With knowledge of an indolent leukemia lurking in our minds, this prompted the NCF to take an objective look at other current CFIDS/ME research. As a Foundation, we frequently get mail or phone calls from CFIDS/ME patients who wish to inquire about testing, treatments, various protocols, research, theories, etc. One that we often hear about and are asked to comment on is from Martin Pall, Ph.D. from the School of Molecular Biosciences at Washington State University. Dr. Pall has published numerous articles on peroxynitrite/nitric oxide and the relationship to CFIDS/ME from a regulatory perspective. Dr. Pall has also published an extensive new book titled "Explaining 'Unexplained Illnesses': Potential Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, and Gulf War Syndrome." The NCF's comments regarding this are really quite simple especially in light of the preliminary leukemia findings. Though Dr. Pall has published a thorough book on this topic, he failed to address what we consider will become a significant concept that will be applicable to CFIDS/ME patients.

Let us explain. Dr. Pall's efforts focus on peroxynitrite/nitric oxide excess. However, because of the leukemic cell findings, we know that cells can be either 'normal' or 'abnormal/malignant.' We also know that apoptosis is critically important in the malignant cell process. This is a basic fact when considering cancer cell biology. Likewise, the true objective of oncology is to eradicate malignant cells typically via an apoptotic process. To do so requires agents (chemotherapy, radiation, adjuvants, etc.) that induce apoptotic cell death in malignant cells. The generation of Reactive Oxygen Species (ROS) and oxidative stress, for example, can play an important role in depolarizing mitochondria via the loss of mitochondrial membrane potential which is an early event in apoptosis. Peroxynitrite/nitric oxide is produced to induce cellular apoptosis. This can be representative of an anti-cancer effect. In fact, several chemotherapy agents act by inducing peroxynitrite/nitric oxide and oxidative stress as part of this necessary cell death process to kill malignant cells. Under these very circumstances, antagonism of peroxynitrite/nitric oxide acts to negate the malignant killing capabilities or anti-cancer activities of the chemotherapy. Now, if CFIDS/ME patients are in a pre-malignant state moving along a disease process towards a defined malignancy, is scavenging peroxynitrite/nitric oxide the best approach to take since the production of peroxynitrite/nitric oxide and oxidative stress may be the body's attempt to eradicate
abnormal cells? This is certainly worth considering. Perhaps this apparent peroxynitrite/nitric oxide imbalance is actually telling us more than what has been previously considered.

Let us now extend this thought process for a moment. For example, could this entire CFIDS/ME disease process really be oncogenic? If CFIDS/ME was represented by an underlying and persistent/slow oncogenic virus, wouldn't this help to also explain why peroxynitrite/nitric oxide and ROS are being produced? The 'SER' strain of Parainfluenza Virus-5, reactivity of which was initially found in CFIDS/ME patients by Dr. Steven Robbins, was first identified in swine. Since it apparently has crossed-over into humans, due to finding the same fusion protein sequence for this virus in both swine and humans, then one question to be asked is could this apparently zoonotic virus be oncogenic? In other words, could this virus be a cancer-causing virus? Viruses that cross species can be oncogenic. In 2000, Dr. Brian Mahy wrote an article entitled "Emerging Zoonoses: Crossing the Species Barrier" that included the role of parainfluenza viruses in zoonotic infections.

Since parainfluenza viruses have been proven to be very capable of producing persistent infections, couldn't the CFIDS/ME disease process then be represented by such an infection? This is one of many scientific questions that should be considered. As for peroxynitrite/nitric oxide, one also needs to consider then what is its proper role in infected (abnormal) cells that may potentially lead to malignancy. This role may be opposite to its role in normal cells. These are not simple questions to answer and that is why the NCF has been working with scientists at Northwestern University and other institutions to assist us in executing laboratory research to
provide answers to these very questions. No doubt, there is a great deal to learn here. Lastly, we must admit that in Dr. Pall's new book, the index does not have entries for either 'cancer' or 'malignancy' and so the NCF views peroxynitrite/nitric oxide and oxidative stress as a true double-edged sword given what we currently know. Unfortunately, these concepts aren't nearly as 'cut and dried' when malignancy issues are taken into consideration because of their inherent impact regarding potential patient outcome.

