Brain Resuscitation

Brain

Resuscitation

  (A review article by Dr. RAJ KUMAR DHAUGODA FROM NEPAL-

 MBBS, MD IN FAMILY MEDICINE AND DIALECTICAL MATERIALIST)

Clinical features of Hypoxic-Ischemic Encephalopathy

·         Neonatal seizure - over stimulation of excited neurons and reciprocal membrane depolarization

·         Resp. depression, poor suck - impaired action of neurotransmitters in brain stem.

·         Coma - Metabolic disrupt of reticular activating system

·         Brain edema - Disturbed - ability to pump water at of hugely- breakdown of blood brain barriers.

Patho-physiology of Hypoxic- Ischemia Brain Injury and chemical changes

            Main 3 mechanism –

                               -Hypoxic- hypoxic (decreased O2 concentration)

                                             -Anemic hypoxia (decreased O2 delivery)

                                             -Ischemia hypoxia (decreased Blood flow)

·         Global Ischemia - results from inadequate blood flow.

E.g. during cardiac arrest.

Or sever hypoxia, severe hypotension.

·         Focal Ischemia - Results from local disruption of Blood supply e.g. ischemia / stroke, vascular anomalies.

1.Cerebral blood flow :-

Reduction of CBF 15ml / min / 100 gram (CBF) results in failure of electrical activity severity of the hypoxic - Ischemic insult is a function of both the duration and degree of CBF reduction. Delayed Hypo perfusion (which is occurred in post ischemia) is the result of brain injury rather then the cause.

2)Histological changes: -

 After prolonged global ischemia, there are seen mitochondria, endoplasmic reticulum, per neuronal & astrocytic swelling. Also develops eosinophilia & intracellular organelles becomes disrupted. The disruption of organelles is evidenced by the loss of Nissl substances, the formation of ribosomal rosettes, and swelling are reversible, DNH fragmentation is a characteristic of apoptosis, has been demonstrated after both focal and global Ischemic insult, found in CA1 region of hippocampus.

  

3.Biochemical change

During Hypoxic- Ischemic Brain injury.

 

(1)Adenosine 5 - Triphosphate Depletion (ATP).

·         ATP is needed for numerous cell metabolism, occur very early stage.

·         Most importantly needs for preservation of cell membrane ionic gradients.

·         The cause of ATP depletion is the - After hypoxia or ischemia. Oxygen is depleted and oxidative phosphorylation stops ATP depletion leads to membrane depolarization and massive Tran membrane ionic fluxes. Lock of Na+ / K+ ATPase activity leads to net influx of Na+, chloride, and calcium and net efflux of potassium.It is reversible if the Ischemic insult is of limited duration.

   

(2)Acidosis

·         During complete global ischemia, a substrate delivery to the brain is interrupted. The oxygen supply is depleted almost immediately. But glucose is available to the brain for a short time during the ischemic period via the breakdown of glycogen. Since glycogen storage in brain is small and anaerobic degradation of glucose is relatively inefficient, the energy obtained by this metabolism is not sufficient for normal brain metabolism. As glycol sis produces lactate and H+, causes tissue injuries (due to acidosis). Hence it is very danger to give glucose during ischemic & Hypoxic brain injury - more probes to produce lactate causing more acidosis. Peri ischemic hyperglycemia has been shown to result in a more pronoun ad fall in both intracellular and extra cellular brain PH during ischemia.

·         The mechanism of acidosis- Induced injury- Direct cytotoxicity, cellular swelling, oxygen- radical mediated damage, and alterations in intracellular calcium homeostasis.

·         Acidosis may promote cellular swelling by inhibition ATP production and there by reduce Na+ /K+ ATPase activity.

·         Acidosis also promotes the change of super oxide radical (O2) to more lipid soluble form (HO2*). Acidosis also promotes nitric oxide (NO) coupled production of hydroxyl radicals to form peroxynitrite.

(3)Excitatory Amino acid (NMDA receptors), (non- NMDA receptor) (AMPA )

·         NMDA (N-methyl- D- aspartate) receptor is an ionotropic (Excitatory) glutamate receptor. Glutamate is an excitatory neurotransmitter, as mediator of hypoxic- ischemic brain injury. Extra cellular glutamate level in bran is increased during ischemia, dramatically and after 30 minute of ischemia, exceeds by six fold the concentration required to kill neurons after 5-minute exposure in vitro. Glutamate receptor antagonists have been shown to ameliorate injury in animal models of focal and global ischemia, Finally glutamate receptors antagonists attenuate injury of cultured neurons when the neurons are exposed to oxygen deprivation.

·         The NMDA receptor is the most widely studied glutamate receptor. The channel gated by this receptor allows entry of sodium, potassium and calcium, and calcium accumulation via this channel is felt to be responsible for the neuro toxicity of glutamate.

·         The NMDA receptor- ion channel complex is unique in that calcium entry modulated by several factors including. Glycine, polyamines, magnesium and zinc 

·         The non- NMDA receptor (AMPA/kainate): - alpha- amino- 3- hydroxy- methyl- 4- Isoxazole- 4- pripionic acid. This channel is permeable to only monovalent cations (Na+ / K+) and relatively impermeable to calcium ion.

But in ischemic injury, the structure of this non-NMDA receptor is altered and influx of Ca++ is occurred causing more cell damage.

