1. Origin and Pathomechanism of the Diseases of Civilization (Hypothesis)
11th IN VIVO PHYSICIAN-CONFERENCE
Szent Rokus Hospital, Budapest
17th August 2016
By András Sikter
Municipal Clinic of Szentendre
Ladies and Gentlemen! Dear President!
I am grateful to President Szabolcs Horváth, head physician, who invited me to lecture at the eleventh in Vivo Physician-Conference. I will present how I imagine the origin and pathomechanism of diseases of civilization. You can be sure that it will be unconventional.

2. History
: The lecturer applied the rules of Second Law of Thermodynamics in Biological Systems. He also demonstrated a new dimension of ions’ tasks. (Also See: Sick Cells Theory from Elkinton, 1956, Lancet: Editorial)
The theory (modified by lecturer) models the operation of cytoplasm and energetic alterations of diseases. (Sikter A.: Modeling of cytoplasm. Card. Hung. 2007; 37: Suppl. B. B3-B ResearchGate)
: In humans, the prevalence of pathologic breathing patterns is extremely high. It is a consequence of the civilized behavior. We can also model the consequences of pathologic breathing patterns. (Sikter A, Faludi G, Rihmer Z: Neuropsychopharmacol Hung. 2009;11: )
I have dealt with this project since I should mention that I changed and developed Elkinton’s Theory of Sick Cell Syndrome. I think that the new theory is suitable for modeling cytoplasm and also the mechanism of organic and functional diseases.
I published my new model of diseases in the Cardiologia Hungarica in September Unfortunately, I failed to convince my cardiologist colleagues; they honestly did not even listen to me.
However, no less a person than Professor Zoltán Rihmer, who won the Psychiatrist of the Year award in the U.S. in 2000, accepted my thesis and worked with me. He said to me: “You have a phenomenal theory. Unfortunately, colleagues will not accept it.”
I can do nothing but continue the work; I lecture if I get a forum like this.

3. Modeling of Cannon’s Fight or Flight Reaction
Catechol.
FIGHT or FLIGHT IC pH AROUSAL
Hypocapnia 2.
Muscular work IC pH AROUSAL 1.
Hyperventilation (hypocapnia) plays a central role in the nearly 100-year-old Cannon’s stress-model, although this is not usually emphasized.
Both acute hypocapnia and increased catecholamine levels cause IC (intracellular) alkalosis — in this way, they reinforce each other. (Hypothesis of the lecturer)
First step: Both the targeted prey and also predator fall into hyperarousal because of IC alkalosis.
The hyperarousal will neutralize during the second step: because muscular activity (fight or flight) restores the pCO2 level, IC pH – in this way also arousal.
In the case of wild animals, the stress response is a subconscious process; the reflexes happen in the amygdala and hippocampus, although previous experiences also have a role.

4. Freeze behavior in willow ptarmigan (JB. Steen et al: Acta. Physiol
Freeze behavior in willow ptarmigan (JB. Steen et al: Acta. Physiol. Scand. 1988,234: )
At the end of the 20th century, it turned out that there is another stress-response too. (both in wild animals and in humans). It was named the freeze behavior or freeze response.
A Norwegian research team presented the freeze response of the willow ptarmigan hen very impressively (1988). They offered a new mechanism.
The bird perceived the danger at the point A/, her respiratory rate dropped to half, her pulse reduced to 20-25/min (para sympathicotonia). Her breathing accelerated at point C/ - The hypoventilation changed to hyperventilation (a reflex of medulla oblongata), her pulse can speed up to 380/min (they are birds!) The bird flies away.
(The level of catecholemines increased during the first (para sympathicotonia) period, but they could not effect tissues because of acidosis. At the point C/ hyperventilation, alkalosis + effect of catecholamines results in hyperarousal (sympathicotonia). It is a cumulative effect. The bird flies away – muscular activity.
This stress response has three periods, although the second and third ones are very close together.
In the case of humans, Barlow wrote this stress-response. (Barlow, DH.: Anxiety and its disorders. 2. New York: Guilford Press; 2002.)

5. The willow ptarmigan.
Willow Ptarmigan

6. 2. 3. Freeze, Fight or Flight pCO2 Hypocapnia IC pH
Hypercapnia
Freeze resp. pCO Hypoarousal
(Listening, cowering)
Switching over
Hypocapnia IC pH
Catechol.
Hyperarousal
The freeze response and Cannon’s stress-reaction often occur together.
In the first phase, the prey estimates the situation, keeps a cool head. He/she tries to remain invisible. The second and third phases are equivalent with Cannon’s stress-response. It is important that the hypocapnia is always followed by a muscular activity (fight or flying away), at least in the case of wild animals; the pCO2, pH and arousal levels normalize.
Another possibility of the freeze response is "playing dead.”
pCO2
Muscular activity 3.
Playing dead
pCO2, pH
Arousal

7. Sympathicotonia (pCO2 ) -
The FULL Stress Reaction, with Simplifications
Vagotonia (pCO2 ) -
Sympathicotonia (pCO2 ) -
Muscular activity (pCO )
With simplifications. Meaning, if the reaction goes to the end: We also could say: hypoarousal, hyperarousal, muscular work.

