Martin L. Pall

 

Other web pages:

Main Web Page

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Multiple Chemical Sensitivity

Fibromyalgia

Other Proposed NO/ONOO- Cycle Diseases

Approaches to Therapy

Allergy Research Group Nutritional Support Protocol

 

 

The five principles underlying the NO/ONOO- cycle as an explanatory model are as follows:

 

1. Short-term stressors that initiate cases of multisystem illnesses act by raising nitric oxide synthesis and/or other cycle elements.

 

2. Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of nitric oxide and peroxynitrite and other cycle elements is produced and maintained.  This principle predicts that the various elements of the NO/ONOO- cycle will be elevated in the chronic phase of illness.

 

3. Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress, mitochondrial dysfunction and elevated NMDA and TRPV1 receptor activity.

 

4. Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because the mechanisms involved in the cycle act at the level of individual cells, the fundamental mechanisms are local.

 

5. Therapy should focus on down-regulating NO/ONOO- cycle biochemistry.

 

Each of these principles, explains, then very important properties of these illnesses:  How they are initiated (principle 1), why they are chronic and what features are predicted for the chronic phase of illness (principle 2), how symptoms and signs are generated (principle 3), why cases of these are so variable from one case to another or why one or more specific tissues may be impacted in specific illnesses (principle 4) and how they should be treated (principle 5).  Thus we have, for the first time, an essentially complete model of these multisystem illnesses.  Indeed, this mechanism argues that CFS, MCS, fibromyalgia and PTSD are all true diseases, albeit unusual ones because of their high variation from one case to another.

 

The five principles are important in a separate but related way.  They each provide a  distinct type of evidence for the causal nature of the NO/ONOO- cycle.  Are cases of a specific disease/illness initiated by stressors predicted to be able to initiate the cycle?  (principle 1)  Are the elements of the cycle elevated in the chronic phase of illness?  (fit to principle 2)  Can symptoms and signs be generated by one or more elements of the cycle? (fit to principle 3)  Do we see a lot of  symptomatic or tissue impact variation from one case to  another, or do we see  evidence for the required involvement of a specific tissue or  set of tissues in a specific disease?  (fit to principle 4)  Are agents predicted to down-regulate the NO/ONOO- cycle useful in therapy?  (fit to principle 5)  Thus, we can see a diverse set of criteria that test the causality of the NO/ONOO- cycle as constituting these five principles. 

 

The five principles are important for a third reason.  In science, you need to have observations from very different perspectives, in order to test a particular theory effectively.  If you are looking at that a scientific phenomenon through a narrow window, there are almost always multiple interpretations that may fit the observations.  It is only by looking through multiple and very distinct windows that one can get compelling evidence for a specific theory of causation!  Thus it is very important that the fit to each of these five principles provides a very different type of evidence for the causal role of the NO/ONOO- cycle in a particular disease or illness.  

 

Does that mean that we can be assured that the NO/ONOO- cycle as diagrammed on these web pages and on my book is complete and without flaw?  No, there may certainly be some minor flaws in the description and it is likely to be incomplete, involving still additional features than are described in my book or elsewhere.  Still, I would argue that the many agents reported to be helpful in therapy that are also predicted to down-regulate the NO/ONOO- cycle as it is diagrammed suggest that the cycle as currently proposed is sufficiently complete to make useful predictions for therapy.  And that suggestion is terribly important both to those who suffer from these illnesses and to health care providers who wish to treat them effectively. 

 

These three distinct ways of looking at the five principles are important not only for the multisystem illnesses.  They are also important if one wishes to ask whether additional diseases/illnesses are good candidates for inclusion under the NO/ONOO- cycle paradigm.  And I argue in my book and elsewhere that there may be many additional diseases caused by the cycle – including many chronic inflammatory diseases.  Because the fit to the five principles serve as criteria for deciding whether a particular disease/illness may be a strong candidate to be a NO/ONOO- cycle disease, they function a bit like Koch’s postulates do for deciding whether a specific disease may be an infectious disease, caused by a particular infectious agent.  However, the five principles are both stronger and weaker than are Koch’s postulates.  They are stronger because as an explanatory model, they provide an almost complete explanation for the etiology of any NO/ONOO- cycle disease.  They are weaker, however, because unlike Koch’s postulates, the fit to each principle is basically a judgment call.  There needs to be a judgment as to how much evidence is needed for one to infer that there is a good fit to each of the five principles.  This is different from Koch’s postulates where there are clear cut criteria for deciding whether specific postulate is fulfilled or not.