·         Metabotropic Glutamate receptors: - are coupled to Adenyl cyclase or phospholipase- C via G-proteins. G-proteins are membrane proteins that facilitate Trans- membrane signaling. Thus, stimulation of the Metabotropic receptor leads to increased production of diacylglyceral and inositol triphosphate (IP3) or decreased production of cyclic adenosine monophosphate (cAMP) seen subtypes of the Metabotropic glutamate receptor have been identified e.g.

·         M GluR1               stimulates phospholipase-c

·         M GluR2               inhibits adenylate cyclase

·         M GluR3               inhibits adenylate cyclase

·         M GluR4               inhibits adenylate cyclase

·         M GluR5               Stimulates Phospholipase - C

·         M GluR6               Inhibits adenylate cyclase

·         M GluR7               Inhibits adenylate cyclase

Calcium plays a pivotal role in glutamate neurotoxicity, proposed that glutamate - induced neuronal death is a three-stage process e.g.

a)    Induction

b)    Amplification and

c)     Expression

During inductions, glutamate activates a neuronal receptor activation of NMDA receptor leads to an influx of Calcium, where as activation of non-NMDA receptors leads to influx of sodium and obligatory influx of chloride and water, and also influx of Ca++. Stimulation of the Metabotropic receptors leads to increased production of IP3 and Diacylglycerol. The cellular injury cascades initiated during the induction stage can be divided into two components .

a)    Acute cellular swelling (sodium dependent) and

b)    Delayed neuronal degeneration (calcium dependent)

Amplification Results - from the damaging cascades initiated by increased concentrations of Ca++, IP3 and Diacylglycerol. Altered calcium homeostasis leads to activation of phospholipase, proteases, endonucleases, protein kinese and calmodulin - regulated enzymes e.g. Nitric oxide is an important mediator of glutamate neurotoxicity. IP3 causes release of sequestered intracellular calcium, resulting in further increase in intracellular Ca++ concentrations, and Diacylglycerol causes activation of protein kinase - C.

The expression stage - consists of actual cell destruction resulting from activations of catabolic enzyme system and oxygen radical production.

(4)Calcium metabolism: -

·         Role in the regulation of many cellular metabolic processes, and there fore, normally, the concentration of cytosol free calcium is tightly controlled.

·         In hypoxic - ischemic injury of brain, there is impaired intracellular calcium homeostasis, resulting in massive increases in the intracellular calcium concentration.

·         This intracellular calcium accumulation causes irreversible cellular injury by activating phospholipase, proteases, and endonucleases and uncoupling oxidative phosphorylation.

·         Recent works suggests that calcium play a key role in triggering nitric oxide syntheses, protein kineses, oxygen radical production and alteration in gene expression.

·         It has been exclusively demonstrated that intracellular calcium accumulation occurs during and after Ischemia. Evidence for role of calcium in the pathophysiology of ischemic injury exists in the form of numerous studies that demonstrate that pharmacological blockade of calcium entry during and after global ischemia confers protection (improves outcome).

·         Several vitro studies provide more direct evidence favoring a role for calcium accumulation in ischemic cell death. Removing calcium from the extra cellular space has been shown to decrease cellular injury in neuronal and astroglial cultures exposed to oxygen and glucose deprivation.

·         There are two major types of calcium channels located in the cell membrane of neurons:-

Receptor operated calcium channels e.g.

1.     NMDA – receptor

2.     Non-NMDA – receptor

3.     Voltage sensitive calcium channels e.g. L, N, P & T type

Long lasting (L-type) - High voltage (activation) - function is dihydropyridine sensitive. N-type - (Function - neuro transmitter release, P-type (function - neuro transmitter release), & T-type (transient) - low voltage type, rapid inactivation occurred function is as pacemaker activity.

Cerebral ischemia is accompanied by a significant decrease in extra cellular calcium concentration, which is consistent with an intracellular shift of calcium.

·         Energy failure (depletion of ATP) during cerebral ischemia results in membrane depolarization, which allows calcium influx via voltage sensitive calcium channels also and causes glutamate release. Glutamate can promote calcium influx by three different mechanisms namely

·         Via opening NMDA receptors gated calcium channel

·         Via stimulation of Non-NMDA receptors opens Na++ channels and resulting in massive influx of Na++ and subsequent membrane depolarization. These membrane depolarizations then allow calcium entry via voltage - sensitive Ca++ channels.

·         Via the ion channel gated by Non-NMDA receptors allows direct influx of calcium.

In summary, intracellular calcium accumulation is assumed to play a significant role in ischemic brain injury, and its accumulation appears to be initiated by energy failure (ATP depletion) and glutamate - mediated calcium influx.

(5) Phospholipid hydrolysis: -

·         Metabolism of membrane phospholipids is to play a key role in the pathophysiology of ischemic brain injury.

Early in the cause of ischemia, free fatty acids are released from membrane phospholipids by enzymatic hydrolysis.

Fatty acids appears to be released via two pathways –

·         Membrane phospholipid degradation by the action of phospholipase A1 and phospholipase A2

·         Degradation of phosphoinositides by the action phospholipase C, leading to production of diaglycerol, which is then, hydrolyzed by Diacylglycerol and monoacylglycerol lipases

·         Energy depletion (ATP depletion) leading to a greater rate of deacylation relative to reacylations (energy dependent) is one during ischemia. Stimulation of NMDA receptors leads to activation of phospholipase A2, this activation appears to be calcium mediated.

