12 step treatment approach – Available only to Concierge Members

In Physics as in all the hard sciences, one looks for principles that are never violated and for which there are no exceptions in nature. We call these first principles the foundation of Physics and they are our guiding lights as we explore the universe around us. In biology there are also first principles though they are not well known and not translated well to the management of patients. This is because Biology and the allied medical sciences have for most of their history been observational science as distinct from the more theoretical sciences such as Physics and Mathematics with first principles as their foundation and expressed in elegant as well as simple mathematical formulas.

I explore here one of the guiding principles of medical science and indeed all biological science. That principle is that tissue demand for the supplies delivered to meet that demand will ALWAYS match. Failure to match supply/demand in small ways or briefly leads to cell suicide or apoptosis and catastrophic failure to match supply/demand leads to death of the entire organism. Starvation or hibernation or the “dauer” state is an example of smaller tissue demand for energy to match the lower supplies of oxygen and carbon bonds (nutrients) available while starving or hibernating. As such, these low demand states like the dauer state are adaptations to survive a relative lack of supply and recently proven for CFS by Naviaux et al, PNAS July 2016 using next generation metabolomics. Whether or not that deficient supply be nutritional and/or blood flow (ie low cardiac output) does not matter from the point of view of the cell. In the face of reduced supply, the tissue or cells MUST adapt to a lower energy state or the outcome will lead eventually to a fatal disease, either over time or acutely with a diagnosis of acute organ failure and shock which is fatal within minutes.

There are a number of mechanisms or levers that can be pulled by the individual to prevent supply/demand mismatching. At the cell level, the quickest way to correct a supply problem is to desaturate hemoglobin which delivers extra stored oxygen otherwise bound to hemoglobin. When one sees excess desaturation of greater that 3 points using pulse oximetry after a 30 second, end-expiratory breathhold, in the setting of CFS is proof of on-going supply/demand mismatching. Other ways to correct a supply/demand problem includes increased sympathetic tone from the brain sympathetic nuclei as well as the release of epinephrine and cortisol from the adrenals. This increased sympathetic tone drives up supply via heart rate and vasomotor responses as well as increased LV and RV strain and increased EF% we see in nearly all CFS cases. Unfortunately, this increased sympathetic tone causes severe sleep disturbance and a feeling of being wired and tired. Furthermore, the adrenals can be exhausted causing a functional collapse. Nocturnal pulse oximetry can provide details of CNS hypoperfusion in CFS and thus supply/demand mismatching during stage IV sleep if we observe low nocturnal baseline oximetry and excessive desaturation during the first four hours of sleep. The treatment for this would be low dose oxygen starting at 1-2 lpm via nasal cannula during sleep. Oxygen above 1-2 lpm should be guided by nocturnal pulse oximetry. Otherwise, excess oxygen can be deleterious to CFS cases as excess oxygen ends up as free radicals and can cause down-regulation of the mitochondria as compensation to preserve the redox buffer.

The reason behind the lethality of a mismatch of supply/demand is that re-perfusion injury to hypoxic cells (ie insufficient supply of oxygen), causes a lethal but programmed release of oxygen free radicals that threatens the cell and the DNA with corruption. Corruption of the DNA will not be tolerated as it will lead to species extinction. Likewise, chronic mismatching leads eventually to organism death to avoid DNA corruption which will never be tolerated as it causes extinction of the species. Reduction of cell mass and therefore demand via cell suicide serves to improve supply/demand matching and is a survival mechanism. Failure of this mechanism to achieve supply/demand matching will eventually lead to a fatal outcome for the organism to prevent DNA corruption and the potential loss of the entire species.

