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These physiological processes
battling fatigue, as enumerated, are such that the sudden expenditure
of a large part of the potential energy of the muscle, by the conversion
of glycogen to lactic acid, does not mean a permanent loss of glycogen
capital. This is so because one-fifth of the lactic acid produced
is subsequently, completely combusted. Paradoxically, this re-yields
energy which is sufficient to convert four-fifths of the lactic
acid produced back to glycogen. The grade of muscle effort which
an individual can endure before reaching his fatigue point is governed
by his capacity for absorbing oxygen and discharging carbon dioxide
during respiration. Each of us is absorbing some 200cc to 300cc
of oxygen per minute. If we should suddenly start to run for a
bus, or climb several flights of stairs, the amount of oxygen required
might rise to 2,000cc to 3,000 cc and even 4,000cc. One liter of
oxygen will remove seven grams of lactic acid. The individual who
can absorb four liters of oxygen per minute can endure the production
of 28 grams of lactic acid per minute by his muscular effort. This
tells us that our ventilating system must be in grade A condition.
Anything such as smoking, or even chronic sinusitis will have a
detrimental effect on neurological diseases, and supportive treatment
along these lines must also be entertained if success is the desired
end point.
Mental Fatigue
There are other types of fatigue
besetting humans. Mental fatigue can best be considered in the
light of active
and passive. Passive mental fatigue
represents that type of medical syndrome which includes such symptoms and
signs as "brain lag," sensations of pressure in the head, poor
memory, loss of power of concentration, irritability of temper, increased
reflexes, insomnia, anorexia and a general variety of aches and pains – the
classical syndrome of neurasthenia. Active mental fatigue is elicited by
continuous work, and is proportional to the duration and difficulty of the
task performed. The effects are manifested by lessening in feeling, in tone,
in output and in organic change. The organic change is small compared to
that from equivalent periods of heavy muscular work. Most of this change
can be attributed to the sensory-motor rather than to the neural element
of the mental work. Mental performance is never perfectly continuous, but
is alternated with pauses which become longer and more frequent in proportion
to the length and difficulty of the task. Mental effects are accumulative
in that they are transferable from one task to another in proportion to the
tasks' similarity. Total sleep during a day off is not necessary, since
the primary area of this phase of fatigue is the synapses which beg only
diversion of interest and activity – something foreign to one's
usual occupation. In this manner, the fatigued synapses can rest while others
are busy.
Chemical Fatigue
Chemical fatigue represents one
of the major groups of internal medicine. Passive chemical fatigue
represents that group which
makes itself known through body
lassitude following the administration of a chemical compound. This group
of compounds is represented by the soporific drugs, the analgesics, the many
tranquilizers, and those which lower blood pressure. One must guard against
seemingly harmless chemicals. Sodium bicarbonate, for example, is capable
of rendering hemoglobin less capable of normal oxygen surrender to tissues.
Sodium bicarbonate can take up as much as 70% of the available oxygen. The
immediate result of this anoxia is weakness, even collapse; the remote effect
is tissue breakdown. Sodium bicarbonate can mimic the action of carbon monoxide.
This gas, as you know, combines with reduced hemoglobin, displacing oxygen
from oxyhemoglobin to form the specific compound carboxy-hemoglobin. Proper
doses of ascorbic acid will prevent or relieve this syndrome. It is good
to remember that monoxide poisoning can exist from many sources other than
auto exhausts. Smoke poisoning from fires is nothing other than monoxide
poisoning, and carboxy-hemoglobin blood levels up to 7% have been reported
in cigarette smokers. This can be serious, especially in a patient with a
neurological pathology. Patients with Myasthenia Gravis and Multiple Sclerosis
will not make progress if they use tobacco. There are other reasons against
the use of tobacco. The hypoxic effect of carbon monoxide may act in a synergistic
manner with other factors operative in ischemic heart disease, outstripping
the limited coronary reserve and augmenting the production of stress-induced
myocardial ischemia. (I need not remind you that adequate ascorbic acid intake
will also "handle" this situation.)