·         Farooqui and Colleagues - have shown that NMDA receptors stimulation also leads to activation of monoacylglycerol and diacylglycerol lipases.

·         Diacylglycerol is a substrate for further free fatty acid release and by activating protein kinase -C. IP3, mobilizes intracellular calcium and destructed to neuron cells and diacylglycerol activate protein kinas C and inhibit Na+ / K+ ATPase and promote brain edema.

In addition, release of free fatty acids at the onset ischemia provides the substrate (arachidonic acid) for production of eicosanoids and oxygen radicals during reperfusion.

(6) Eicosanoids Metabolism: -

·         A arachidonic acid released at the onset of ischemia becomes the substrate for eicosanoids production during reperfusion.

·         Products of cyclooxygenase pathway i.e. thromboxane and prostaglandin and the lipoxygenase pathway i.e. leukotriens are formed during reperfusion after ischemia. Thromboxane causes vasoconstriction and platelet aggravation and causes delayed hypo perfusion. Leukotriens also causes vasoconstriction of cerebral vessels.

·         In addition, the cyclooxygenase and lipoxygenase pathways produce super oxide radicals (oxygen radicals during reperfusion).

(7)Oxygen radicals: -

·         Oxygen radicals have been implicated in numerous disease processes, including pulmonary oxygen toxicity, carcinogenesis and perfusion injury after ischemia.

·         Indirect evidence in support of oxygen radical mediated injury after cerebral ischemia includes decreases in tissue antioxidant levels during ischemia and reperfusion, increased productions of lipid peroxides during reperfusion, improved outcome after Global and focal ischemia in animals treated with antioxidants, and reduction in infarct volume.

·         Radicals are molecules that contain at least one unpaired electron in the outer (valance) electron orbital. Some of the more common oxygen radicals include super oxide radical (O2.-), hydroxyl radical (OH.), and hydrogen peroxide (H2O2.). These molecules are very reactive and as a result very short-lived.

·         Potential mechanisms of oxygen radical production during reperfusion injury include oxidations of hypoxanthine by xanthine oxidase, and lipoxygenase pathways.

·         ATP is metabolized through a series of intermediates to hypoxanthine, the substrate for xanthene oxydase. Adenosine and hypoxanthine concentrations in brain increase dramatically within seconds after the onset of Ischemia.

·         More importantly, ischemia has been shown to induce the conversion of xanthine dehydrogenisis to xanthine oxidase, leading to significant levels of xanthine oxidase in brain. This conversion appears to be a calcium dependent process, convey vascular endothelial damage. Recent work by Phillis and Sen provides direct evidence that the xanthine oxidase pathway contributes to oxygen radical production during perfusion. They demonstrated that oxypurinol, a xanthine oxydase inhibitor, significantly decreased production of hydroxyl radical after cerebral ischemia in rats.

·         Lipid peroxidation - is an iron-dependent process in which oxygen radicals oxidative rearrange the structure of double bonds of unsaturated fatty acids of membrane phospholipids. A hydrogen atom is removed from polyunsaturated fatty acids; thus can only do by the hydroxyl radical, Alternately, this lipid peroxidation process from malandialdehyde (a lipid peroxide radical). These lipid peroxidation reactions are intensified in the presence of calcium and acidosis. Lipid peroxidation C and inhibit Na+ / k+ ATPase. Causing cellular injury during reperfusion, after cerebral ischemia.

·          

(8)Nitric Oxide: -

·         The function of nitric oxide in CNS-It is appeared to be involved in regulations of cerebral blood flow and in cell-to-cell signaling. In some neurons, nitric oxide synthesis activity is regulated by the NMDA-receptor. NMDA receptor stimulation results in calcium influx and activation of nitric oxide syntheses. Nitric oxide is produced and then diffuses to target cells and stimulates guanidine cyclase leading the production of cyclic GMP. GMP then produces the physiological effect, e.g. Vase relaxation cell signaling.

·         Nitric oxide stimulates macrophage, microghia and astrocytes in response to stimulation by cytokines, causing cytotoxicity.

·         Nitric oxide appears to be a mediator of glutamate neurotoxicity. It is postulated that NMDA receptor over stimulation leads to massive calcium influx and activation of nitric oxide syntheses. Nitric oxide produced via this mechanism contributes to the cytotoxicity of glutamate.

·         Nitric oxide is produced during both focal and global cerebral ischemia. It is detrimental to reasons if produces more hydroxyl radicals.

(9) Protein phosphorylation: -

·         Many cellular processes are regulated by protein phosphorylation.

·         The Phosphorylation State depends on the relative activities of two opposing types of enzymes - kinase and phosphates.

·         Kinesis add phosphate groups to protein where as phosphates remove phosphate groups from protein.

·         Second messengers such as calcium, diacylglycerol, and acid activate protein kinese.

·         Protein kinase regulates important neuronal functions, including ion channel activity, transmitter release, receptor function, gene expression and protein synthesis.

·         These important kinases have been shown to have changes in activity after cerebral ischemia.