When you take the principle of supply/demand matching and apply it to CFS, a whole new world of looking at CFS treatment strategies emerges. Many of the best treatments we have used over the decades and the ones that have best stood the test of time either reduce demand or increase supply. Typically, the best immediate treatments for CFS reduces demand and include such treatments as Klonopin, Doxepin, Trazadone, LDN and transdermal CBD CSF oil as well as staying within boundaries with long periods of rest. There are other treatments that improve supply in an indirect as opposed to a direct manner. These include redox buffer support measures such as Magnesium, hydroxyB-12, Inosine, Aronia Berry Concentrate, California Heritage olive oil, catabolic paste CSF, anabolic paste CSF and MTF paste CSF. By improving the redox buffer, mitochondria will automatically up-regulate and that will improve blood supply immediately. Direct stimulation of supply via stimulants or exercise or stress or SSRI’s or T3 hormone are dangerous in the setting of an impaired redox buffer state like CFS as it challenges the redox buffer further and will backfire over time as it may cause a supply/demand mismatch and eventual collapse of function to compensate if you are lucky and a fatal disease if you do not collapse function.

Going forward, NanoVi technology (see www.eng3corp.com) which improves the functionality of all 30,000 human enzymes all at once and in all cells within minutes can be a conundrum. After testing 17 consecutive CFS patients on NanoVi, we see a drop in mitochondrial function within minutes while on NanoVi by IVRT criteria in real time. I believe this is due to the fact that NanoVi increases oxygen demand at the cell level faster than organ systems can adapt to this and thus creates a supply/demand mismatch with a positive or negative clinical effect that depends on how long one breathes the activated water vapor using NanoVi. We also see this effect when we use oxygen alone by nasal cannula if there is normal baseline oximetry of 97-98% and termed oxygen toxicity by IVRT criteria. Excess oxygen demand or oxygen supply above the ability of the cell to functionally adapt its redox buffer to that increased supply or demand causes a downregulation of the mitochondria seen as a rise in IVRT in real time on the echocardiogram. It is a dramatic demonstration of the dauer state coming on line in real time. There have been no exceptions to these observations after 17 consecutive patients examined with NanoVi using echocardiography and after over 500 patients examined with oxygen alone at 4 lpm NC using echocardiography.

On the flip side, we notice that the combined use of oxygen at 4 lpm and NanoVi at the same time seems to cause oxygen toxicity to be abolished or even reversed and is associated with dramatic clinical improvement on the table in real time. Two recent patients felt a sense that they had recovered on the table with both treatments given simultaneously and their brain function improved immediately on the table. One of the patients started to cry as he felt normal for the first time in a very long time. I believe what happened was that the increased oxygen demand with NanoVi was met with increased oxygen supply using oxygen by nasal cannula so there was matching of increased supply of with increased demand for oxygen. The clinical benefit was astonishing and immediate. I therefore believe that NanoVi should only be used with nasal oxygen at the same time in CFS patients for a period of time between 4 and 12 minutes on the professional NanoVi model (~$8,500) per day and between 8 and 24 minutes per day on the home NanoVi model (~$5,500). Sicker patients should start at 2-4 minutes per day using both NanoVi and nasal oxygen set at 4 lpm TIW. The primary endpoint will be the clinical response over three months and the effect of this treatment on Nitrotyrosine blood levels as a redox buffer biomarker pre- and post-treatment over that ninety days. Patients wishing to be part of this study should contact Dixie. Be aware that no such study has ever been done on CFS cases so we cannot know whether this will be worth the cost or even the exact risks. I do think, however, that the gain could be significant and the risks low and I base this judgement on the use of NanoVi by a few CFS cases in the Pacific Northwest that are not my patients. It is also advisable to use all or most of the primary steps in the treatment hierarchy previously posted BEFORE the use of NanoVi and oxygen combined.

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©2017 Cheney | cheneyinstitutemail@gmail.com
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Summary taken from http://m.pnas.org/content/early/2016/08/24/1607571113.long

Study: 45 CFS patients and 39 controls from a Northern California clinic were studied, equally divided between males and females. Ave. KPS was 62 for males and 54 for females. Males were ave age 53, females were ave age 52. 612 metabolites from 63 biochemical pathways were measured using advanced liquid chromatography on plasma. 60 metabolites in both males and females out of 612 were abnormal compared to controls. CFS cases showed abnormalities in 20 metabolic pathways (9 common to both and 11 with gender differences). 80% of the diagnostic metabolites (8 in men and 13 in females) were decreased and consistent with a hypometabolic state with low mitochondrial function, low peroxisomal function and low NADPH. An average of 10 metabolite abnormalities contributed to the diagnosis of CFS and an average of 30 metabolite abnormalities were unique to the individual.

