamma (NR1C3), and beta/delta (NRC1C2) with a differential tissue distribution.

PPAR alpha is expressed primarily in tissues with a high level of fatty acid catabolism such as liver, brown fat, kidney, heart and skeletal muscle.
PPAR beta is ubiquitously expressed.
PPAR gamma has a restricted pattern of expression, mainly in white and brown adipose tissues, whereas other tissues such as skeletal muscle and heart contain limited amounts.
Activation of the subtype PPAR-gamma improves insulin sensitivity.

Furthermore, PPAR alpha and gamma isotypes are expressed in vascular cells including endothelial and smooth muscle cells and macrophages/foam cells.
PPARs are activated by ligands, such as naturally occurring fatty acids, which are activators of all three PPAR isotypes.

In addition to fatty acids, humulones from hops (agonists for alpha and gamma), several synthetic compounds, such as fibrates (alpha), one angiotensin receptor blocker (telmisartan (gamma), and thiazolidinediones (rosiglitazone and pioglitazone), bind and activate PPAR alpha and PPAR gamma.

Rosiglitazone, which acts on the alpha receptors, has some adverse effects on lipids, but pioglitazone, which acts on the gamma receptors, does not adversely affect lipids.
These are not indicated long term and must be avoided in persons with any heart failure. They appear to increase the risk of osteoporosis and fractures.

Telmisartan has about 1/3 the PPAR agonist effect of pioglitazone, and Trevor Marshall says it is an antagonist to the 1,25 D3 receptor.

At present I do not use thiazolidinediones or telmisartan in CFS.

As well, apigenin, chrysin, and kaempferol significantly stimulated PPAR gamma transcriptional activity in a transient reporter assay. In addition, these three flavonoids strongly enhanced the inhibition of inducible cyclo-oxygenase and inducible nitric oxide synthase promoter activities in lipopolysaccharide-activated macrophages which contain the PPAR gamma expression plasmids.

There are also PPAR agonist actions with curcumin.
In order to be transcriptionally active, PPARs need to heterodimerize with the retinoid-X-receptor (RXR).

Upon activation, PPAR-RXR heterodimers bind to DNA specific sequences called peroxisome proliferator-response elements (PPRE) and stimulate transcription of target genes. PPARs play a critical role in lipid and glucose homeostasis, but lately they have been implicated as regulators of inflammatory responses.

A role for PPAR gamma in inflammation has also been reported in monocyte/macrophages, where ligands of this receptor inhibited the activation of macrophages and the production of inflammatory cytokines (TNF alpha, interleukin 6 and 1beta), although part of the anti-inflammatory effects of these ligands seems to be mediated by a mechanism not involving PPARgamma.

All these findings suggest a role of PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases.

Actions of some PPAR agonists will probably play important roles in many inflammatory diseases.

Protection from hepatic fibrosis is another recent hope, as Xu, Fu and Chen demonstrated, for the first time, that curcumin dramatically induced the gene expression of PPAR-gamma and activated PPAR-gamma in activated HSC.

Blocking its trans-activating activity by a PPAR-gamma antagonist markedly abrogated the effects of curcumin on inhibition of cell proliferation.

Orphan nuclear receptors belong to this gene super-family but their target genes and physiological function are still being studied.

The orphans belonging to the PPAR, LXR and FXR family function as lipid and bile-acid sensors while PXR and CAR function as xenobiotic sensors.

Small-molecule modulators of LXR and FXR control key genes involved in cholesterol and lipid metabolism. PXR is a highly promiscuous xenosensor that responds to xenobiotic ligands (antibiotics, statins, glucocorticoids) and induces the Cyp3A gene, thereby playing a role in hepatoprotection and bile acid metabolism.

A related receptor from the gene subfamily, CAR, displays high ligand selectivity and modulation of its activity in humans may significantly alter metabolism of drugs and other xenobiotics.

The role of the ER relatives, the ERRs will become more apparent as ligands are identified and linked to target genes and physiological function. These targets offer multiple opportunities for therapeutic intervention with small-molecule drugs, in diseases related to neuronal function, inflammation, lipid homeostasis, metabolic function and cancer.