                                a)    Protein kinase - C,

                                b)    Calcium - calmodulin dependent kinase - II

                                c)     Casein kinase -II

·         Activation of protein kinase - C  requires translocation from cytosol to cell membrane; this translocation is promoted by a rise in the intracellular concentration of calcium. After association with membrane phospholipids, protein kinase - C becomes fully activated in the presence of diacylglycerol.Calcium - calmodulin dependent kinase - II acting is decreased after ischemia, during ischemia its activity is increased.

(10)Protein synthesis: -

·         Protein Synthesis is essential for cell survival. Proteins are involved in nearly every process in the cell e.g., Enzymatic reactions, transport, storage, intracellular sygnalling, intracellular signaling and cytoskeletal support.

·         Hence, protein synthesis is very important for cellular recovery after hypoxic ischemic injury.Kleihues and Hoss Mann 1^st demonstrated that total protein synthesis is impaired after cerebral ischemia and reperfusion.

·         Protein synthesis requires: -

                                Energy (ATP, GTP)

                                Intact DNA

                                Functional transcription mechanism

                                Processing and transport of m RNA from the site of transcription to site of translation

                                Functional translation mechanism

·         As the concentration of ATP, GTP is rapidly decreased during ischemia, and this is adequate to explain inhibition of protein synthesis during ischemia and reperfusion.

·         Recovering of protein synthesis is correlated with cell survival.

(11)Gene expression: -

There is increased expression of C-for and C-jun has been demonstrated after global cerebral ischemia.

Increased synthesis of heat in the protective action.This HSP70 protein in the protective action

(11) Inflammation: -

Dietrich et al.were able to demonstrate polymorph nuclear leukocyte infiltration; in rat model of global ischemia. And increased level of TNF-alpha.

POTENTIAL THERAPIES( current practices of Brain resuscitation)

1.   Barbiturates: -

·         Decrease seizure

·         Decrease intracranial pressure

·         There is some evidence of giving thiopentone 120 mg / kg IV after 30 & 60 minutes of post ischemia, outcome is ameliorates of brain damage, After global ischemia in monkeys.

·         But same type of study did not show the thiopental amelioration of brain damage.

·         in summary. Barbiturates have been proposed for use after global ischemia. But it is not supposed by data obtained in animal and human.

2.   Super oxide dismustase: -

·         Dimutation reaction of super oxide radical, The capper zinc super oxide dismustase has been proposed as therapeutic agent for reperfusion injury, because of its ability to scavenge oxygen radicals.

·         Recently, a novel supervise dismustase derivative, polybutyl ester covalently linked to super oxide dismustase, has been shown to ameliorate delays hypo perfusion and improve neurological out come after global ischemia in dogs.

·         21-amino-steroids (oxygen radical scavenger) a portent inhibitor of lipid peroxidation but lack classical steroidal activities

·         to summary: it is obvious that there is no current role for oxygen radical scavenger therapy in children with brain injury. There is only preliminary evidence supporting the efficacy of this agent after a global ischemic insult.

3.   Calcium channel Antagonist:

·         The use of Calcium Channel blockers after global cerebral ischemia is considered e.g. flunarizine, lidoflazine, and nimodipine.

·         Nimodipine shows increase survival rate up to 12 months after global cerebral ischemia.

4.   Glutamate Antagonists:

E.g. dizocilpine maleate _(NMDA receptor antagonist)      

NBQX (2,3 dihydroxy –6-nitro-7-sulfamoxylbenzoquinoxaline)

(Non- NMDA receptor antagonist)

5.Nitric oxide syntheses inhibitors:

     No satisfactory out came has been reported with N-omega -nitro –L-arginine.

6.Hypothermia:

In the global ischemia, the temperature out came is that hyperthermia. (During intra and post ischemic period)

In study it is shown that intra ischemic hypothermia is protective in both focal and global cerebral ischemia

Post ischemia hypothermia is protective after global ischemia provided that it is initiated very soon after the inset of reperfusion

(Ref:  Mark c. Rogers, David G Nichols, Text book of Pediatric intensive Care, 3^rd edition, 1999, chapter 20, theories of Brain Resuscitation, by Steven E. Haun, Jeffrey R. Kirsch & Michael Dean, page 699-733).

Summary/lesson

  

1.    The approach to the patient with global Hypoxic Ischemic brain injury is a difficult task, by using above drugs separately gives the incomplete results and not fully satisfactory result.

2.    It is necessary to understand the more detailed patho- physiology of neuronal damage and recovery & its limitations, information of time, space,motion and stress factor magnitude of ischemic damage.

3.    It is necessary to ongoing research & correlation of newer knowledge for newer more effective drugs( magnesium compound) or techniques e.g. gene therapy,stem cell therapy etc.

"63 years old definition of HEALTH by WHO is wrong --DR. RK DHAUGODA "

Features of The newer Concept

of Health and Disease-

( Features of Dialectical materialistic

view of Health and D disease)

(a)  It is a original thought and research work of Dr. Raj Kumar Dhaugoda of Nepal, author of the book -RK DHAUGODA'S GENERAL THEORY OF VASCULITIS. Many people have risen to add philosophical concept in health. But no one directly said that the importance of dialectic materialism in the modern concept of health and disease so far.

