THE BIOLOGY OF AGING REVISITED,THE ROLE OF CELL SPECIFIC CARBONIC ANHYDRASE ENZYMES IN CONJUNCTION WITH TELOMERASE IN HEALTH AND IN DISEASES SUCH AS ALZHEIMER'S DISEASE INCLUDING CANCER, AS GROWTH FACTORS OF STEM CELLS AND AS AN ALTERNATIVE TO STEM CELL THERAPY

THE BIOLOGY OF AGING REVISITED,THE ROLE OF CELL SPECIFIC CARBONIC ANHYDRASE ENZYMES IN CONJUNCTION WITH TELOMERASE,IN HEALTH AND IN DISEASES SUCH AS IN ALZHEIMER'S DISEASE,INCLUDING CANCER,AS GROWTH FACTORS OF STEM CELLS AND AS AN ALTERNATIVE TO STEM CELL THERAPY.
Copyright 2011 all rights reserved                 by Victorio C. Rodriguez M.D.
Parma, Ohio                                               victorio.rodriguez@sbcglobal.net
October , 2011
        During the past few decades, much has been written about the biology of aging,but nothing more except lately,about Cell Specific Carbonic Anhydrase Enzymes,their evolution leading to their most important functions specially to that belonging to the Alpha Carbonic Anhydrase Enzymes.
       If we look back in time and follow the creation of the Earth,the evolution of carbonic anhydrase enzymes parallels that of the evolution and the beginning of life on Earth. Carbonic Anhydrase Enzymes are primordial enzymes starting first as Gamma Carbonic Anhydrase Enzymes and are about 4 billion years old.They are mostly found in Bacterias, Methanogens(Methane producing bacterias)) and Cyano bacterias(oxygen producing bacterias). The Beta Carbonic Anhydrase enzymes are mostly found in plants producing oxygen and glucose as by products. They are about 3.5 billion years old. The Alpha Carbonic Anhydrase Enzymes are mostly found in mammals and are about 200 to 300 million years old. The delta and the Iota Carbonic Anhydrase Enzymes were just recently discovered.Carbonic Anhydrase Enzymes are structurally distinct from each other but they perform the same reversible function: H2O  + CO2-----------H+     +     HCO3-1. Aside from their previously known functions, specially for the Alpha Carbonic Anhydrase Enzymes,they are found to produce Hydrogen ions which are then acted upon by the cytochrome system found in the mitochondria of all living things and are utilzed as: 1. Fuel of the ion pump that maintains the integrity of the cell wall membrane. Decreased Hydrogen fuel results to the depolarization of the cell wall membrane,hence toxic substances and substances that displace the Zinc from cell specific carbonic anhydrase enzymes enters the cell resulting to dying and dead cells. 2. Fuel for all cellular activities; 1/2 for cell division and 1/2 for all other cellular activities. Hydrogen ion(H+)   plus ADP(adenosine diphosphate)----------ATP(adenosine triphosphate). 3. Neutralizes all reactive radicals including reactive oxygen(O2)-2 as illustrated in the following steps: In the mitochondria of all living things glucose is utilized as a source of fuel for all cellular activities;(a) glucose   + oxygen------------H2O  +   CO2    +  (O2)-2(reactive oxygen is produced , 1 to 5 %).(b) H2O    + CO2--------------(reversible reaction acted upon by carbonic anhydrase enzymes)  H+   + HCO3-1. (c) Hydrogen ions(H+) produced by carbonic anhydrase enzymes are acted upon by the cytochrome system found in the mitochondria of all living things: (1)  H+    +  (O2)-2 (reactive oxygen)-----------------(HO2)-1--(Superoxide)  (2)   H+    +    (HO2)-1-----H2O2(hydrogen peroxide)  (3). 2(H+)     +   H2O2----------2(H2O) water final product    (4).  H2O2  ---------2(OH)-1 (hydroxyl)  (5) 2( H)+   + 2(OH)-1------- 2(H2O)-- water final product
            As the organism becomes more complex,they evolve producing new pathways to neutralize reactive radicals including reactive oxygen.Examples of these pathways are: 1. Coenzyme Q1   +   (O2)-2(reactive oxygen)-----(HO2)-1--superoxide 2.Superoxide Dismutase   + 2(HO2)-1----------H2O2(hydrogen peroxide)  + O2  
3. Catalase------4(H2O2)-----4(H2O)   + 2(O2)  4.Glutathione Peroxidase  ----- 4(H2O2)---4(H2O) + 2(O2)   5. Heat Shock Proteins(HSP 70)-----protects the cells from heat and also from toxic substances and heavy metals 
CHAPERONE PROTEINS:At the beginning of protein synthesis,the double helix structure of the DNA uncoils inorder for the mRNA  to replicate the genetic sequence responsible for the coding of a particular protein. The mRNA genetic information is found inside the nucleus but protein synthesis occurs in the ribosome found in the cytoplasm rough endoplasmic reticulum.The newly formed cellular protein folds into 3 divisional shapes within the barrel shaped cavity of Chaperones Hsp60 and Groel. These are classes of Chaperone proteins studied by Hartl and Horowitz and others.They established the details of the chaperone assisted folding mechanism,allowing the protein to perform their biologic functions and also prevents them from sticking with other proteins. ATP(adenosine triphosphate) is used by chaperone proteins as their source of fuel to perform these functions.Decreased Hydrogen ions due to the decreased level of cell specific carbonic anhydrase enzymes results to decrease ATP production. This results to, Chaperone proteins are unable to perform their functions. As a result misfolding of proteins occurs  inside the cell,intra cellular amyloid precursor proteins(APP) are formed. They are acted upon by Beta and Gamma secretase forming intra cellular  amyloid beta proteins. These proteins alter the cellular membrane, displaces the ZINC from cell specific carbonic anhydrase enzymes. These results in dying and dead cells. All the nuclear materials that are toxic from the dead cells enter the surrounding normal cells causing a chain  reaction that spreads to other cells. Remnants of dead brain cells,the cytoskeleton become NEUROFIBRILLARY TANGLES and the nuclear proteins as TAU PROTEINS. 