Homocysteine (Hcy) induces nuclear factor-B (NF-B) . On the other hand, a negative correlation between high levels of Hcy and peroxisome proliferator-activated receptor (PPAR) expression has been demonstrated
Also, PPAR agonists inhibit the metalloproteinase activation in macrophages.



CAUTION


Thiazolidinediones (pioglitazone and rosiglitazone should not be used in patients with heart failure, and seem to increase the risk of fractures. Both have measurable effects in decreasing bone strength.
At this time I am avoiding their use!

I note that Dr Ritchie Shoemaker had a phase of recommending them, but in my view, this can no longer be supported.

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

I have restated this to illustrate that there are complex aspects of the use of specific substances in therapy.
With the discovery of significant under perfused medial temporal regions of the brain by Casse and colleagues, vasodilators are being considered to improve this blood flow.
Several vasodilators are being tried, and my emphasis is in finding safety and efficacy in these medications.

Angiotensin inhibitors could vasodilate the brain areas shown on the SPECT scans (R Casse, R Kwiatek et al), but telmisartan is also a PPAR agonist and down regulates inflammatory cytokines!

.
Olmesartan has been used by clinicians working with Dr Trevor Marshall in both sarcoidosis and CFS, with claims of success.


THE MARSHALL PROTOCOL (top)

I have decided to comment upon this much-publicized material, noting that this material needs to be repeatedly re-evaluated.
The material here comes from Trevor Marshall PhD from California
.http://www.marshallprotocol.com with my own added comments, as I was in a meeting for the visit of Trevor Marshall to Adelaide in Dec -06.

I am indebted to Marshall for opening up my thinking around ligands and receptors. 

Marshall makes quite strong claims about persistent diseases that seem to be related to microbial infections either directly, indirectly or as post-infective and immune response (probably mostly mediated through macrophage and lymphocyte responses including genetically related cytokinevariations.

The Marshall Protocol springs out of someone thinking about biology, with certain observations and certain ability to explore patterns, here informed by advanced X-ray crystallography and computer images of receptors
and their ligands.

The basic property of atoms allows certain arrangements, and the coming together of hydrogen in stars allows the emergence of more and more complex elements. (This is the subject of some of my other reflections)
When life appears in this corner of the cosmos, it has critical properties and this includes abilities to coexist with,connect to, and in various ways to interplay.

We call these processes “evolution”. In fact there are many “co-evolutions.”

 
Bacteria exhibit the flexibility to survive and replicate in various places and various phenomena such as plasmid transfer, viral trans-fection and curious microtubular structures connecting some cells, mean that DNA and RNA are being continuously traded between life forms. Intracellular bacteria, lacking one kind of cell wall, have learned to live inside animal and plant cells, deriving their energy from those cells.They also incite immune cell activations and chemical release, both inside and outside the cell.

We are often using inadequate methods to discover the presence of bacteria!

In any event antibodies alone are not able to deal with intracellular cell events as they do not cross into cell interiors nor reach cell wall deficient bacteria, living inside cells.
Serology alone is also inadequate in determining and dealing with pathogens that incite specific TH1 activations.
The MP is part of the unraveling of these processes and patterns.

Marshall writes
 “Yet vitamin D is actually a secosteroid transcriptional activator, at the heart of innate immunity. Vitamin D is immunomodulatory, and molecular biologists are working as fast as they can to more fully elucidate all of its actions, and those of its nuclear receptor, the VDR, upon the human body, and upon human disease.
The knowledge that vitamin D activates the VDR to transcribe (or repress) 913 genes, and the possibility that it might affect expression of as many as 27,091, portends a paradigm shift in the way that clinical medicine has visualized this ‘‘Sunshine Vitamin’’. Historically, it has been associated solely with bone formation and calcaemia, yet physicians are now being told that vitamin D closely regulates genes associated with diseases ranging from cancers to multiple sclerosis."

