Dear Drs Kaushik, Fear, Richards, McDermott, Nuwaysir, Kellam, Harrison, Wilkinson, Tyrrell, Holgate, Kerr, and Editors at JCP,

I hope this note finds you well. Congratulations to the Physicians and Researchers who completed such admirable work regarding the possible etiology of the CFS (Chronic Fatigue Syndrome), as they made the observations that were "consistent with a complex pathogenesis involving T cell activation and abnormalities of neuronal and mitochondrial function, possibly as a result of virus infection or organophosphate exposures."

While the Chronic Fatigue Syndrome (CFS) is considered to be a multifactoral disease affecting several organ systems, there are many who believe that the mitochondria should provide answers to its etiology.

The results of Dr Kaushik et al, to the effect of,

"The involvement of genes from several disparate pathways suggests a complex pathogenesis involving T cell activation and abnormalities of neuronal and mitochondrial function"

and "These results suggest possible molecular bases for the recognized contributions of organophosphate exposure and virus infection"

remind me of another study of Patients, some with malabsorption syndromes, who seemed to have the most reduced levels of Interferron. If Interferon levels are severely reduced, then perhaps that would explain a smoldering virus which wasn't very aggressive, but persistent.

A malabsorption syndrome would very possibly cause reduced Thiamine, Niacin and other Nutrient levels. I've always thought that one must fill the Nutritional Tank before much should be expected from the usual and corrective Metabolic Pathways.

I was most surprised to recently find what could be described as a mitochondrial specific toxin found almost everywhere, which is synthesized by the Streptomyces griseus strain of bacteria.

Writing in the January 2000, Infection and Immunity, p165, V68, Drs Paananen and Timonen found that "human blood lymphocytes treated with small doses (30 ng/ml ) of pure valinomycin, or high-pressure liquid chromatorgraphy- pure valinomycin from S. griseus quickly show mitochondrial swelling and reduced NK cell activity. Larger doses (>100 ng/ml1) induced NK cell apoptosis within 2 days. Within 2 h, the toxin at 100 ng/ml dramatically inhibited interleukin-15 (IL-15)- and IL-18-induced granulocyte- macrophage" and "Here we report that pure commercial valinomycin and high- pressure liquid chromatography (HPLC)-pure valinomycin from S. griseus inhibit human NK activity and cytokine production and induce apoptosis of NK cells at doses 10 to 500 times lower than those previously used. Thus, a toxin derived from bacteria that are abundant in the environment has the potential to cause immune suppression."

Since S griseus is ubiquitous, found in both soil and household dust, the possibility exists that the toxin, valinomycin, could cause or worsen a CFS by disrupting mitochondrial function. The Respiratory chain inhibitor, valinomycin, is a Thiamine triphosphate inhibitor in the mitochondria.

My impression is that fatigue:depression::dementia:psychosis. Significant deficiencies or blockage of the Thiamine and/or Niacin Metabolic Pathways cause severe fatigue and dementia, which is possibly misdiagnosed as depression and psychosis.

The fact that valinomycin disrupts the mitochondrial Thiamine Pathway is significant.

Overseas, the CFS is known as the systolic hypotensive syndrome, which could be how a different toxin, reserpine, presents itself. During the 1950's, reserpine was added to chicken and turkey feed to improve productivity, and could have then entered the Human Food Chain.

In the Article titled "Thiamine Triphosphate Synthesis In Rat Brain Occurs In Mitochondria, And Is Coupled To The Respiratory Chain," the Authors Dr Gangolf et al, comment on how "In animals, thiamine deficiency causes specific brain lesions, generally attributed to decreased levels of thiamine diphosphate (, an essential cofactor in brain energy metabolism. However, another derivative, thiamine triphosphate , may have a neuronal function" and "ThTP synthesis is severely inhibited by respiratory chain inhibitors such as myxothiazol-" and "ThTP synthesis is impaired by disruption of the mitochondria or depolarization of the inner membrane (by protonophores or valinomycin)-." (Journal of Biological Chemistry, Published on November 11, 2009 as Manuscript M109.054379)

Dr Gangolf et al's Discussion ends with- "Such a mechanism could help to better understand the events involved in the onset of neurodegenerative diseases. It is therefore interesting to note that thiamine deficiency has been shown to exacerbate the pathology of Alzheimer disease and that there are dysfunctions of thiamine metabolism in neurodegenerative diseases."

I would suggest that while competitive inhibition of the Thiamine Pathway could be overcome with higher levels of Thiamine, the valinomycin toxin mechanism which inhibits ThTP synthesis needs further study

Perhaps the mitochondrial genome needs to be studied separately for gene expression, since it is always derived from a maternal source.

Best wishes always. Keep up the Good Work.