8. Stress Response of Human
SUBCORTEX: instinctive 2.
Hypercapnia
Freeze resp. pCO Hypoarousal
(listen, cower)
Switches over
Hypocapnia IC pH
Catechol.
Hyperarousal
In the case of wild animals, as I mentioned, the stress-response is an instinctive process.
In humans, the situation is quite different. We can stop the process in either the hypercapnic (para sympathicotonia, hypoarousal) or hypocapnic (sympathicotonia, hyperarousal) stage and we will do it most of the time.
This is an educated, conscious decision: we have learned not to harm our fellow human beings (only as a last resort or if ordered from above). In fact, we are fighting for social integration and rarely against the forces of nature. To do this, we have to learn the rules of social coexistence; we often have to practice self-restraint.
According to ethologists, there is not another species as tolerant as humans, who are satisfied with such a small territory. Civilized behavior is its tool (when the human remains in the stress), and civilization diseases are its price!
The consequence of self-restraint is that the human often does not complete the stress reaction. The muscular activity, which would restore pH and pCO2 levels, frequently falls short.
In this way, the hypercapnia (hyporousal- blue arrow) or hypocapnia (hyperarousal- red arrow) can persist, which will have severe consequences during regulation!
CORTEX:
Learned behavior during socialization
SELF-RESTRAINT!
Motor activity 3. Vs
Arousal

9. ”They look askance with a furtive glance, The noblemen of Wales;
Their cheeks turn white in deadly fright,
As crimson anger pales.
Deep silence falls upon the halls,
And lo, before their eyes”
Arany, János*:The Bards of Wales
*Hungarian poet in XIXth century (translated by Peter Zollman )
You will know what the "freeze response" means if you read lines of János Arany. Present standard talk is less lyrical, but it also expresses "freeze behavior" in a proper way: "Swallowing your stress.„
You will know what the "freeze response" means if you read these lines of János Arany. Modern standard talk is less lyrical, but it also expresses "freeze behavior" in a proper way: "Swallowing your stress."

10. Types of Chronic Stress
In the case of wild animals, pCO2 and arousal levels normalize quickly through muscular activity after acute stress.
Humans frequently remain in stress situations because if the learnt behavior blocks muscular activities – a chronic stress will develop.
In the case of humans responding to stress with hyperactivity chronic hypocapnia develops, while in the case of hypoarousal, chronic hypercapnia develops.
The chronic hypo- and hypercapnia can maintain themselves (if they have already developed) - the pathological breathing becomes habitual.
We are mostly harmed by fellow human beings and by our social situation, etc. There is no room to escape — all places are already occupied. There is no other choice but to live with chronic stress and to try to prevent its adverse consequences.
If hypocapnia or hypercapnia caused by stress is sustained for at least a week, there is a chance that, even without a new stress, this condition will be permanently maintained (even for years and decades). These pathological patterns of breathing can become habitual. (We can say it in another way: an addiction can develop to hypo- or hypercapnia).

11. It is not the stress itself responsible for human diseases of civilization (and also of trained animals), but rather
the lack of muscular activity. Therefore, the civilized behavior is responsible.
The First Thesis.

12. Homeostasis, allostasis
Claude Bernard: The constancy of the internal environment (milieu intérieur) is (would be) the most important
Homeostasis (Cannon, 1926): The constancy of the milieu intérieur could be preserved by homeostasis
Péter Bálint (1965): The concept of mil. int. can include the intracellular space The constancy of mil. int. is impossible (aging)b
Starling and Eyer (1988): It is not the constancy of milieu intérieur but rather (allostasis)* its stabilty, which is important
McEwen (allostatic load, 1993) Even the stability of m. i. cannot be preserved for the long run. In this way diseases will develop after a continous load
*N.B.: Homeostatic regulation works well for the wild animals, but not for civilized people!
Homeostasis vs. Allostasis
The stress means a load on the organism and on the cells of the body, which causes changes in the "milieu intérieur."
But exactly what is the "milieu intérieur„?
The milieu intérieur was coined by Claude Bernard ( ); it means the internal environment of the life (living cells). The solution contains soluble particles.
My former professor of physiology Peter Balint declared several things in this regard:
1. We can interpret the thesis of C. Bernard as “If the milieu intérieur would not change, we could stay healthy forever.” (Namely, the changes of the milieu intérieur and diseases are inseparable.)
2. The intracellular spaces belong to interior milieu; if C. Bernard were alive, he would agree because its constancy is at least as important as that of extracellular space.
3. However, in the long run, the unchanged interior milieu cannot be maintained. If it could be preserved, we would be assured of eternal life.
Professor Bálint thus was far ahead of his time.
Cannon created the concept of homeostasis. According to him, the organism (neuroendocrine system) is capable of preserving and restoring the internal environment.
Eyer and Starling created the concept of allostasis. They previously found that homeostasis does not work in the case of humans. Therefore, it not so much the constancy of the internal milieu, rather its stability, that is important.
McEwen went even further: he firmly declared that even the stability of the milieu intérieur cannot be preserved. The stress load leads to harm and diseases in the long run.