Challenges

Marshall writes

”Low values of vitamin D in disease are a result of the disease process, and not the cause. Molecular biology has now taught us that the body is capable of making its vitamin D directly from 7-dehydro-cholesterol, and that the generation of the vitamin D metabolites is modulated by inflammatory disease processes.

Not only does the whole concept of vitamin D deficiency need reconsideration, one should question whether it is misleading to even use the word ‘vitamin’ when discussing this secosteroid.
VDR—the vitamin D nuclear receptor and the transcriptional pathways that it controls

The VDR is a type 1 nuclear receptor, a transcription factor that forms homodimers and heterodimers active in the transcription and transrepression of genes.

In their 2003 BioEssay, Lin and White examined the structure of the VDR, endogenous vitamin D synthesis, and its subsequent hydroxylation to active metabolites in the liver and kidney.

Their research group at McGill University has since identified 27,091 genes that might be transcribed or repressed by the VDR.
Several of these genes, and the resulting proteins, are known to be active in cancer. Included are the beta-defensin(2) and cathelicidin, antimicrobial peptides, key to innate immunity and to the body’s response to intracellular pathogens.
D is needed for at least one of the toll like receptors.

It is thus becoming clear that the clinically accepted role of the vitamin D metabolites, that of regulating calcium homeostasis, is just a small subset of the functions actually performed by these
hormones."


The essence of the Marshall Protocol seems to me to be as follows. (top)

(1) Some Chronic diseases are TH1 set.
TH1 cytokines are IL6, TNF alpha and IF gamma.There are genes that code for these cytokines and their receptors.

(2) These cytokines are likely to be driven by intracellular bacteria that avoid phagolysosomal dissolution, and Marshall is exploring mechanisms.

(3) The presence of these bacteria can result in direct activation of IKB kinases and production of NF kappa beta, which translocates to the cells nuclei and switches on the genes for the above cytokines.

(4) The cytokines contribute in a major way to the inflammatory changes in target sites

(5) Sarcoidosis is the initial disease which Marshall and colleagues studied.
Classical RA, Crohn’s disease, some CFS and many FMS states are probably such disorders

(6) Overactivity of immune cells possessing the 1 alpha hydroxylase enzyme, results in increasing local 1,25 D3 production and in some cases raises the serum levels of 1,25 D3.
Marshall pays attention to the 1,25/25D3 ratio, and believes >1.7 is significant.
There is no living cell work or independent research to validate this claim.

(7) Decreasing the level of 1,25 D3 decreases the recruitment of and activation of monocytic stem cells into macrophages. Marshall continues to claim that 25 D3 is partially blocking the VDR .

I quote his writings,

”Molecular biology has now taught us that the body is capable of making its vitamin
D directly from 7-dehydro-cholesterol and that the generation of the vitamin D metabolites is modulated by inflammatory disease processes.

Not only does the whole concept of vitamin D deficiency need reconsideration, one should question whether it is misleading to even use the word ‘vitamin’ when discussing this secosteroid.
VDR—the vitamin D nuclear receptor and the transcriptional pathways that it controls

The VDR is a type 1 nuclear receptor, a transcription factor that forms homodimers and heterodimers active in the transcription and transrepression of genes. In their 2003 BioEssay, Lin and White examined the structure of the VDR, endogenous vitamin D synthesis, and its subsequent hydroxylation to active metabolites in the liver and kidney.

Their research group at McGill University has since identified 27,091
genes that might be transcribed or repressed by the VDR.
Several of these genes, and the resulting proteins, are known to be active in cancer. Included are the beta-defensin and cathelicidin antimicrobial peptides, key to innate immunity and to the body’s response to intracellular pathogens.

It is thus becoming clear that the clinically accepted role of the vitamin D metabolites, that of regulating calcium homeostasis, is just a small subset of the functions actually perfor med by these hormones.
Most biologists understand that the murine model frequently fails to accurately model human immune disease and human cancers. Much of this is due to evolutionary divergence between the murine and human VDR. Wang et al. found many differences between the genes targeted by the murine and human VDR.