(b)  Like wise; there is basically, Health is explained conventionally as isolated form, from disease.But there is nothing any isolated thing in this world, which can be purely isolated, and not associated. That means previously health is defined as complete absence of disease and complete social / mental / physical well being. This means, it is overlooked that the defense mechanism (Immune status) of human body. Which is an important part of our health, no one tries to explain the health in terms of host defense mechanism and the factors, which really governs the host defense mechanism and human physiology.

(c)   It stablizeses the influencing area of dialectical materialism is universal (which affects the scientific thoughts scientific behaviors of an individual and alters all the anti-human activities in the society, e.g. Unpeace, war between known ethnic groups, species inequity, & human crisis)

(d)  Previously, it is not taken, that the Health is an issue of social justice, hence, this newer concept of health, stresses that, the health should be an issues of social justice, it is well known that this Dialectical materialism, theory of Marx is strong guideline and principle for socialism.

(e)   Health is not an element of chance and state of complete absence of disease or stable matter. By this new concept, Health is explained by means dialectical view, that is health is a dynamic thing, in every moment there is a risk of being diseased / illness of an individual and basically depends upon Immune status of an Individual,level of stress factors ,outer stress factors and the level of understanding of Scientific thought. Dialectical thought governs to their surroundings (Social, Cultural, Economical, Educational, Psychological, Philosophical, Biological, Environmental, and scientific activities).

(f)   This scientific newer concept of health, guides to understand the pathogenesis of disease as well as to solve the unsolvable problems from previous concept of health; That means, This newer concept Integrates with every activities of human beings, thoughts and their reflections to surroundings. And finds out the key factors that governs the health of human being, fundamentally.

(g)  This newer scientific concept of health - criticizes the definition of Health given by WHO very strongly.

WHO defined the health “Health is a state of complete physical, mental and social well being and not merely absence of disease or infirmity”. And latest amplified by “Socially and economically productive life”.

When we analyze the WHO definition of Health: -

(a)        “Health is a state of Complete Physical, mental and social well-being” According to law of dialectics, there is nothing complete / absolute things and being in the state of stable”. And health is not an isolated thing, It can not be isolated from disease, According to WHO defined, to be healthy a man should be completely free from disease for a long time, (stable time). It is just opposite to reality and practice. As we know that the status of health and disease is dynamic thing, in every moment there is changing status of health relatively either toward more healthy or towards less healthy or appearance of disease.

This means health should be defined in term of relative phenomena, but not in absolute phenomena.

B.“An absence of disease or infirmity” this is a second part of WHO health definition- which means to be healthy there should be absence of disease in an individual” or that means, It is totally isolated health from disease. When there is an individual simultaneously there is occurred Health and disease Status in various quantities or ratios, the ratios between Health and disease, determines the individual health status positive or negative forms. This is the law of dialectics, e.g. from magnet you can’t isolate North pole from South Pole, It will only disappears when there is disappearance of magnetic property. It is proved that, the health and disease status of an individual can not be isolated. Even relatively healthy. The level of healthy status of an individual there is 20% risk of presence of disease at the same moment, at the same time the individual having a chance to develop a various spectrum of disease process up to death. That means, the relative optimally healthy individual is actually 80% healthy, the ratios of health & disease are 4:1. (At this stage, Healthy Status dominates the disease status), e.g. proto-oncogene. The normal body bacilli, normal hormonal and neurotransmitters of body, normal ANTISTRESS ELEMENT level. In Healthy condition these all are in physiological range. At any time, there may occur alteration of their physiological range, causing disease. That means there is presented some prodisease factor in the body by burn and even in healthy condition, still they are present in our body, and may cause disease at anytime. This new concept will prove mathematically, later on in this book.

              

By this newer scientific concept of Health (Dialectical materialistic view of Health): -

Health “As a Relative balance state of Dialectic materialistic thought in relation to idealistic thought of an individual and the relative level of intracellular ANTISTRESS FACTOR in relation to various stress factors(TNF-alpha) in the body of an individual”.

This definition is proved by mathematical equation, by practical application of this theory in our daily life and researches, and It gives generalized view, which helps in solving many problems of human beings in relation to health and human rights.

In physics the law of Newton, is replaced or super shaded by theory of relativity or Einstein’s most popular equation i.e. E=Mc2, which is applied in space and quantum mechanics and nuclear science. In same way, this newer concept of health, supper shades  the previous unscientific concept, in our society.

h) This concept helps to develop the principles of dialectical materialism in advance form itself.as historical bio-medical materialism(see in details in page__-).

I)This concept helps to maintain the health of general people of world themselves  as preventive as well as curative ways with very very low cost  and in effectve manner.

J)this concept able to bring worldwide revolution in the field of health and disease management , importance /reality/validity of dialectcal materialism principle in the field of remaining all most all branched sciences.

l) This concept works as one of the most powerful weapon to fight against idealism,unscientic or metaphysic thoughts, capitalistic monopoly in health sectors . It empowers the general oppressed people of world  gradually and makes ready to struggle against antisocial , unscientific , exploiter forces.Thus it has power of equavant to that of thusands of progressive political parties for changing the world for the oppressed people of world.

• The health and disease are opposite phenomena, are connected dynamically with another opposite phenomena i.e. stress factors(cytokines-TNF-alpha) and antistress factor of an individual.