13. The Handicapped Psychosocial State as a Risk Factor for Psychosomatic (Civilized) Diseases
McEwen and Stellar Proved statistically that the handicapped social state leads to a more serious appearance of psychosomatic diseases and will lead to early mortality. There are several dozen of psychosocial lectures published on this topic. They studied occupational stress, mental health, the role of personality, housing instability, social isolation, and quality of sleep. Several psychic mechanisms can play a role in pathomechanism, e.g. the feeling of being humiliated, hopelessness or insecurity. (It is proven that fear and inhibited anger together can lead to somatic diseases.) What is the exact pathomechanism?
McEwen and Stellar (and many others after them) statistically proved that the presence of handicapped psychosocial status results in the earlier more severe onset of psychosomatic (civilized) diseases and leads to more premature mortality than in the control group.
Both real and imagined grievances can play a role which are mentally poorly tolerated. Feelings of superfluousness, uselessness, or humiliation also may play a role. (Eg. Less educated humans die significantly earlier than more educated.)
If I could highlight only one of the psychological factors, I would mention inhibited anger. It has been proven for 75 years that it can cause breath holding (hypercapnia) and hypertension.
However, McEwen did not give the mechanism of the cascade of events. A quotation: ”One of the problems with the original conceptualization of allostatic load and its measurement is that the components were not organized and categorized with regard to what each measure represents in the cascade of events that lead from allostasis to allostatic load. …….. Allostasis and allostatic load are concepts that are mechanistically based and only as good as the information about mechanisms that lead to disease.” (McEwen, BS: Allostasis and Allostatic Load Implications for Neuropsychopharmacology 2000; 22: ).

14. Most Diseases of Civilization Have a Psychosomatic Origin and are Caused by Psychological Stress
How can the abstract spiritual become a somatic substance? The answer is surprisingly simple:
1. Most psychical processes change the breathing pattern: Speed up, slow down, or make it irregular.
2. The alterations of carbon dioxide tension recoil the function of neurons; alterations also act on somatic cells and can harm them during an extended period.
3. That is: the carbon dioxide is an important link between psyche and corpus. According to the hypothesis, the diseases of civilizations are mainly caused by lack or surplus of carbon dioxide. (See: Sikter, A., Faludi G., Rihmer Z.: The role of carbon dioxide (and intracellular pH) in the pathomechanism of several mental disorders. Are the diseases of civilization caused by learnt behaviour, not the stress itself? Neuropsychopharmacol Hung. 2009; 11 : )
An important and fascinating question is: How does a psychic entity become a somatic thing — an emotion into a material?

15. Stress = the alteration of milieu intérieur
Allostasis = the stabilization of milieu intérieur ( pH)
Our goal: restoration of the milieu intérieur – as it is possible: RESTITUTIO ad INTEGRUM.
We can simplify the essence of stress, namely that stress is everything that changes the internal environment of the cells (the "milieu intérieur"). According to the recently favored allostasis, it is sufficient if the internal environment is stable or stabilized. The stabilization can often be achieved by normalizing the pH. According to this theory, the pCO2 could remain persistently on an abnormal level.
I think that the target is: the perfect restoration of the interior milieu (accepting that this is not always possible).
Our goal is to achieve homeostasis as it was thought of by Cannon. It seems it happens automatically in the case of wild animals, while we should provide help for humans (to restore interior milieu after stress). .

16. (Metabolic Remodeling!)
Why is the Constancy of the Milieu Intérieur Important?
The alterations of the IC ion-concentrations (being coenzymes) activate or inhibit proper enzymes of cells as activators or inhibitors.
The changes of ionic modifications increase many biochemical reactions while others decrease them – the network effect multiplies. (It is very explicit in the case of pH alterations : the alkalosis usually accelerates while acidosis decelerates biochemical reactions.)
The ions influence concentration and function of each other in a manifold way; e. g. hormones and regulators try to restore the original conditions. Significant (and chronic) changes of any ion can affect an organism in an unforeseeable way, and can generate diseases.
(Metabolic Remodeling!)
I could talk about this issue for at least an hour.
The most significant activity of the intracellular ions (if there is a priority in this case at all because all of them are indispensable and irreplaceable) is the coenzyme function. Changing the concentrations of IC ions will activate or hinder the work of various enzymes in the cytoplasm.
The biochemical processes form reaction lines. The plurality of alterations — and the arrangement of enzymes in a network — can multiply the effects of both positive and negative directions, resulting in metabolic remodeling.
Ions can affect the concentrations of each other with many mechanisms (due to humoral counter-regulation, the energetic status, genetic causes, etc.) These modify ion patterns of some cells so much that we cannot predict the consequences caused by a single ion (e.g. bicarbonate induced by decrease or increase of pCO2).
It is probable that there is a real chance of developing diseases because of the consequential metabolic remodeling.