For example, the gene encoding cathelicidin antimicrobial peptide is not expressed by the murine VDR at all.

Further, we have described how the relatively low structural homology between the murine and human VDR can help to explain murine modeling inaccuracy.
Unraveling the intricacies of the human D metabolism is often made extremely difficult by the inter mingling of murine and human biologies in the literature.”

This is why he recommends stringent methods to avoid daylight with its UV B frequencies that convert 7 dehydrocholesterol into Vitamin D3, and why he recommends reduction of dietary vitamin D3.

I do not like vitamin D3 levels to be low but try to get 1,25 D3 to normal levels.

(8) The angiotensin receptor blocker olmesartan has a high affinity for vascular A2 receptors, but also has affinity for the chemokine receptors CCR2b on monocytes.

The best-known ligand for CCR2b is monocyte chemotactic protein 1 (MCP1).Olmesartan locates on this receptor and evidence suggests that it blocks the monocyte activation, and the IKB kinase activation.(9) Marshall and colleagues have demonstrated a rapid fall in 1,25 D3 levels within 2 weeks of starting patients on olmesartan.

Interestingly olmesartan also locates on intranuclear 1,25 D3 receptors, with agonist effects.
These researchers report clinical improvement in brain fog and energy, with olmesartan use. They stress that the required dose of olmesartan is 40mg 3-4 times per day, spaced evenly. This dose may be important to adequately inhibit the CCR2b activations.

The dose can be started at a lower level to ensure patient tolerance of this dose.
Baseline and follow up renal function, initial and serial sitting and standing BP and maintenance of adequate blood volume are part of a safe plan.

Doctors who are accustomed to thinking of olmesartan and other sartans (A2R blockers) as anti-hypertensive agents can find it difficult to understand these new aspects of olmesartan use.(10) Specific antibiotics are used because they penetrate into infected cells and enter the bacterial ribosomes blocking peptide assembly of proteins.

Minocycline enters the 30 ribosomal location, and is started at a low dose to avoid Herxheimer reactions (see Marshall protocol website).
50 mg on alternate days or even lower.
If tolerated, the dose can be increased to the usual antimicrobial doses.

Azithromyin, an azolide enters the 50 S site, and has a very long persistence in cells.

It can be started at 250mg every 3 days and increased if tolerated.
Marshall holds the view that the long duration of the illness and the persistence of bacteria, means the therapy will usually be very long (12-24 months.)

 

Cautions (top)

Trevor Marshall has training in computer technology and has access to sophisticated computer programs, which are able to represent biological molecules in 2D and 3D images. It is too early to confirm the exact relevance to inflammatory states and human TH1 diseases.

As there is elegant data on precise structures of receptors, specific proteins in bacteria and the ligands which bind to them, he is able to look at molecular affinities right down to positions of atoms on the ligand which locate close enough to specific atoms on the receptor to enable interactions to occur. (Van der Waals forces)

At this computer image level, he can work out Ki values suggesting affinities of both natural ligands such as 1,25 D3 or drugs such as olmesartan to cell membrane receptors that are G coupled protein receptors and intranuclear receptors such as Vitamin D receptors. PPAR receptors, steroid receptors and thyroid receptors.
 
There is serendipity about discovery of some drug actions.
Any number of 1 or less indicates high affinity for the agent for the receptor

ligand

A2R
CCR2b
VDR
PPARg
PPARa
GCR
MCR
Talpha
T beta
ProgR
olmesartan
0.1
9
10
12
3
1
4
28
2
0.3
irbesartan
0.17
9
10
6
0.9
0.8
47
6
0.5
4
telmisartan
0.1
25
0.04
0.3
0.7
no
no
no
no
no
candesartan
1.5
39
30
61
3
6
16
0.4
0.7
7
losartan
0.5
25
74
3
4
4
2
2
0.5
0.6
valsartan
0.3
22
14
12
26
10
2
6
1
4
                     
pravastatin
0.2
38
62
21
2
8
6
80
0.3
simvastatin
0.4
23
4
0.3
4
2
2
5
0.3
0.4
atorvastatin
2
61
no
4
2
1
no
no
no
no
lovastatin
1
16
10
0.2
19
15
2
2
0.3
0.5
rosuvastatin
0.9
no
no
24
18
7
3
no
0.6
 