                                            ANTISTRESS ELEMENT

                                               ↑

                                               │

                                               │

      Health ←----------------------------------------------------→Disease

                                               │

                                               │

                                               ↓

                                             TNF-alpha

• likewise day and night are opposites  related with other sets of opposite phenomena, rotation of Earth from west to east in its own axis, and sun arise from east / sets from west.

            Rotation of earth from west to east in its own axis

                                               ↑

                                               │

                                               │

      Day←---------------------------------------------------------------→Night

                                               │

                                               │

                                               ↓

                           Sun arise from east and sets from west

10. 
    

11. IMMUNITY AND STRESS FACTORS LINKED WITH HEALTH AND HUMAN DISEASES.PRODUCTIVE. MIND OF HUAMN LINKED WITH ECONOMICAL PROSPERITY. THERE BY RELAEASE FROM MOST OF HUMAN DISEASE INCLUDING PROVERTY, HUNGER SOCIAL UNPEACE.

FOR DETAILED - SEE IN THIS SLIDE PRESENTATION.

 http://www.slideshow.com/users/rajkumardhaugoda/dialectical-concept-of-health-and-disease--1373957015

creative application of MARXISM IN POLITICS , SCIENCE AND MEDICINE.---Madan bhandari, SOICHI sakata, And R.k. Dhaugoda.

SOICHI SAKATA- PHYSICIST

Dialectical Materialism and Science This materialist philosophy is the Dialectical Materialist Philosophy of Science, which the development of sciences in the last one hundred years has shown to be the only satisfactory philosophy of science, capable not only of a, description of the knowable, but also of predicting new objects and phenomena. According to Dialectical Materialism, nature exists externally and independently of our consciousness, and is projected into consciousness through our senses. According to Engles, Nature is by no means an accidental collection of objects and phenomena which are mutually separated, isolated and independent. It consists of one thing that is mutually related, dependent, restrictive and connected The all of nature from the smallest elements to the largest, has its existence, in the eternal coming into being and passing away, in ceaselesflux in unresting motion and change. The dialectical materialist view of nature described above is not one,, imposed on nature but is the one abstracted out of the latest discoveries of science till about 1870. The discoveries in sciences since then have only confirmed the above dialectical view. It has not contradicted it. Dialectical Materialism insists on the approximate, relative character of every scientific theory of the structure of matter and its properties^ it insists on the absence of absolute boundaries in nature, on the transformation of moving matter from one form into another. According to the Japanese physicist, Soichi Sakata: Current science has found that in nature there exist qualitatively different levels'?a series of levels such as elementary particles? atoms molecules?masses?heavenly bodies?nebulae. These levels form various qualitative modes of existence of matter in general.

Madan Kumar Bhandari (Nepali: मदन कुमार भण्डारी)

(June 27, 1952 )– 1993) was a Nepali politician and great communist leader of Nepal.

He used Marxism creatively in Nepali context, and applied to build a new 21^st century’s Marxism in Nepali politics-as PEOPLE’S MULTY PARTY DEMOCRACY.

Bhandari was born in Taplejung. He studied in Varanasi, India and in 1972 was named central committee member of the Janabadi Sanskritik Morcha (Democratic Cultural Front), a student's movement launched by Pushpa Lal Shrestha. Around 1976 he left Pushpa Lal's Communist Party of Nepal to launch the Mukti Morcha Samuha ("Liberation Front Group"), which formed an alliance with the survivors of the Jhapa Movement in 1978. He was a founder member of the Communist Party of Nepal (Marxist-Leninist) preceding the 1980 referendum and was elected general secretary at its fourth national in 1986.

When CPN (ML) merged into Communist Party of Nepal (Unified Marxist-Leninist) in 1991, Bhandari became the general secretary. Bhandari was the engineer behind the programme of CPN (UML), People's Multiparty Democracy, which led his party as the strongest communist party of Nepal for several years even after his death.

In 1993 Bhandari died, supposedly in a car crash without anyone as eye witness. Many believe he was murdered. Among the three passengers inside the car, only the driver Amar Lama survived and two leaders Madan Bhandari and Jeev Raj Ashrit died. The then government formed a probe committee but officially the car crash was reported as an accident without any sign of conspiracy. Possible conspiracy again came into concern after the only survivor of that crash; Driver Amar Lama was murdered after about 10 years by unknown person.

His main contribution to communist movement of world and like Nepal is that he stressed to democritization for peaceful social change , and gaining  social achievement and he used Marxism creatively to form peoples’ multi-party democracy. It’s a great theoritical achievement in communist movement of world.

The old concept of communist  movement is only basing to war with bullet, which is breaked by him , showing that the organised people of communist party can ballet peacefully rather than forcefully immature so called peoples war( the war , less involement of general people volunteerly, low level of awarness and  without feasible circumstances) .

In context of Nepal ,the 10 years MAOIST’S peoples war ( around 15000 people were killed )  is lastly converted into 19^th days successful peaceful movement of -2005-2006 ,held collaboration of various seven partieis including NEPALI CONGRASS, CPN (UML) ,CPN ( MAOIST ) and various 4 parties ( only around 25 people were killed ), which helps to establish Nepal as republic ( this is a sort of wining power of peaceful movemnts of communist parties with  collaboration of democratic forces  against  feudalistic-Monarchism .).