17. The Intracellular Ions (as Second Messengers) Transmit the Effects of Hormones and Regulators
The role of Ca++ as second messenger is already generally accepted.
Mg++ as an Intracellular Messenger. (Romani et Scarpa: Frontiers in Bioscience, 2000; 5: d ,)
The Chloride Anion Acts as a Second Messenger… (Valdivieso et al.: Cell Physiol Biochem 2016; )
Zinc is a novel intracellular second messenger (Yamashaki et al. J. Cell Biol ; 177: )
Is hydrogen ion the real second messenger in calcium signaling? (Molinari G.: Cell Signal ; 27:1392-7)
Conclusion: The intracellular ion-pattern (as a whole) has a second messenger role.
It was raised the second messenger role of almost all of the physiological ions, so likely the whole of the cytoplasmic ion-pattern has second messenger function.
Most hormones also have a role in affecting the intracellular ionic milieu; in this way the ions as second messengers could mediate the metabolic effects of the hormone on the cells. (Because the ions as coenzymes regulate enzymes of cells.)
Does the above-written theory have possibilities? I think it does. Can be it evidenced? I think it has a good chance. However, I am sure elite researchers would speak about it and confute it. (If it has realistic elements, why was there not a dispute about it?)

18. Chronic stress often leads to chronic hypo- or hypercapnia
Chronic stress often leads to chronic hypo- or hypercapnia. The metabolic compensation of respiratory pH alterations will change the HCO3- concentration identically in the EC and IC spaces, which is unacceptable for the long run, as
the Compensation can Lead to the Fixation of Pathological State and Diseases of Civilization!
The Second Thesis.

19. It is said: "The devil is in the details
It is said: "The devil is in the details!" Unfortunately, I do not know how to present the details, but if I knew, there would be hardly anybody in the room who would hear it out.
The network of cellular enzymes of human cells is orders of magnitude bigger than you can see on this slide. It has four digits.
Everything affects everything — more or less. As is apparent from the previous reasoning, the H + ion (or lack of it!) is probably the most potent second messenger in the cytoplasm: and the major part of regulation as well acts against its alterations.
Acidosis slows down most processes while alkalosis accelerates them. Carbon dioxide, in turn, transmits (or carries away) H+ ion to everywhere (and from everywhere) instantly. (Carbon dioxide plus water = carbonic acid).
What kind of genome ("hardware") does anybody have? The metabolic pathways will be multiplied or faded according to this.
Hidden genetic defects could manifest after altering of interior ionic milieu (the "software" according to my theory), which would not be a mistake if the "software" had not changed!
The network of the cellular enzymes can raise the multiplication of particular metabolic after routes. Meanwhile, other metabolic processes shorten through the alterations of intracellular milieu intérieur – The hidden genetical failures manifest themselves!
(The network on the picture is the only illustration.)

20. Handerson-Hasselbalch Equation
Carbonic acid converts to CO2 in water, so its changes involve the alteration of pH and HCO3-. The change in CO2 level leads such ionic alterations (H+ and HCO3-), which cannot be restored metabolically — except pH (clinicians name this procedure to ”compensation”).
It takes several days for the "compensation" to occur in the serum — the level of bicarbonate stabilizes.
The changing of the bicarbonate level also stabilizes the pathological state, which is good in the short-term, but it can lead to diseases of civilization due to a ripple effect, in the long run, in my opinion.
The organism stabilizes not only the metabolism (with compensation), but also the failure. The stabilization means that hypercapnia or hypocapnia becomes habitual (chronic).
Handerson-Hasselbalch Equation

21. Acid Etruders and Acid Loaders
ANG II
The slide shows the known H+ pumps (transporters). Their tasks are to restore the original pH of the cell or — as a part of second messenger system to act on "superior orders” — to change pH and consequently metabolism to another direction.
Many regulators and hormones use H+ ion pumps situated in cell membranes — that is ion pumps operate as receptors for the humoral regulators and hormones (for example the catecholamines, angiotensin II, leptin, IL-1, IL-6).
Ang II enters twice as much sodium into the cytosol during alkalization as the other similar pumps. Excess sodium increases the influx of Ca++, it will result in smooth muscle hypertrophy of the precapillary arterioles and myocardium, which leads to hypertension.
In other words, it is not all the same which ion pump alkalizes cytosol.
Boron, W. F. Advan. Physiol. Edu. 28: ;
doi: /advan
Copyright ©2004 American Physiological Society

