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

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

Conflict of Interest:

None declared

Dear Editor

We are astonished by Wiwanitkit's inaccurate remarks regarding the number of subjects studied and analytical methodology in our study [1]. The data set was of more than sufficient size to be subjected to rigorous statistical analyses. If Wiwanitkit had bothered to even casually read the articles he cites [1,2], he should have immediately realised that firstly the thrust of Lenters-Westra's and Slingerland's paper was to highlight poor analytical performance of some HbA1c point-of- care (not laboratory based) instruments and secondly that laboratory HbA1c analyser used in our study (Tosoh G7, cation-exchange HPLC) was a reference method for measurement of HbA1c in study of Lenters-Westra and Slingerland [1,2]. In addition our HbA1c assay, and indeed all our assays, are subject to stringent internal quality control procedures and external quality assurance. We had hoped our article would stimulate meaningful debate rather than inane comment.

Dr Taruna Likhari, Professor Rousseau Gama

References

1. Likhari T, Gama R. Ethnic differences in glycated haemoglobin between white subjects and those of South Asian origin with normal glucose tolerance. J Clin Pathol 2010; 63:278-280

2. Lenters-Westra E, Slingerland RJ. Six of eight hemoglobin A1c point-of- care instruments do not meet the general accepted analytical performance criteria. Clin Chem 2010;56:44-52

Conflict of Interest:

None declared

Dear Editor,

Elizabeth H Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects chromosomes from degradation. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA. These discoveries explained how the ends of the chromosomes are protected by the telomeres and that they are built by telomerase. If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cellular senescence is delayed. This is the case in cancer cells, which can be considered to have eternal life [1]. Cancer cells have the ability to divide infinitely and yet preserve their telomeres. How do they escape cellular senescence? One explanation became apparent with the finding that cancer cells often have increased telomerase activity [1] Telomeres, repeated sequences of DNA at the end of chromosomes, prevent degradation of genetic material. Each time chromosomes replicate a small amount of the DNA at both ends is lost, by an uncertain mechanism. Because human telomeres shorten at a much faster rate than many lower organisms, we do speculate that this telomere shortening probably has a beneficial effect for humans, namely mortality. The telomere hypothesis of aging postulates that as the telomeres naturally shorten during the lifetime of an individual, a signal or set of signals is given to the cells to cause the cells to cease growing (senesce). At birth, human telomeres are about 10,000 base pairs long, but by 100 years of age this telomere reduces to about 5,000 base pairs. Scientists discovered an important enzyme that can turn the telomere production on the DNA molecule "on" and "off." It's called telomerase. It seems that as we get older, the amount of telomerase in our cells decreases. Naturally, the exploration of this enzyme is now the focus of much investigation, but unfortunately the research is aimed at understanding how to turn telomeres "off" to limit the spread of "immortal" cancer cells. Telomerase is actually an enzyme (a catalytic protein) that is able to arrest or reverse this shortening process. Normally, telomerase is only used to increase the length of telomeres during the formation of sperm and perhaps eggs, thus ensuring that our offspring inherit long "young" telomeres to propagate the species. The telomere hypothesis of cancer is that the function of telomere shortening is to cause cells that have lost normal control over growth to senesce (i.e. stop growing) before being able to replicate enough times to become a tumor, thus decreasing the frequency of cancer. Immortal cells like cancer have an unfair advantage over normal human cells which are designed to senesce. But nature seems to have planned this human telomere shortening perhaps to prolong life by hindering the otherwise unchecked growth of non-immortal or benign tumors. Malignant, or immortal tumors can simply outlive the rest of the organism. Malignant cancer cells are being studied because they appear to have altered the shortening of telomeres by turning "on" the telomerase. Thus it appears that some cancers and aging are both connected with the biology of telomeres. So telomerase-inhibiting drugs would probably kill the cancer cells before much damage is done to normal cell