THE  MAOIST  PRESIDENT PRACHANDA HAS ALSO THANKED TO MADAN BHANDARI’S IDEA THAT IS PEACEFULL PEOPLES GENERALISED MOVEMENT IS MORE POWERFUL AND LEGALISED THAN ANY SORT OF  POWERFUL ARMED WAR.THIS IS ALSO A BITTER TRUTH FOR MAOIST OF NEPAL, AND THERE ARE EXERCISING  THEIR WAY TO GO  WITH EITHER COSEVATIVELY OR  IN THE WAY OF PEOPLE’S MULTIPARTY DEMOCRACY FOR LIGELISED SOCIAL CHANGE GRAGUALLY RATHER THAN FORCEFULLY.THE MAOIST OF NEPAL HAS REACHED TO ABLE TO FORM GOVERNMENT ACTUALLY DUE TO BALLET  with  some thing triky THE YCL  SEMI-ARMED YOUTH LEAGE NOT DUE TO DIRECT BULLET  FORWARDING TO NEPAL ARMY.

THE MAIN FEATURES OF MADAN BHANDARI’S PEOPLE’S MULTI –PARTY DEMOCRACY CONCEPT ARE-

1.  He is an upholder of the principles of socialism and pursues the road of People's Multi-Party Democracy, which is a creative application of Marxism and Leninism in the Nepalese condition.

2.  Consolidation of democracy, strengthening people's sovereign rights, changing the socio-economic relation and acceleration of the economic development in the country are the major concerns of the Party.

3.  Periodical election and the government of the majority, pluralism, rule of law, human rights are other important elements of the People's Multi-Party Democracy.

4.   Economically self sustained society, quality education and health service, full employment and social security are important features of the Party program aiming to achieve the welfare state.

5.  The Party fully believes in the harmony and the unity among the people of all religions, castes, communities and ethnic groups living in different geographical regions of the country.

6.  The Party works against any discrimination based on race, religion, caste, ethnicity, sex and geographical region.

7. It restricts any sort of class over sensation e.g. racial conflicts/ religious conflicts( it restricts any racial or religious federalism in the country ). Should stop any sort of class over sensation, which leads any social and national conflict unnecessarily.Maoists  of Nepal ,are anti- communist – because – believing in any sort of racial federalism in the country is unscientific to any communist party ).

8. The world is  in a age of generalization or globalization,so talking about racial fedaralism is just going back to 15^TH century’s isolated society .21^st century is  the age of mobilization, immigration ,massive-integration of people ,socially,technically,economically, linguelly,and  culturally.Every thing will be mutual integrated and hybrided.world is being so narrow and try to divid or isolate a nation to in many slices is unscientific .Racial federalism helps to weak socialization and democratization in the nation.The cause of collapse of former USSR is just due to class over sensation(the slogan of racial liberation ) after 1990.

He believes that the material development of society should be closely linked with the spiritual enlistment of the people and it should be guided by the ideals of democracy and socialism.

DR. RAJ KUMAR DHAUGODA.

 R.K.DHAUGODA’S

General Theory of Vasculitis

A  SPECIAL RECENT  ADVANCES IN MODERN MEDICINE

A creative application of  DIALECTICS ( MARXIST PHILOSOPHY) , IN MEDICAL SCIENCE.

By-Dr.Raj Kumar Dhaugoda,MBBS (TU),MD Family Medicine(BPKIHS),Nepal.

 (MEDICAL SCIENTIST AND MARXIST PHILOSOPHER)

.R.K.Dhaugoda’s-GENERAL THEORY OF VASCULITIS    

    From the various conclusions of various literature reviews, discussions, and various studies and findings, which are presented previous chapters( THE BOOK -    RKDHAUGODA'S GENERAL THEORY OF VASCULITIS -PART-I). It is hypothesized to build the general theory of vasculitis, with the help of guide line theory that is dialectical materialism, to express the objective reality of the physiological and pathological laws within the human body and to solve many problems in the field of management of health and disease in the huge proportional of population, in terms of effective, preventive, curative with least costs and simple techniques and coordinating with other various scientific approaches. According to this theory:
(1) Any inflammatory (infectious or non infectious & endogenous or exogenous originated disease is associated with varying degree of vaculitis in relation to time, space, motion and matter (antigen specific/strss factors/antistress factors). It means the main / key pathology of any inflammation is the vaculits (primary or secondary vaculitis). Vaculitis is the inflammation of vascular system,and associated with inflammation of any types of cells of the body. The vascular system in human body is widely and extensively distributed (except hair, nail and cornea). The vascular system e.g. micro vessels namely capillaries, sinusoids, venules are connected with every cells of the body by means extra cellular fluids. Hence any tissue or cell damage is associated with vascular abnormalities.
(2) All the inflammatory originated diseases having the common pathology vasculitis are principally mediated by the major factor TNF- alpha). It means TNF- alpha is the principle cytokine, and principle pathogenic mediator for all types’ vasculitis diseases (from boils to cancer pathology).
(3) All these vasculitis pathology have relatively high level of TNF- alpha in the circulation, which are associated with relative hypo- ANTI-STRESS ELEMENT). Because in any hypo- ANTI-STRESS ELEMENT condition, there is increased synthesis of TNF- alpha and they’re appearance of inflammatory response, and then various degree of vasculitis process is developed.