Active chemical fatigue represents that type of exhaustion which results from
the breakdown or inability to handle the normal physiological processes in
the body. A classical example of this is Myasthenia Gravis. Before the advent
of Prostigmin, Mestinon and Mytelase, all those who have had this disease have
died unless favored with spontaneous remission and one special type of treatment
which will be outlined later. The physostigmine class of drugs inhibit the
action of cholinesterase. They also have a direct effect on muscle fibers,
on neurons and on ganglion cells of the central nervous system, much like jumper
cables on an automobile, or like a cardiac pacemaker. Their action is limited.
Although the etiology differs markedly, Multiple Sclerosis is also the end
result of an active chemical problem.
Metabolic Pathways – Carbohydrate
Metabolism
From any textbook of physiology, one might read concerning the
metabolic pathways. The sequence of enzyme-mediated reactions
leading to formation of a particular
product is known as a metabolic pathway. When dealing with glucose it is
termed glycolysis. The primary function of carbohydrates in the body is to
provide a source of chemical energy. The metabolic pathway for glucose degradation
to carbon dioxide and water is divided into two parts:
1) Involves the breakdown
of glucose to pyruvic acid or lactic acid;
2) Conversion of pyruvic acid
to carbon dioxide and water in the presence of oxygen.
Whether the end product
of glycolysis is pyruvic acid or lactic acid depends upon the supply of oxygen
in the cell. When the oxygen supply is adequate, pyruvic acid is formed;
conversely an inadequate oxygen supply will lead to lactic acid formation.
These are generally referred to as aerobic and anaerobic glycolysis. Adequate
oxygen can be made available not only through a high rate of gas exchange
in the lungs, assuming that the pulmonary function tests are within normal
limits, but also by taking 10 to 30 grams ascorbic acid by mouth every 24
hours. Oxygen from vitamin C becomes available through the loss and eventual
break-up of water in the reaction of ascorbic acid to dehydroascorbic acid.
We reported this chemistry in several papers dealing with the use of massive
doses of vitamin C in Monoxide poisoning. Enzymes are also necessary in making
the glucose reactions possible. Many pathological conditions can be traced
to faulty enzyme production. This is usually due to genetic fault.
Food, regardless the kind, must be reduced to glucose if it is to be used to
produce energy. We have already implied that only glucose can undergo glycolysis,
which produces as one type end point, pyruvic acid. Pyruvic acid is a critical
agent in Multiple Sclerosis, because it is the starting component of the Krebs
Cycle. Each step in glycolysis, that is, the change in chemical structure occurring
along the pathway to pyruvic acid from one molecule to the next is relatively
small, but the total sequence of reactions alters the structure of glucose
dramatically. Bio-chemists record that in the first glucose reaction, one of
19, the phosphate from adenosine-5-triphosphate (ATP) is transferred to glucose
to form glucose-6-phosphate. In the third reaction a second molecule of adenosine-5-triphosphate
(ATP) is used in the transfer of phosphate to fructose-phosphate. Two molecules
of ATP, the key power source for life, being utilized in getting to fructose
1, 6-diphosphate, but eventually four molecules of ATP are formed resulting
in a net gain for the cell of two Adenosine-5-triphosphate molecules. During
glycolysis reaction number six, additional ATP molecules are synthesized from
or by way of the coenzyme nicotinamide adenine dinucleotide plus 2 hydrogen
atoms (NADH2) by the process of oxidative phosphorylation. This, however, cannot
occur without oxygen since in the reaction NADH2 is reduced to NAD by transfer
of the hydrogen atoms and electrons to the cytochrome system. Fortunately,
adenosine-5-triphosphate (ATP) can be synthesized by direct substrate phosphorylation
occurring during anaerobic glycolysis. Adenosine-5-triphosphate (ATP) provides
the ionized phosphate groups that trap the intermediates within the cell and
forms the intermediate structures required for the later stages of glycolysis.
It is important to recognize that all the intermediates between glucose and
pyruvic acid contain an ionized phosphate group and that ionized molecules
are generally unable to cross the lipid barrier of a cell membrane. Once glucose
has been phosphorylated, the intermediates of glycolysis are trapped within
a given cell. Glucose enters the cell through a carrier-mediated facilitated-diffusion
system. The amount of energy transferred to ATP is roughly 5% of the total
potential of glucose. Thus, 95% of the ATP synthesized from the energy released
from glucose depends upon oxygen and the oxidative phosphorylation occurring
in the mitochondria. This gives us notice concerning the importance of good
ventilation practices to maintain a high degree of vital capacity. It also
argues for high daily intake of vitamin C.