         Telomerase is a product of evolution as the orgnism becomes more complex. Telomerase and Telomeres-their mechanism of actions and the effects of altering their functions by Elizabeth Blackburn.--- states that telomerase RNA bases play important roles in enzyme functions. 1. is to synthesize the correct telomeric  DNA sequence is needed not only to counteract telomeric terminal attrition but also synthesize the correct telomeric DNA binding sites for sequence specific protective telometric proteins 2. To prevent chromosomal fusions.The complete replication of telomeric DNA needs telomerase. The shortening of the telomeric DNA is compensated by adding new DNA sequence.To make the chromosome stable the end of the chromosome is capped by telomeres by the action of telomerase. These are DNA protein complexes at the ends of eukaryotic chromosomes. They are also primordial enzymes and existed about about 3.5 billion years ago. They are present in plants and in mammals These telomerase enzymes are fueled by cell specific carbonic anhydrase enzymes.
         In mammals ,cell specific carbonic anhydrase enzymes(Genes) are further divided into carbonic anhydrase enzymes CA-I to CA-XIV and counting: CA-I---are cystosolic enzymes and are found mostly in red blood cells,vascular endothelial cells, gastrointestinal mucosa; CA-II--are cystosolic enzymes and are found in almost all tissues but mostly in the brain,bones and kidney; CA-III--are cystosolic enzymes and are found mostly in the muscles and synovial tissues; CA-IV---are membrane bound and are found in the capillary endothelial cells,brain and kidney; CA-V--mitochondrial,beta cells and pancreas; CA-VI--secretory,mostly found in tears,saliva,milk,mammary glands,nasal and respiratory mucosa; CA-VII--are cystosolic enzymes and are found in the brain,hippocampal CA I pyramidal cellscells, respiratory mucosa; CA-VIII--CARP(carbonic anhydrase related proteins); CA-IX--membrane bound, M/N protein(tumor associated)catalytic; CA-X--CARP(carbonic anhydrase related protein); CA-XI--CARP(carbonic anhydrase related protein); CA-XII--membrane bound; CA-XIII---cystosolic; CA-XIV--membrane bound.
    AGING IS FURTHER DIVIDED INTO:
1. primary: (A)  Normal Gene linked cell specific carbonic anhydrase enzymes. In normal aging ,the normally  gene linked cell specific carbonic anhydrase enzymes are  markedly increased during fetal development and peaks during fetal maturation. Afterwards there is a gradual progressive decrease level of all cell specific carbonic anhydrase enzymes.This results in the gradual decrease  production of hydrogen ions which fuels all cellular activities. As a result, there is a gradual diffuse dying and death of all cellular elements.Coupled with this, there is a decrease production of ATP(adenosine triphosphate)which is needed  by chaperone proteins to prevent misfolding of proteins.As a result of this decreased level,there is intra cellular formation of APP(amyloid precursor proteins). This is acted upon by Beta and Gamma secretase leading to the formation of intra cellular amyloid beta proteins.Aggregates of these proteins forms into plaques which are diffusely located to all tissues.
         (B) Defective Gene Linked Cell Specific Carbonic Anhydrase Enzymes. Aging is accelerated because of the defectively transmitted gene linked cell specific carbonic anhydrase enzymes. This causes malfunction resulting in the decrease production of hydrogen ions fueling the specific cell and or tissue. The specific tissue fueled by the cell specific carbonic anhydrase enzyme bears the brunt of the accelerated aging- dying and death of cells and it's sequelae. 
2. SECONDARY AGING DUE TO OXIDATIVE STRESS- This maybe due to environmental factors such as ionizing radiations,toxic substances, diseases and or conditons that alter the vascular endothelium and the cell wall membrane.These allow the entry into the cell, toxic substances and substances that displace the ZINC from cell specific specific carbonic anhydrase enzymes. As a result, the level of cell specific carbonic anhydrase enzymes decreases and so are the production of hydrogen ions that fuels the specific cell or tissue. Aside from the effects of normal aging, aging is further accelerated by oxidative stress and so are it's sequelae such as  production of amyloid plaques.