(4) These relations of vasculitis, TNF- alpha and relative level of intracellular ANTI-STRESS ELEMENT, remains in functional state, when there remains constant i.e. the possibility of reversion of pathogenesis of involved organ. This functional limitation of reversibility of pathogenesis is represented by the R.K.Dhaugoda’s. constant equals to 1, this value remains constant up to before irreversibility damaged of organic function (e.g. chronic renal failure, chronic liver failure, brain death, chronic brain damage /severe encephalopathy).
(5) All these disease, which is associated with vasculitis pathology, are treated with pharmocotherapy of ANTI-STRESS ELEMENT principally, and with adjunctive therapeutic tools, antimicrobials, antiviral, antifungal, antiparasitic, and other various supporting drugs and techniques viz biomechanical (surgical/mechanical ventilation) until stabilization of severe disease pathology, and clinical stability. Then oral ANTI-STRESS ELEMENT is given for chronic and long-term preventive as well as curative management of various incurable diseases are treated with various integrated ways (to maintain the optimum level of intracellular ANTI-STRESS ELEMENT relatively), e.g.(a) By increasing education level of individual/ society regarding scientific understanding of disease process, causation, intervention, complications, prevention, and ways of scientific management, and the biological, physiological role of ANTI-STRESS ELEMENT and its importance via increasing the knowledge and practice of dialectical materialism thought and principles, broadly throughout the world. Because this dialectical materialistic view is the core/root science for all the remaining branched sciences. Without its knowledge, we can’t understand the laws of universe and its contents scientifically.(b) By modifying nutrition, lifestyle and behaviors (being anti sadists to ownself and to others). Viz taking, low fat diet, low sugar diet, moderate physical exercise, relatively high ANTI-STRESS ELEMENT containing diets avoiding smoking, alcohol, excess tea, coffee, sodium, azinomotto ( mono-sodium-glutamate), and avoiding excessive worry ness and anxiety these all positive activities cause increased intracellular ANTI-STRESS ELEMENT  relatively.(c)  Practicing various types of physical exercises:-anaerobic exercise, yoga,pranayam .      

 (6) In this theory, it is estimated even sub clinical stage of diseases or pre-estimation of relative risk of diseases. By means measuring the relative level of the C- reactive protein (a functional biological marker of hypo-ANTI-STRESS ELEMENT, inflammation in the body, and the level of cytokine e.g., TNF- alpha in the circulation). It says that even a person with relatively non-significant clinical disease, by measuring of C-RP level, if it is relatively high comparing to normal value, it is predicted the various risk for various diseases, specially Chronic diseases.  A person having Type -2 DM, arteriosclerosis, vascular diseases and with high C-RP level has more risk for cardiovascular diseases e.g., Heart attack, Angina, Ischemic heart disease, CRF and stroke etc.


(7) In this theory, it is applied the dialectical materialism principle which is the root science for all the branched sciences. The pathology of any disease is represented relatively & commonly by vasculitis. The intracellular relative level of ANTI-STRESS ELEMENT    represents body’s physiological status (immune status), Vasculitis and magnitude of Intracellular ANTI-STRESS ELEMENT (immune status) are opposite phenomena in the human body but not isolated from each other, but interdependent and interrelated each other by the relative level of TNF- alpha and C-reactive protein or stress factor in the circulation.In the physiological level range there is relatively less stress factors and less level of TNF- alpha and C- reactive protein (very low level is dominated by bodies immune status) and not causing disease. But when there is relative low level of intracellular ANTI-STRESS ELEMENT. Relative hypo-ANTI-STRESS ELEMENT in comparison to stress factors. It is started to synthesis and activations of TNF- alpha and starts inflammatory response by the body causing various degree of tissue / cell injury. Causing pathogenesis of vasculitis, and synthesis of C-RP in the liver is increased in response to inflammation in the body, overall causing increased level of TNF- alpha, C-RP and appearance of various degree of vasculitis, (Sub clinical to clinical stages). Hence, here the two opposite phenomena immune status (optimum level of intracellular ANTI-STRESS ELEMENT) and disease process /         Inflammation (vasculitis) is connected in terms of TNF- alpha and C-RP and stress factors.
(8) In this theory, it is correlated the level of intracellular ANTI-STRESS ELEMENT, TNF- alpha, and degree of various vasculitis, by blood circulation level of C-reactive protein. In practice, it is very difficult to measure sub clinical & clinical vasculitis, like wise the TNF- alpha level and intracellular ANTI-STRESS ELEMENT level very difficult, needs sophisticated instruments, highly qualified man power and excessive costly. But here it is correlated by the level of C-RP with the level of other three parameters e.g. severity of vasculitis, level of TNF- alpha and intracellular ANTI-STRESS ELEMENT level. When there is increased value of C-RP there should be relative hypo-ANTI-STRESS ELEMENT, increased level of TNF- alpha and various degree of sub clinical to clinical form of vasculitis. In absence of other interfering factors for C-RP level in the body e.g. use of Steroids, NSAIDS, Vigorous exercise, excessive Coffee / tea, Hormone replacement therapy, Intra-Uterine device, Pregnancy, use of Statin etc.
(9)  highly sensitive C-RP is non-specific biological marker of inflammation and body stress, raised its value in various types of Inflammations and exposure to stress factor by the body systems.

dialectical concept of health and disease

dialectical concept of health and disease