Other work that the NCF often hears about from patients, regards 'Glutathione Depletion and Methylation Blocks in CFIDS' by Rich Van Konynenburg, Ph.D. In the 1990's, the NCF had the good fortune to come into direct contact with the Herzenberg Laboratory at Stanford University. Drs. Leonard and Leonore Herzenberg pioneered research on HIV and cellular redox reactions focusing on glutathione (GSH) and the effects of N-acetylcysteine (NAC) on HIV infection. During this same time period, one of our upstate NY CFIDS/ME patients was evaluated by the Herzenbergs for cellular apoptosis. The work was found to be so interesting that an infectious disease physician at the University of Rochester (U.of R.) Medical School flew to the Herzenberg Lab to learn more about their research. Subsequently, this CFIDS/ME patient was entered into
a clinical trial using effervescent NAC. The Herzenberg's studied the effects of NAC on this patient as did the U.of R. physician. Now, what you don't know is that this is the very same patient identified now with identified leukemia and PIV-5 infection mentioned in another article in a former Forum! Furthermore, this CFIDS/ME patient was also identified as having "HIV negative AIDS" according to this physician's assessment that was sent on U.of R.'s letterhead! Thus, now that we know that malignancy issues are very important and may ultimately come to define CFIDS/ME, glutathione has important clinical implications as well. In chemotherapy applications, not only can drug resistance occur due to higher GSH levels within malignant cells but GSH-depletion has been utilized as a method to improve cancer outcomes. Clearly, glutathione has an effect on cellular apoptosis, a process that is critically important in malignancy issues. Again, this is a double-edged sword given the fact that the role of malignant cells can't be ignored. In other words, altering the rate of apoptosis in malignant cells may prove to have dire consequences. One must consider the role of glutathione depletion in both normal as well as malignant cells because many of the same questions that apply to glutathione depletion also apply to peroxynitrite/nitric oxide and oxidative stress, especially when you add malignancy into the equation. These questions add to the scientific conundrum and that is why it is essential to consider the role of cancer in these issues.

While we're on the topic of research, let's talk about AIDS for a minute because it may interest you, the reader! In 1996, Dr. Anthony Fauci (NIH) published an article in Science titled "Toward an Understanding of the Correlates of Protective Immunity to HIV Infection." Let us quote him directly from the article. Dr. Fauci stated "Progression to AIDS is strongly associated with generalized activation of the immune system, manifested by elevated serum concentrations of neopterin, soluble IL-2 receptor, sCD8, and beta2-microglobulin, and with activation of a large proportion of CD8 T cells." The NCF has closely followed CFIDS/ME research and so we can comment on these parameters as they relate to our disease. First of all, Dr. Dedra Buchwald and others found neopterin to be elevated in CFIDS/ME patients. Second, Drs. Cheney and Hilgers found soluble IL-2 receptor to be elevated in CFIDS/ME. Third, Cheney found sCD8 to be elevated in CFIDS. Fourth, Buchwald and Dr. Patarca-Montaro found beta2-microglobulin to be elvated in CFIDSME. Fifth, Dr. Jay Levy found activation of CD8 cells in CFIDS/ME. If the progression to AIDS is strongly associated with generalized activation of the immune system, as Dr. Fauci says, then we have shown that this criteria is also satisfied in CFIDS/ME! Immune activation is certainly one characteristic that CFIDS/ME shares with AIDS. However, we must remember, CFIDS/ME is merely malingering while AIDS is a real disease. Oh, yes...right! We should also mention that each one of the above parameters has been found to be elevated in hematologic malignancies.

One last comment on CFIDS research: Dr. Paul Cheney has identified patent foramen ovale (PFO or hole in the heart) in some patients. This is in addition to diastolic dysfunction that he had previously found in patients. Looking through various research papers, the NCF found atrial septal defects, of which PFO's are included, to be associated with the activation of various oncogenes! This would be in agreement with our discussion above of potential oncogenic involvement in CFIDS/ME. In addition, diastolic dysfunction has been seen in leukemia patients prior to therapy. Again, perhaps not a surprising finding given the 'quality of life' studies that have been published on leukemia patients. Lastly, STAT1, a protein found to be abnormal in CFIDS/ME, not only plays a vital role in leukemic cells but it has also been found to be an important factor in heart failure.