22. Dysregulation will develop because of ripple effect.
Types of Cells and Tissues
Compensatory mechanisms
kidneys
buffers
Growth factors Cytokines
(24 groups!)
IL-1, IL-6, leptin
ANG II
CATECHOL
pCO2
Hormones
HPA
Autonomic
Nervous System
Let us start with Claude Bernard: the cell works correctly (according to its task) when the ions are everywhere in their 'original' places.
The organism tries to restore concentrations of H+ with a huge apparatus — given that the IC alkalosis accelerates dramatically (but not steadily), by contrast, the acidosis significantly slows down the metabolism of cells.
The CO2 gets to everywhere* steadily in no time (or it is removed just as quickly), and it changes the internal milieu everywhere. First, the concentration of carbonic acid increases or decreases (and concentration of the H+ alters to similar direction, too.)
A surprising number of hormones (regulators, cytokines, growth factors, etc. — signified by red) connect to the various H + ion pumps and presumably most of them "strive" to restore the changed IC pH. (Or also maybe they "want to give a new direction" to the metabolism?)
Even assuming the 'favor' of the regulators, is it believable that the highly fragmented counter-regulation (lots of hormones, cytokines, growth factors, etc.) could accurately restore alterations created by the changes of pCO2? Hardly! **
Above all, the regulation of an organism tries to restore the pH, but it cannot succeed. There will be over-regulated tissues, while others would be under-regulated. Namely, a DYSREGULATION occurs.
I am most surprised at the involvement of cytokines (IL-1, IL-6) in the regulation of IC pH. Now we can understand the relationship between stress and inflammation as well.
In short: The left side of the figure is not the mirror image of the right side, so we cannot expect the restoration of the "milieu intérieur" everywhere.
* There is a little difference in the pCO2 between the arterial and venous end of the capillaries and tissues.
** A. The hormones and regulators do not affect all of the tissues and cells, at least not to the same extent.
B. The regulation is highly fragmented ("the child is lost among many midwives')
C. The different H+ ion-pumps often have different secondary and tertiary effects on the ion composition of cells (see: ANG II)
D. The diffusion of the carbon dioxide is very fast, while transmembrane- transport with ion pumps can only follow it after several hours. The alteration of pCO2 in the tissues interferes with the pH level changes produced by the humoral regulation.
E. There is no humoral regulator, which could restore the original pCO2 level. Without this, it is impossible to restore the milieu intérieur. The levels of bicarbonate and/or H+ surely will change; this is going to trigger tertiary, quaternary changes.
Ion-pumps of Cells
(without outer
regulators)
Dysregulation will develop because of ripple effect.

23. SAPOLSKY: WHY ZEBRAS DON'T GET ULCERS? (1994)
Homo sapiens, 1758
Carl von Linné
vs.
SAPOLSKY: WHY ZEBRAS DON'T GET ULCERS? (1994)
Carl von Linné created the name "Homo sapiens" in He died after two strokes, a disease of civilization, in 1778.
By contrast, Sapolsky's bestseller book suggests, “zebras never get diseases of civilization” (except if they perform in a circus.)
Linné died after two strokes -- a disease of civilization – in By contrast, animals living in nature never get diseases of civilization, e.g. ulcers.
What could be the explanation?

24. My answer is surprisingly simple, if we look at what are the fundamental physiological, pathological differences between healthy zebras and people threatened by civilized-disease: The Blood Gas.
The pCO2 level varies momentarily, so we should compare the levels of bicarbonate and base excess (which resulted from the average of pCO2 over several days).
On this basis, it can be assumed that half of the human population (if we look more strictly, 2/3 of the population) is abnormal physiologically (It differs basically from zebras or other wild mammals).
I highlight the change in carbon dioxide because it is the only known material response, which affects the "milieu intérieur" during stress. I am convinced that the harm of stress (the distress) can be deduced from this.
A note: So far, I have found few data on the prevalence of chronic (non-COPD) hypercapnia: (including the cases of OSA, syndrome of hypercapnia + obesity, etc.).
So far it seems that the prevalence of chr. hypercapnia is similar to that of chr. hypocapnia, but the difference in pCO2 from the normal level is less in the case of hypercapnia.
It is possible that we should modify the hypothesis in above: namely that chronic hypercapnia + metabolic origin of acidosis together cause these diseases (through intracellular acidification). (see below).
Base Excess
Distribution of Blood-gas Parameters in the Population of Homo Sapiens vs. Zebras. (Hypothetic Figure.)