25D3
0.3
3
0.7
0.04
1
0.02
0.02
0.5
1,25 D3
0.03
0.5
0.5
0.04
1
0.006
0.002
0.1
cortisol
2
3
0.4
0.5
0.07
16
1
0.2
prednis
3
13
2
3
0.5
31
6
1
DXM
7
2
0.6
0.8
0.3

 

 

It has often emerged that agents have other actions than those first proposed.

For example,
Telmisartan is marketed as an A2R blocker, and has a high affinity for and strong binding to the A2R receptor.

It also has high affinity for the VDR and the PPAR gamma receptor.It would be predicted to be a blocker on the VDR and an agonist on the PPAR gamma receptor.
(This might mean it is not the A2R blocker to use in CFS.)The latter action has been well verified in animal and human studies.

Candesartan has adequate A2R blocker effects but is predicted to have significant blocking effects on both the alpha and beta thyroid receptors.

Irbesartan has high affinity for A2R receptors where it is a blocker, a mild moderate agonist effect on PPAR gamma and a greater affinity for the PPAR alpha receptor. It also has predicted affinity for the glucocorticoid receptor, and should be a significant blocker of the T beta 1 receptor.

Olmesartan has high affinity for and strong binding to A2R receptors as a blocker, and also the chemokine receptor CCR2b on monocytes and monocytic stem cells. It is likely to exhibit strong binding to the progesterone receptor and interestingly docks on protein SAR 0276, which is a membrane protein on MRSA 252 staphylococci.

This should alert us to the possibility that doctors are likely to be getting effects that are not planned.
Marshall thinks olmesartan is very safe, but uses a higher than usual dose.

He thinks its Vitamin D agonist action is significant, but its Ki value is not suggestive of this and I so far cannot find evidence for this.

He says it provides palliation, protects from organ damage by cytokines and is anti-inflammatory.
 
Simvastatin is an inhibitor of HMG CoA reductase, but also has predicted high affinity for A2R, PPAR gamma, progesterone receptor and the thyroid beta receptor.
 
There is a need for laboratory work to check out these computer predictions!

The vitamin D receptors (VDR) are located in gut cells, bone, skin, renal tubule cells, breast, gonadal cells, muscle, heart muscle, parathyroid, brain and immune cells such as monocytes and macrophages.
Aside from the well known action in enabling intestinal cells to absorb calcium

When 1,25 D3 docks on its receptor, the vitamin D receptor (VDR)
activation

(1) Decreases PTH transcription,

(2) Enables intestinal epithelium to absorb calcium

(3) Regulates Toll-like receptors (TLR2 and 4) in macrophages as part of the innate immune response (especially to bacteria),

(4) Transcribes cathelicidin antimicrobial peptide (CAMP)(anti LPS)

(5) Regulates TAGO gene (involved in mycobacterium TB intraphagocytic survival)

(6) As VDR/RXR, binds IL2 promoter,

(7) Promotes transcription of insulin receptors

(8) Is involved with steroid receptors SRC-1 and SRC-3, and GM-CSF.

(9) Is involved in regulating cell differentiation and apoptosis.

Items (2)-(5) suggest that vitamin D is very important in immune responses.

One can say that we see parsimony in biology (one signaling substance acting in many places) and that regulation is more complex than we first understand. Concentrations at receptor sites and affinity are crucial to actions. (e.g. 1,25 with greater potency by a factor of 10 compared with 25 D3, works at picomolar concentrations) Ki for 1,25 D3=0.03, and Ki for 25 D3=0.3

The hydroxyl group at the 1 position is crucial to this potent agonist action of 1,25 dihydroxy D3!
It is one reason why we should not lose familiarity with mathematics, physics, chemistry and basic sciences

Perhaps it is not an exaggeration to say that from mathematics to physics and chemistry through the amazing existence of complex biology and the existence of consciousness we are contemplating who we may be in panoply of dancing patterns, representing specificities of the energies of our Kosmos at every level from origins to evolutions and current measurable elements, patterns,links, connectiveness and even outcomes.