What is CFS?
Many of the pathways and metabolites that were abnormal in CFS are also known to be features of dauer, a well-studied, long-lived survival and persistence state triggered by environmental stress. Interestingly, the direction of CFS abnormalities was opposite to metabolic syndrome and opposite to the metabolic response to infection, inflammation, or environmental stress that has been called the CDR (Cell Defense Response). For example, cholesterol, phospholipid, sphingolipid, and purine metabolism are all decreased in CFS and dauer but are increased in metabolic syndrome and the stereotyped CDR. These facts suggest that CFS is an evolutionarily conserved, genetically regulated, hypometabolic state similar to dauer that permits survival and persistence under conditions of environmental stress but at the cost of severely curtailed function and quality of life.

What is Dauer?
Dr Naviuax’s results show that the metabolic features of CFS are consistent with a hypometabolic state. Sphingolipids, glycosphingolipids, phospholipids, purines, microbiome aromatic amino acid and branch chain amino acid metabolites, FAD, and lathosterol were decreased. The decreases in these metabolites correlated with disease severity as measured by Karnofsky scores. Much research has been done on the hypometabolic phenotype in other biologic systems, including dauer, diapause, hibernation, estivation, torpor, ischemic preconditioning, ER stress, the unfolded protein response (? NanoVi responsive), autophagy, and caloric restriction. Dauer, which means persistence or long-lived in German, is an example of one well-studied system. The developmental stage of dauer is a hypometabolic state capable of living efficiently by altering a number of basic mitochondrial functions, fuel preferences, behavior, and physical features. Dauer is comprised of an evolutionarily conserved and synergistic suite of metabolic and structural changes that are triggered by exposure to adverse environmental conditions. Entry into dauer confers a survival advantage in harsh conditions. When the dauer response is blocked by certain mutations (dauer defectives), animals are short-lived when exposed to environmental stress. These mutations show that the latent ability to enter into a hypometabolic state during times of environmental threat is adaptive, even though it comes at the cost of decreasing the optimal functional capacity. Similar to dauer, CFS appears to represent a hypometabolic survival state that is triggered by environmental stress. The metabolic features of CFS and dauer correspond to the same pathways that characterize the acute CDR and metabolic syndrome but are regulated in the opposite direction. For example, cholesterol, phospholipids, and uric acid are often elevated in the acute CDR and metabolic syndrome, but these metabolites were decreased in CFS patients. A prediction based on these findings is that patients with CFS would be more resistant to the constellation of hypertension, dyslipidemia, central obesity, and insulin resistance that increase all-cause mortality associated with metabolic syndrome, but at the cost of significant long-term disability, pain, and suffering.