25. Parati, G. et al.: Journal of Physiology 2007; 293:R1671-R1683
Obstructive sleep apnea (OSA) is the largest segment of chr. hypercapnic population. OSA is proven to be a hypercapnic disorder, though the hypercapnia is often interrupted by acute hypocapnic and then followed by apneic periods.
It is evident that OSA is a hypercapnic disorder because of elevated serum bicarbonáte and positive base excess.
(The old name for the lite form of OSA is ”habitual snorers.” The figure was originally published: Lugaresi E, Cirignotta F, Coccagna G, Piana C. Some epidemiological data on snoring and cardiocirculatory disturbances. Sleep 3: 221– 224, 1980.)
We can see that the prevalence of habitual snorers is nearly 20%!
Parati, G. et al.: Journal of Physiology 2007; 293:R1671-R1683

26. Distribution of Chronic Hypocapnia in Sex and Age (Hypothetic Figure of Lecturer).
men
Wo-men ?
I tried to reconstruct the prevalence of chronic hypocapnia, which can be the most common blood gas disorder, on the base of the literature.
Some authors state that its prevalence can exceed 15% of the population.
I did not find data from childhood. The majority of hyperventilators are young and female. (The latter is primarily a consequence of the effects of progesterone.)
When we compare this to the previous figure, we can conclude that most of the patients changed their breathing pattern around years-old: The most "hot-headed" youngster gradually becomes a paunchy (and snoring) middle-aged man.
I note that hypocapnia is not always a harmless phenomenon!
In severe organic diseases (cardiovascular, respiratory, cerebral, etc.) — when hypoxia also develops — often the hyperventilation-induced vicious cycles bring the end of life. (This is why the prevalence of the hypocapnia increases again at the end of the life!)
age

27. Lindberg, E. et al: Respiratory Medicine 2007;101:1283-90
Age:44+-17,2y, women
4,3%
16,9%
11,5%
63,3%
This figure presents a Swedish questionnaire study. Surprising data: 36,7% is the prevalence of the diseases among middle-aged women which can go together with hypercapnia. (The incidence of hypertension and diabetes increased as well.)
Fig.3. Prevalence of Hypertension and Diabetes by Symptom Group.
EDS=Excessive Daytime Sleepiness

28. Comorbidity of Diseases with Chronic Hypercapnia
The prevalence of hypertension (68%), diabetes (53%) cardiovasc. disorders (29%) is 2-3 times higher in COPD than in control group. (Siva and Gayathri: IJSR, 2013).
Comorbidity is similar in OSA. Prevalence of hypertension is (36,5%, 46%, 53,6% vs. 22,8%). ( Philips and O’Driscoll: Nature and Science of Sleep 2013; 5:43-52.)
Hypertension is often severe and drug-resistant in OSA. (CPAP!)
Excessive Daytime Sleepiness also has a hypercapnic background. It develops frequently. (Measuring of serum HCO3- is useful!)
1. Alteration of hyper- and hypocapnic periods causes definitive sympathicotonia. Levels of angiotensin II (13,3 vs. 7,8pmol/L), aldosterone (94 vs. 62pmol/L) are significantly increased. (Moller et al: Am. J. Hypertens. 2003; 16: )
2. It is probable that the effect of hypercapnic periods is irreversible and accumulative. (According to several researchers.)
Surprisingly high is the coincidence of diseases of metabolic syndrome X with COPD, which is a known hypercapnic disease. (This is not a usual topic of lecture.)
But it is known that many diseases (including the previous as well) occur with high coincidence in OSA.
Rather, there are discussions regarding the pathomechanism, e.g. that the hypercapnia or hypoxia could cause the complications of the two together.
It is a fact that the odds ratio (OR) is elevated (2,29) even in mild OSA (now: „SDB”=Sleep Disordered Breathing), which is an effect of the pathogenic role of hypercapnia. (There is no or minimal hypoxia in this case.) The OR was 6.85 in moderate to severe OSA.
It is also well known that drug-resistant hypertension, responding only to CPAP, is not rare either.
Little is spoken about excessive daytime sleepiness), which frequently occurs also without OSA.
It is likely that its pathogenesis is also linked partly to the intermittent hypercapnia, partly to hypertension and T2DM (Type 2 diabetes mellitus).
Presumably, that hypercapnia is only intermittent in this case, so we should pay attention to bicarbonate and base excess instead of pCO2 measurements.
In the case of hypercapnia, the regulation (level of angiotensin II) presumably overcompensates the IC acidosis (at least in the smooth muscle cells of precapillary arteriola: in the VSMCs). Perhaps this would be the most important cause of hypertension; but other factors, the rise of aldosterone level and Na-sensitivity, also can play a role.
The humoral regulation can follow the changes of pCO2 with a delay, so the alkalosis-caused decrease of the pCO2 level after waking up is added to alkalosis induced by counter-regulation (ANG II) in VSMCs. This could be a reason for spikes of hypertension in the early morning! (The lecturer's hypothesis)
According to several authors, the effects of hypercapnia on the blood vessels are imperishable and cumulative over time.
A note: The prevalence of hypercapnia is underestimated, this is partly because of the unreliability of pCO2 measurement (i.e., its high degree of volatility), partly because the normal parameters of pCO2 (35-45 mmHg) are too wide.