Everything is indeed connected, but some connections are very different from others
To say the least there is the potential for better refining of what we do in ” therapeutics”

There is now independent evidence that angiotensin can be pro-inflammatory in some situations, and that A2R blockade is anti-inflammatory in its own right. (Especially in vessels walls)

Marshall is emphatic in maintaining that olmesartan is best in the TH1 set forms of CFS.

He adds, ”Pretty well all the VDR ligands also are PPAR gamma and alpha ligands too. It is important to view the Type 1 nuclear receptors which are active in the immune system as a unity, as the function with a delicate balance of their primary ligands, and the primary ligands of their partner receptors.
They are VDR PPAR-g PPAR-a GCR MCR Thyroid-alpha1 Thyroid-beta1.”

Olmesartan has an affinity of between 1 and 28 nanomolar across this whole spectrum. Pioglitazone is a ligand for the Thyroid alpha and beta and the PPAR gamma and Alpha, with highest affinity for the Thyroid receptors.”
 
Olmesartan is at least as safe as any other available A2R blocker!!This is cheaper than through international pharmacies.

At this early stage of research, I have used irbesartan instead of olmesartan, and Quercitone or Lymphodran plus as my preferred forms of quercetin, but I encourage doctors to watch closely for more research in this field.

Because telmisartan has been used extensively in hypertension, we have good data on its safety aside from potential effects on bone! We now need to note its high affinity for the VDR.
It binds firmly to the receptor and has a long duration of action.

I repeat that the world’s vitamin D experts have so far not verified Marshall’s claims.

In practice, most CFS sufferers are not worse when we give them vitamin D3.
I never let vitamin25 D3 fall below 60 nmol/L.

Clearly if people have low blood pressure as part of CFS, caution with olmesartan is needed, but so far this is rarely a problem.

How do we choose what to use in particular people as we draw from this enormous range of options?
I try to discover the particular differences that the history and tests reveal and design treatment plans to fit
with these patterns.


SPICES. (top)

So far evidence suggests that we could safely use more spices in therapies and at the same time experience good flavours.

I note that use of cinnamon make foods tasty with less need for other sweeteners, and some hypoglycaemic effect.

Ginger is anti-emetic, anti nausea, properistaltic, and smooth muscle relaxing while enhancing intestinal secretions, and makes platelets less sticky.
Like turmeric it is anti-inflammatory.

Turmeric contains curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin), which are potent antioxidants, inhibit NF Kappa beta activation and are also elastase inhibitors.

They appear to decrease LDL oxidation, protect the liver and give some protection against Alzheimer’s disease.

Hops and stinging nettle have impressive anti-inflammatory effects.

Pepper has good anti-oxidant properties.

I also check carefully to avoid drug-drug, herb-drug, and herb-herb interactions.

SLEEP THERAPIES (top)

Correction of sleep disorders has improved with the advent of sleep clinics.
I try to avoid the use of medications in most sleep disorders.


DEPRESSION

Clearly there is much yet to be worked out about the mechanisms of chronic fatigue but I think the evidence now is in that we should regard it as an organic disease where the degree of the symptoms can provoke secondary depression.

It is important to be very aware of all the varieties of depression, since very effective therapies are available in major depressions and bipolar disorders.
Competent health professionals need to explore this area in depth in order to be clear about each form of depression.

Some people will have both CFS and depression.

Since depression is also common in the community, we can’t exclude that some cases of depression can feel fatigued, but I think the degree of fatigue is seldom this great and it is still a bit unclear as to which case with chronic fatigue can be helped by the various anti depressants. Moclobemide is said to be helpful in some cases.