The Importance of Mitochondria, Redox, and NADPH Metabolism in Chronic Fatigue.
All of the metabolic abnormalities that Dr Naviaux identified in CFS were either directly regulated by redox or the availability of NADPH. About 60% of NADPH is produced by the pentose phosphate pathway under baseline conditions (Glucose to D-Ribose). The other 40% is produced by the combined flux through five NADP+ dependent enzymes: (i) malic enzyme (ME), (ii) isocitrate dehydrogenase (IDH), (iii) glutamate dehydrogenase (GDH), (iv) nicotinamide nucleotide transhydrogenase (NNT), and (v) methylene tetrahydrofolate dehydrogenase 2-like protein (MTHFD2L). Each of these enzymes has at least one mitochondrial isoform and is known to be up-regulated under conditions of environmental or developmental stress. It has recently been shown that mitochondrial MTHFD2L is responsible for producing 20–40% of cellular NADPH by the oxidation of methylene tetrahydrofolic acid to 10-formyl tetrahydrofolate. These data show that folates are important not only in methylation reactions but also in regulating intracellular redox and NADPH levels. A number of single nucleotide polymorphisms (SNPs) have been identified in the MTHFD2L gene that correlate with the CDR and interleukin 1β (IL1β) production triggered by smallpox vaccination. Mitochondrial pools of NADPH are in continuous communication with NADH levels through the enzyme NNT. Therefore, NADPH acts as a global barometer of cellular fuel status by interrogating both mitochondrial electron (NADH) consumption and the availability of cytoplasmic reducing equivalents as NADPH. When mitochondrial electron transport decreases for any reason, fewer molecules of oxygen are converted to water (H2O) by cytochrome c oxidase. If capillary delivery of oxygen to the cell is unchanged, the concentration of dissolved oxygen rises in the cell like water in a bowl in response to instantaneous decreases in mitochondrial oxygen consumption. This activates scores of enzymes that are kinetically regulated by the availability of dissolved oxygen and can act as oxygen sensors. Some of these include NADPH oxidases like Nox4 that make hydrogen peroxide (H2O2) from the excess diatomic oxygen (O2) to initiate the oxidative shielding response (? Oxygen toxicity by IVRT criteria). When reduced (NADPH) and total (NADPH plus NADP+) pools are low, sterol, fatty acid, protein, and nucleotide synthesis fall to baseline survival levels. When NADPH levels are higher (anabolic stimulation), metabolism is shifted from persistence to normal cell function and growth, anabolic pathways are stimulated, biomass is created, and carbons and electrons are stored as biopolymers for cell growth and repair in the form of lipids, protein, glycogen, glycans, and nucleic acids.

Six paragraph treatise – Available only to concierge members

I have posted a long description of and historical rationale behind Cell Signaling Factors (CSF’s) on www.cheneyinsitute.com using the Cell Signaling Factors link button on this web site. We now have available Bison Heart Cell Signaling Factors which historically has been demonstrated to be the most powerful of all the transdermal CSF’s by IVRT response criteria on the echocardiograph machine in terms of improving cellular and mitochondrial energy production in real time. I suspect this is because the Bison Heart consumes more oxygen per pound than any other land mammal with a trachea diameter of four inches which allows it’s 2,000 pound body to consume oxygen at a prodigious rate to run across the hot prairie at 30 mph all day long. This prodigious use of oxygen implies an equally prodigious ability to metabolize oxygen metabolites such as superoxide produced by such a high level of aerobic energy production.

My guess is that the small peptides in Bison Heart act by binding to G-protein coupled receptors (GPCR’s) which have flanking receptors for very small peptides which activate the GPCR (see https://en.wikipedia.org/wiki/G_protein–coupled_receptor). Note that eight Nobel Prizes have been awarded to researchers in either the field of GPCR’s or the many metabolic pathways they regulate. The exact number of GPCR’s is unknown but over 800 genes are suspected of coding for these GPCR’s. Pay special attention to the list of physiologic roles for GPCR’s listed in the Wikipedia link. I strongly suspect that Bison Heart CSF’s up-regulate the enzymes SOD and GPx which are the key enzymes controlling the ability of the cell to control excess superoxide, a dangerous by-product of high aerobic energy production. If true then the combination of Bison Heart CSF’s in the daytime along with anabolic support via both MTF and Porcine Liver at bedtime which support NADPH and GSG/GSSG will be the best combination to support the otherwise impaired redox buffer state at the core of CFS.

If you are interested in Bison Heart CSF’s, please call or email Dixie to order it. The dose is two – four drops to the forearm on arising every day. Porcine Heart CSF’s are now discontinued in favor of Bison Heart which is much stronger in terms of aerobic energy production support. Note that MTF is basically stem cell peptides derived from porcine placenta and acts similar to stem cells which supports anabolism though it disfavors catabolism (aka ATP production) and Porcine Liver supports NADPH production which supports detoxification, peroxisomal function, GSH/GSSG and also inhibits HHV-6A via its similarity to Kutapressin. MTF is very potent and will cause energy collapse if used at higher doses (aka applied to the forearm or neck as opposed to the top of the foot) or too frequently.