29. D. E. Anderson is a Pioneer on the Topic of Behavior- Hypercapnia-Hypertension
One of the earlier papers of David E. Anderson Ph.D. (University of California, San Francisco) was published in the Handbook of Hypertension, 9. chapter: Behavioral factors in hypertension, in (Elsevier- New York)
His main research project is the relationships of hypertension, behavior and hypercapnia, (His team published nearly 100 articles on this topic.)
One of his recently published works is a book chapter: D. E. Anderson et M. A. Chesney: Inhibited Breathing and Salt-Sensitive Hypertension in Women Jan. Springer book.
David E. Anderson works at the San Francisco campus of University of California. His main research area for 30 years is the relationship between hypercapnia and hypertension. He is also interested in the role of behavior in this topic. He and his group have significant results, although they are still far away from deciphering the exact pathomechanism of primary hypertension.

30. Metabolic Syndrome X (hypertension, T2DM, cardiovascular disorders).
Diseases Connected to Chronic Hypercapnia and/or Intracellular Acidosis
Metabolic Syndrome X (hypertension, T2DM, cardiovascular disorders).
+ Obstructive Sleep Apnea Syndrome (Metabolic Syndrome Z)
Depression
GERD and ulcer
etc…….
(There is a broad range of diseases of civilization connected to hypercapnia and the freeze response — a much wider range than we can see on the slide.)
As I mentioned above, the hypothesis should refine. According to the literature and logical arguments, acidosis plays a highlighted role in the pathomechanism of the organic diseases of civilization (approximately in cases of metabolic syndrome X).The intracellular metabolic acidosis and organic acids (the anion gap increased, due to lactic acid, pyruvic acid, etc.) also can play a role.
I do not want to go into the exact details. It's a biological manifestation of the Second Law of Thermodynamics (see above: pathogenic mechanism of sick cell theory) — humoral dysregulation also occurs. (The pyruvic acid and lactic acid are able to be formed only under alkaline intracellular ionic milieu; there is not acidosis in all tissues, but the ripple effect was initiated by acidosis.)
Literature:
1. Souto G, Donapetry C, Calvono J et al. Metabolic Acidosis-Induced Insulin Resistance and Cardiovascular Risk. Review. Metab Syndr Relat Disord 2011; 9:
2. Taylor EN, Forman JP, Farwell WR: Serum Anion Gap and Blood Pressure in the national Health and Nutrition Examination Survey. Hypertension. 2007; 50:

31. The chronic hypocapnia (caused by stress)
results in mainly sympathicotonia (”hyperarousal”) and functional disorders; the diseases (having plenty of symptoms) remain reversible for a long time.
The chronic hypercapnia (caused by stress) results in mainly para sympathicotonia (”hypo-arousal”), which has few symptoms and signs for a long time. There are already irreversible changes in health when first symptoms appear, the diseases are already developed.
Actually – due to the imperfect regulation – DYSREGULATION, DYSTONIA and DYSFUNCTION will develop in both cases!
The Third Thesis

32. Professional capno-trainers (capnograph) have been available on the market for more than ten years. They can measure reliably the partial pressure of carbon dioxide of the exhaled air in the normal and hypocapnic region.
A professional capnograph, which can measure the carbon dioxide pressure of the exhaled air on a real-time way.

33. A friend of mine, Roberto, has dealt with chronically hyperventilating clients for more than ten years.
He has managed hundreds of clients (whose doctors did not find organic diseases). We can say they suffered from functional disorders. Roberto’s breathing training has about 90% effectiveness.
His clients learn to correct ventilation during an average of one to two months. That means that their carbon dioxide tension in exhaled air becomes normocapnic (pCO2= 38-42mmHg), their breathing becomes slower (5-10/min) and more regular. (We can say that an euventilation develops or restores) — and it is associated with healing and relief of complaints in every normocapnic case. I will present two cases of Roberto’s.
Roberto de Guevara, OTR, MS, Breathing Therapist, Colorado Springs, USA

34. Case Study 1 Jennifer’s story (with permission)
28 year-old physical therapist,
wife, mother of two-year daughter.
Teeth clenching, jaw pain
Migraines, tension headaches
Digestive problems
Chronic fatigue- severe
Muscle weakness
Panic attacks- severe
Aggression when driving
Difficulty relaxing
Mood swings, depression
Muscle tension- neck, shoulders
Avoidance behaviors
Exercise intolerance
Jennifer was suffering from almost all symptoms of anxiety, e.g. teeth clenching, headaches, panic attacks. She became symptomless after capnotraining.
Copyright © 2014 Respiras. All Rights Reserved.