Reversible and Irreversible Reactions
Most of the reactions of the tricarboxylic
acid cycle (Krebs cycle) are reversible, but the reaction in which
pyruvic acid is converted to acetyl co-enzyme A
and carbon dioxide is irreversible. It is true that all chemical reactions
are theoretically reversible, but some are limited to the plant kingdom.
For example: Carbon dioxide and water can react to form glucose and oxygen,
reversing the reaction which led to the breakdown of glucose, but to make
it work in this reverse direction, the same amount of energy (685kcal) released
during glucose glycolysis must be returned to the molecules of carbon dioxide
and water. This actually happens, as you know, in plant cells through a process
called photosynthesis, where the energy is obtained from sunlight. Pyruvic
acid, which comes from phosphenolpyruvate, the last step in glycolysis, and
which cannot be reversed once acted upon by coenzyme A to form acetyl coenzyme
A, can be produced by direct decarboxylation of oxalacetic acid. Pyruvic
acid from this source can be phosphorylated in the presence of ATP to form
phosphopyruvate, and this can then serve as a direct precursor of the hexoses
and glycogen by the reversal of the glycolytic system. Pyruvic acid (plus
CO2), according to Ochoa, can be "shuttled" into the
Krebs cycle through malic acid when this compound is reversibly oxidized
and decarboxylated
using triphosphopyridine nucleotide (TPN) as hydrogen acceptor, and catalyzed
by malic enzyme. We mention these chemical routes for pyruvic acid since
it plays a very important part in Myasthenia Gravis. The reversibility of
the decarboxylation reactions in the Krebs cycle enhances the importance
of the mechanism of CO2 fixation by animal tissues. CO2 fixation implies
the utilization of carbon dioxide for metabolic purposes. As noted in any
text of physiological chemistry, the assimilation of CO2 by green plants
during photosynthesis leads to the formation of phosphoglyceric and phosphopyruvic
acids, and that malic acid is a subsequent product of the reaction. One can
speculate that the fundamental processes of CO2 assimilation known for plants
can also be assigned for people.
There is evidence sufficient to believe that coenzyme A, which is the physiologically
active form of pantothenic acid in animals, is in limited supply in Myasthenia
Gravis. This special enzyme is chemically situated at the gateway to the Tricarboxylic
Acid Cycle where it "intercepts" pyruvic acid at the end point
of glycolysis. The absence or reduced supply of this coenzyme is actually due
to the absence or reduced supply of cocarboxylase. When it is present, it not
only splits the carboxyl group (COOH) away from pyruvic acid to form CO2 and "free" H,
with the "H" being positively ionized, but it also bonds or joins
the remaining two carbon fragments of pyruvic acid, known as active acetate,
to form acetyl coenzyme A. This leaves the low-energy package niacin-adenosine-dinucleotide
(NAD) free to pick up two molecules of hydrogen. (At one time it was thought
that the low-energy package was diphosphopyridine nucleotide (DPN), but through
the employment of radioactive isotopes and the electron microscope, this was
proved to be in error.) One molecule from the carboxyl group of pyruvic acid,
and the second molecule from the sulfur group of coenzyme A, makes a high-energy
package with the "call letters" NADH2. One method in getting coenzyme
A from pyruvic acid, which has been established for heart tissue by Koroes
et al., is the reaction between pyruvic acid, coenzyme A, and diphosphopyridine
nucleotide (DPN or coenzyme I), in the presence of diphosphothiamine, which
is cocarboxylase. There are other important low-energy packages operative in
this system and necessary for good health. Flavin-adenosine-dinucleotide (FAD)
picks up two molecules of hydrogen to form the high-energy package FADH2 and
adenosine diphosphate (ADP). Adenosine diphosphate picks up available PO4 radicals
to form adenosine-5-triphosphate (ATP).
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