Today reduction in mortality in breast cancer is due to early detection through screening by mammography. However at least 25% reduction in mortality could have been achieved due this screening procedure [early-stage pre menopausal breast cancer, for example, 10-year survival rates is today 68% for African Americans versus 77% for Caucasians]. Besides these there played other factors also and these are 1) systemic or improved systemic treatment with chemotherapy 2) adjuduvant therapies after surgery to eliminate micro metastasis like Her2 Nue antagonist Herpentine and to prevent recurrences. Women with steroid hormone receptor[ER+ or PR+] positive and negative cases are benefited by Cyclopshomide & methotraxate & 5 FU chemotherapeutic agents. More effective adjuduvant endocrine treatments are with variuous aromatase inhibitors like letrozole or anastrozole. Cases of breast cancers occur even when there is no family history or only a few cases in elderly relatives are known as sporadic breast cancer. Hereditary breast cancer is different from those of sporadic breast cancer .The increased risk of breast cancer for those with a family history may be caused by inherited factors (genes) like BRCA1 and BRCA2,[both the genes protects breast cells from developing cancer. Certain mutations in BRCA1 stop the gene working properly and therefore make it more likely that breast cancer will develop],or a combination of inherited factors and lifestyle like no breast feeding or unmarried women. Having an increased genetic risk by mutation of these two genes can lead to breast cancer developing even at an earlier age. BRCA1 and TP53 genes are of high penetrance genes for breast Cancers. Mutations in the rare high penetrance breast cancer predisposing genes are BRCA1 and BRCA2 and they account for 16 to 25% of the inherited component of breast cancers in the world scenario.This, in turn, can have an impact on raising your family. So is it today possible to do BRCA1 gene test for people that know they carry a specific mutation that predisposes them to suffer from breast cancer. It is a real fact that most Breast cancers develop sporadically and not related with a familial history or hereditary BRCA genes. It is thought that less than 5% of people those develop breast or bowel cancer do so because of an inherited fault. Unless there is a strong family history of breast cancer in you it is unlikely that your child will inherit a gene that increases the risk of developing cancer. So splicing off BRCA1 gene before embryo may be an advancement for medical technology [2]. Mutations in TP53, which at same time may cause the Li Fraumeni syndrome, STK11 gene causing Peutz Jeghers syndrome, and PTEN causing Cowden syndrome are however very uncommon sporadic causes of breast cancers of NOS type, as are mutations in CDH1, although these mutations may be highly penetrant for breast cancer The intermediate penetrance breast cancer susceptibility genes are mutations in ATM, CHEK2, BRIP1, BARD1, and PALB2. They can cause an increased odds ratio for breast cancer of 2 to 4. These genes are all involved in the same DNA repair pathways, but it is curious that they do not confer the high risk of breast cancer seen in women who carry mutations in BRCA1 and BRCA2. Also of great interest is that biallelic mutations in BRCA2, BRIP1, and PALB2 cause Fanconi anaemia subtypes FANC D, J, and N respectively, further indicating overlap in the functions of these genes. There are also good evidences now that there are up to eight polymorphisms, which are reproducibly found to influence breast cancer risk, particularly the FGFR2 gene. Carriers of two low risk rs2981582 alleles at the FGFR2 locus (frequency 38% of the population) have a relative risk of breast cancer of 0.83 compared with the general population, carriers of one high-risk and one low-risk allele (47%) have a relative risk of 1.05, and carriers of two high-risk alleles (14%) have a relative risk of 1.26

Telomere crisis is also an important early event in the development of breast cancer. In the breast, cells in a milk-collecting duct occasionally proliferate excessively due to development of a regulatory defect and results usual ductal hyperplasia." The chromosomes in these growing cells lose a hundred or so base pairs of DNA every time they divide," ,because the usual DNA replication processes don't copy DNA all the way out to the ends of the chromosomes. This erodes the DNA sequences that interact with proteins to form structures called telomeres, which protect the chromosome ends. Eventually the DNA ends erode so much they can no longer protect the chromosomes. When this happens the chromosomes become unstable, and damage-control mechanisms kick in that kill the unstable cells. This process, known as "telomere crisis Cells in which telomerase is activated can then proliferate indefinitely to form the next stage of cancer, known as 'ductal carcinoma in situ.' The mean telomere length is found decreased from normal tissue to carcinoma in situ, and decreased even more in invasive cancers of breast. It was therefore proposed that breast cancer might be treated by eradicating telomerase. Several studies are underway in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity[1] "

Authors

Professor Pranab kumar Bhattacharya MD(cal), FIC path(Ind.) Mr. Ritwik Bhattacharya, B.Com(cal) Mr. Rupak Bhattacharya BSc Mrs Dahlia Mukherjee BA (hons) Miss Upasana Bhattacharya of Mahamyatala, Dr. Debashis Bhattacharya Ms(cal) FRCS(Edin) Dr. Diptendra Narayan Sarkar Dr. Tarun Biswas MBBS(cal)- Dr. Satyaki Mitra MD(PGT) Dr. Avisnata Das MBBS(cal),

References
1] Press Release on the 5 October 2009 “The Nobel Prize in Physiology or Medicine 2009â€� by The Nobel Assembly, consisting of at Karolinska Institutet, Sweden

2] Response by Professor Pranab Kumar Bhattacharya Published by BMJ on 4th feb 20009 .for the BMJ case reports Blog unnatural selection by author Dean Jankens, published on 9th Jan 2009

Dear Editor

We thank Drs Rotimi and Reall for their comments, but would suggest that their criticisms have been framed by a perspective that is different from our own. Their perspective is the “most striking result” was that sessile serrated adenomas (SSAs) were predominantly right sided. They are welcome to highlight this point, which is readily apparent from the data presented.

Our perspective is that the right sided predominance of SSAs is well known, and widely reported in the literature. Hence we did not highlight this finding. Their perspective is that a frequency of 4% of all polyps is not “common”. From our perspective, four in every 100 polyps is “common”, and we believe this point is worth emphasising because in many practices SSAs are reported rarely, if ever. Again, the quantitative information is available to readers, who are welcome to interpret it as they see fit.

We would argue that although “common” is a relative and qualitative term, it is misleading to propose that SSAs are not common in routine practice. Finally, Drs Rotimi and Reall are concerned that our statistical tests may have been inappropriate. We have the happy perspective of knowing the age distribution of the groups in question (serrated and non- serrated polyps). We can assure them that these distributions are normal, and that the use of parametric tests is indeed appropriate in this case.

Nicholas J Hawkins, Norman J Carr, King L Tan, Hema Mahajan, Robyn L Ward,