Cordially,

Joseph W Arabasz MD

Past Division Chairman, Anesthesiology, Cook County Hospital, Chicago, Illinois

Past Chairman, Respiratory Therapy, Cook County Hospital, Chicago, Illinois

Diplomate ABA

Mensa

Sigma Xi, The Professional Science Research Society

< http://www.SigmaXi.org >

PO Box 6939

Denver, CO 80206

USA 303-316-1740

http://www.topica.com/lists/josepharabasz@topica.com ------------------------------------------------------

Conflict of Interest:

None declared

Dear Editor,

Kaushik et al.[1] have demonstrated significantly different gene expression in a small sample of patients with chronic fatigue syndrome. They suggest these observations are consistent with a complex pathogenesis involving T cell activation and abnormalities of neuronal and mitochondrial function, possibly as a result of virus infection or organophosphate exposures.

We suggest that chronic ricketssial infections would be an equally plausible hypothesis, consistent with Kaushik's observations, and worthy of further study. Like viruses rickettsiae are obligate intracellular parasites. Jadin[2] observed in South Africa that, for 500 patients diagnosed with CFS, ME or depression, 80% tested positive to abnormally high levels of ricketssial antibodies using a multiple microagglutination test for antibodies to R Prowazeki, R Mooseri, R Conori, and Coxiella Burnetti ( itself a neo rickettsia).[3]

In the clinical practice of one of the authors (Kemp) all chronically unwell patients, in whom fatigue and/or fibromyalgia are significant, are routinely tested for rickettsia using IgG serology. Over a recent three year period 67% of 750 such patients returned positive serology to at least one of the four rickettsial groups tested, with a titration level of 1/128 or greater considered positive. This data will be submitted for publication at a later time.

Of the seropositive patients only a very small percentage test positive to rickettsiae via real time PCR testing. Moreover very few can recall any incidents in their medical history which would be consistent with an acute rickettsial infection. Most respond significantly to extended antibiotic treatment, mainly using rotating tetracyclines, as described by Jadin (op cit).

While rickettsiae do produce some energy from independent metabolism[4], and can themselves produce small amounts of protein, the energy required for cell division must come from the host cell's mitachondria and the protein sequences from the host cytoplasm. Krausnik's observations of significant perturbation of mitochondrial gene expression might therefore be consistent with chronic rickettsial parasitic infections.

Unlike most viruses ricketsiae can live for quite extended periods in extracellular fluid. Isolated (i.e. non parasitising) rickettsiae can accumulate lysine and lyse erythrocytes, demonstrating their capacity to operate an electron transport system.[5] Their survival in extracellular fluid might contribute to chronic infection and be consistent with Chronic Fatigue patient histories.

Writing in Nature in 1998 Anderson et al.[6] have demonstrated through phylogenetic analyses that R. prowazekii is genetically very closely related to mitochondria. At the time of writing they observed that no other bacteria was as closely related to mitachondria.

While undoubtedly speculative, it is tempting to think that a parasitic bacteria whose replication is absolutely dependent upon the host cell's mitachondria and whose reproductive DNA formation requirements closely match those of the host's mitachondria will be engaged in competition with both the host cell's own energy and own reproductive needs. If this competition resulted in lower levels of mitochondrial capability then a rickettsial etiology for CFS might also explain the functional fatigue seen as the very essence of chronic fatigue syndrome.

G C M Kemp MB BS(Melb) FRACGP, FACNEM
Burke Road Medical Centre
681 Burke Road
Camberwell 3134 Australia

R F Townsend PhD (UNSW) BE (Melb) BBus(Mitchell)
Honorary Research Fellow, Department of Biomolecular Engineering
University of Melbourne,
Parkville 3004 Australia

References

1. N Kaushik, D Fear, S C M Richards, C R McDermott, E F Nuwaysir, P Kellam, T JHarrison, R J Wilkinson, D A J Tyrrell, S T Holgate and J R Kerr Gene expression in peripheral blood mononuclearcells from patients with chronic fatigue syndrome J. Clin. Pathol. 2005;58;826-832

2. C L Jadin, Common Clinical Windows on CFS and Rickettsial Diseases. Journal of Chronic Fatigue Syndrome, 6 no 3 133-145 2000

3. Fiset, P., R. A. Ormsbee, R. Silberman, M. Peacock, and S. H. Spielman.1969. A microagglutination technique for detection and measurement ofrickettsial antibodies. Acta Virol. 13:60–66 and also Kazar, J., R. Brezina, S. Schramek, A. Palanova, and B. Tvrda. 1981 Suitability of the microagglutination test for detection of post-infection and post- vaccination Q fever antibodies in human sera. Acta Virol. 25:235–240.

4. Rickettsial surival in synthetic in vitro solutions have demonstrated that Rickettsial respiration is possible from a wide range of amino acids and sugars,

5. Smith, D. K., and H. H. Winkler. 1977. Characterization of a lysine-specific active transport system in Rickettsia prowazekii.J. Bacteriol. 129:1349-1355.

6. The genome sequence of Rickettsia prowazekii and the origin of mitochondria Siv G. E. Andersson, Alireza Zomorodipour, Jan O. Andersson, Thomas Sicheritz-Ponte ,U. Cecilia M. Alsmark, Raf M. Podowski, A. Kristina, Ann-Soe Eriksson, Herbert H. Winkler Nature vol 396 no 12 November 1998.