Many people with CFS seem to get side effects from specific serotonin reuptake inhibitor (SSRI) type medications. All of us sometime find someone who improves markedly on SSRIs, even in some one who did not regard himself or herself depressed.

I personally think these agents are overused.
The careful exploration of what the person means by fatigue is central to this area of clinical work.



STRESS AND PSYCHOLOGICAL ISSUES (top)

In old paradigms people often thought “EITHER/OR”, that is problems were either in the mind or in the body.

It is not possible for us not to be physical beings and we must necessarily feel our symptoms in our bodies.

As a whole person physician I am extremely interested in all levels and dimensions of what it is to be human. If you don’t pay attention to each of these levels you cannot really respond to them all.

In particular all symptoms such as anxiety, depression, anger, frustration and grief have a context.
It is always relevant to be vigilant about depression in these conditions.

When people are distressed this reflects difficulties in the processes of living.
In a real sense what is within a person can be described as “conserved in our manner of living and experience”. This is always to be respected.

When we feel ill, for whatever reason, it is impossible for there to be no psychological component.
Chronic fatigue sufferers are often despairing, frustrated and depressed and in the whole management of a life there are many things that people can do to better cope with their symptoms. Many health professionals may have a part to play in the support of fatigue sufferers and many forms of self help are really worthwhile.

The model is that of co-evolving solutions.
Updating our information in all fields of biology has never been so important.


Genomics and proteomics. (top)

We will see the emergence of much more studies on genes and their products and already have practical examples of how this suggests ways of optimizing food and medication use.
Biology. The occurrence of different forms, stages, or types in individual organisms or in organisms of the same species, independent of sexual variations.

Read more: http://www.answers.com/topic/polymorphism#ixzz1DKnvwBvu


Single nucleotide polymorphisms, or SNPs (pronounced “snips”), are DNA sequence variations that occur when a single nucleotide (A,T,C,or G) in the genome sequence is altered.

For example a SNP might change the DNA sequence AAGGCTAA to ATGGCTAA. For a variation to be considered a SNP, it must occur in at least 1% of the population.

SNPs, which make up about 90% of all human genetic variation, occur every 100 to 300 bases along the 3-billion-base human genome.

Two of every three SNPs involve the replacement of cytosine © with thymine (T). SNPs can occur in coding (gene) and noncoding regions of the genome. Many SNPs have no effect on cell function, but scientists believe others could predispose people to disease or influence their response to a drug.

Although more than 99% of human DNA sequences are the same, variations in DNA sequence can have a major impact on how humans respond to disease; environmental factors such as bacteria, viruses, toxins, and chemicals; and drugs and other therapies. This makes SNPs valuable for biomedical research and for developing pharmaceutical products or medical diagnostics. SNPs are also evolutionarily stable—not changing much from generation to generation—making them easier to follow in population studies.

SNPs occur normally throughout a person’s DNA. They occur once in every 300 nucleotides on average, which means there are roughly 10 million SNPs in the human genome. Most commonly, these variations are found in the DNA between genes. They can act as biological markers, helping scientists locate genes that are associated with disease. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function.

Scientists believe SNP maps will help them identify the multiple genes associated with complex ailments such as cancer, diabetes, vascular disease, and some forms of mental illness. These associations are difficult to establish with conventional gene-hunting methods because a single altered gene may make only a small contribution to the disease.

The information on the MTHFR gene and homocysteine is a very practical example of this kind of polymorphism.


You can ask your health professional to go beyond conventional practices as well as checking for yourself just what research is displayed on internet sites such as Medline. (pubmed)


<www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?CMD=Text&DB=PubMed>


Health professionals now can raise their own awareness about staying up to date, and appreciate how exciting it feels to commit to this lifetime of expanding our personal knowledge.

Can you imagine how much more is possible through integral thinking and practices.

It is my hope that people who have chronic fatigue syndromes will reappraise the journey of life that they and others experience, holding on to a belief in their inner strengths, and being open to the many old and new insights that will be available the more we search.

^