35. Jennifer: Correcting Breathing Patterns and CO2
BEFORE
AFTER
AFTER
Jennifer was breathing frequently and very irregularly; the capnograph detected 30mmHg of CO2 partial pressure in the exhaled air, the respiratory frequency was 23/min. At the end of the breathing training, the pCO2 level was 43 mmHg, the breathing frequency 5/min! It is noteworthy that the narrowed heart rate variability (HRV) became normal by the end of the treatment.
“End tidal pCO2 refers to the peak concentration of CO2 in a single breath of air at the end of expiration; it
provides a close estimate of arterial pCO2.” (Schleifer et al., 2002).
Copyright © 2014 Respiras. All Rights Reserved.

36. Copyright © 2014 Respiras. All Rights Reserved.
Helping patients with skills: “I was able to go on a helicopter ride with my husband on Valentine’s Day There is no bathroom in a helicopter ” I have no migraines and zero anxiety!
The most important thing is that Jennifer has become completely symptom-free and a happy, healthy wife and mother.
Copyright © 2014 Respiras. All Rights Reserved.

37. Raef, 9 years old: A student in question
Raef, 9 years old: A student in question? Or should we first question first his physiology?
Fatigue- severe
Mouth breathing
Teeth clenching
Concentration problems
Poor emotional regulation
Lack of initiative (called “lazy”)
Irritability, anger
ADHD* school pushing for dx
Poor grades in school
Unable to exercise, tends to avoid physical activity
The next case of Roberto's demonstrates that chr. hyperventilation and hyperventilation syndrome also exists in childhood and can harm children.
(The prevalence of ADHD (Attention Deficiency / Hyperactivity Disorder syndrome is estimated to be from 4-12% among 6-12 year-olds!)
The etiopathogenesis of ADHD is not entirely understood. Roberto's case proves that chr. hypocapnia certainly plays a role!
Raef had some serious emotional and functional physical complaints. Leading symptoms were the attention deficiency and inactivity.

38. Raef: restoring breathing patterns and CO2
Raef: restoring breathing patterns and CO Learning skills for self-regulation CO2 target is 40 mm Hg
BEFORE
AFTER
A terrible looking captogram. Raef became nearly symptom-free after two weeks of breathing training and he healed quickly.

39. Case study : Raef, Portrait Of An Achiever
“Homework Super Star” of the week Award
“Student of the Month” Award
“Principal’s Award” Winner
G.P.A in 2011
Became Football Team Captain, 2011
Memorial Steelers
Current Model student, athlete, son,
brother and friend.
Colorado Springs, CO
After breathing training, Raef performed correctly both mentally and physically. He was last and became first even in that year of class.
We have to note that Raef did not undergo any other treatment (e. g. psychotherapy). If nothing else, Raef's case history is why it was worth to keep this lecture.
PS. Mens sana in corpora sano.
With permission from the Brown Family

40. Zoltán Szilvássy-Barna Peitl Wrote in their Hungarian Patent Application (P1100545 on 29/09/2011.)
”In summary, it was established that VITION applied as adjuvant therapy was beneficial in the treatment of diabetes requiring insulin therapy. Administration of VITION had positive impact on both diabetes and the disorders caused by insulin therapy.”
”Surprisingly, it has been found that applying a composition containing the Mg2+ ions (VITION), its effect was not manifested only in the enhancing insulin sensitivity, but it also significantly decreased the cardiovascular side effects of rosiglitazone.”
At the beginning of the lecture, I mentioned that the theory of "sick cell syndrome" modified by me is suitable for modeling of cell function and diseases as well.
Well, the VITION capsule is an OTC medication which contains four electrolytes. It is produced according to my invention in Hungary.
I planned the composition of the medication at the desk; the clinical experience confirmed the theoretical considerations.
I deduced and wrote that I think the electrolyte composition can be preventive medicine or adjuvant treatment of diabetes mellitus. It may even decrease the side effects of certain drugs. I published this in Cardiologia Hungarica (a Hungarian cardiological journal) in 2007.
Well, both of my statements are confirmed by these researchers in experimental animals. (Their experiments were published in 2011 as a Hungarian Patent Application).

41. If we succeed in restoring the pCO2 levels of extra- and intracellular spaces (through capnotraining) we have a good chance of restoring intracellular and extracellular ionic milieu, too. And vice versa: The restoration of ionic deficiency of the somatic cells involves the normalization of pCO2 level, too.
Targeted electrolyte therapy can be as effective against the ravages of stress as targeted capnotraining.
The Fourth Thesis. ( The thesis of RESETTING.)
I have dealt with targeted electrolyte therapy, which means complex salt treatment, for 40 years.
Its advantage is that the treatment requires less equipment and therapists than capnotraining.
However, this project does need some equipment, as we have to check the original status and the alterations.
A further advantage of the electrolyte therapy is its low cost and wide usability. I presume there will be a useful salt combination compiled not only in chronic hyperventilation but also in the cases of hypoventilation (e.g. OSA).(I would work on this project if had possibilities.)

42. Thank you for your attention!