     While the Major Theories of Aging promulgated by the National Institute of Aging last updated January 31, 2008 are :
 1. PROGRAMMED THEORIES: (a) Programmed longevity. Aging is the result of sequential switching on and off of certain genes,with senecense being defined as the time when age-associated diseases are manifested. (b) Endocrine Theory. The biological clock act through hormones to control the pacing of aging. (c) Immunological theory. A programmed decline in immune system functions lead to an increased vulnerability to infectious diseases and thus aging and death.2. ERROR THEORIES: (a) Wear and Tear. The cells and tissues have vital parts that wear out. (b) Rate of Living. The greater an organism's rate of oxygen basal metabolism, the shorter it's life span. (c) Crosslinking. An accumulation of crosslinked proteins damage cells and tissues, slowing down bodily functions. (d) Free Radicals. Accumulated damage caused by oxygen radicals causes cells, and eventually organs to stop functioning. (e) Somatic DNA Damage. Genetic mutations occur and accumulate with increasing age,causing cells to deteriorate and malfunction. In particular,damage to mitochondrial DNA might lead to mitochondrial dysfunction.  
        NEURODEGENARATIVE DISEASES-- comprises the slow,progressive dying and finally death of neurons of all diseases of the nervous system. This dying and death results in the loss of structure and functions of neurons.These diseases have almost the same pathophysiology at the cellular level.Gene linked disorders,Misfolding of proteins resulting in the formation of amyloid proteins , oxidative stress, inflammation,programmed cell death,mitochondrial dysfunctions and others. The above could all be explained by the Envolvement of Cell specific Carbonic Anhydrase Enzymes. Decreased levels of Cell Specific Carbonic anhydrase enzymes,whether gene linked or due to other causes,such as oxidative stress,normal aging results to: Mitochondrial dysfunctions,programmed cell death,immune reactions and others . 
       The most common NEURODEGENERATIVE DISORDERS ARE:
1. Alzheimer's Disease 2. Parkinson's Disease 3. Multiple Sclerosis 4. Huntington's Disease 5. Amyotrophic lateral scelrosis(Lou Gehrig's Disease). They are thought to be due to Mitochondrial Dysfunctions(power house), Oxidative Stress.  
       In Alzheimer's Disease,the pathology starts first in the medial temporal structures. From the hippocampus,it spreads into the entorhinal cortex then to the other limbic structures, then into the other regions of the cerebral cortex. The hippocampus is one of the earliest part of the brain that is damaged. It is the seat of short and long term memories,spatial navigation. Severe damage to the hippocampus results in severe difficulties in forming new memories(antero grade amnesia) and also affects the memories formed before the brain was damaged(retrograde amnesia). The hippocampus are divided into the gray matter and the white matter. The gray matter consists mainly of densely packed neurons arranged in 3 layers; the CA I,CA 2 and CA 3. The CA 3 is responsible for short term memories while the CA I is responsible for long term memories. The gray matter is mostly fueled by Cell Specific Carbonic Anhydrase VII(CA-VII), it also acts as a molecular switch of the intra pyramidal brain cells of the hippocampus for GABAergic activities.The white matter of the hippocampus consists mainly of myelenated nerve fibers lined with capillaries and veins and is fueled mostly by cell specific carbonic anhydrase II(CA-II), CA-II is also found in the  oligodendrocytes. The entorhinal cortex is part of the limbic system that acts as like an interface between the hippocampus with other parts of the cerebral cortex. The hippocampus receives input from the serotonin,norepheneprine, dopamine system and the thalamus.The superficial layers of the entorhinal cortes provides input to the hippocampus ,while the deep layers of the entorhinal cortex receives output from the hippocampus. In the hippocampus the flow of information is one way. It starts from the dentate gyrus then to the hippocampal pyramidal layer CA 3 to the pyramidal layer CA-1 layer then to the sibiculum then to the entorhinal cortex. From the entorhinal cortex, information is forwarded to the different areas of the brain.In other cortical areas, the medial septal sends cholinergic and GABAergic impulses to all parts of the hippocampus. It is also envolved in memories and is responsible for the hippocampal theta rythms. The blood brain barrier of the hippocampus is mostly fueled by cell specific carbonic anhydrase IV, CA-IV. CA-IV level indicates the integrity of the blood brain barrier. Diseases or conditions that decrease the levels of cell specific carbonic anhydrase enzymes CA-II, CA-IV, CA-VII results to dying and dead brain cells fueled by that specific carbonic anhydrase enzyme leading to the diseases and or conditions associated with them.
          Specialized neurons produce neurotransmitters such as dopamine produced by dopaminergic neurons from the substantia nigra, acetylcholine from the basal forebrain, histamine from the histaminergic neurons,serotonin from the serotominergic neurons and others. These specialized neurons are fueled by cell specific carbonic anhydrase enzymes. Any disease or conditon that decreases their level results in dying and death of these specialized neurons resulting in the deficiency of specific neurotransmitters. 
       Much had been debated about the hypothesis of Alzheimer's Disease including aging. They are:
      1. Resolving Controversies on the Path of Alzheimer's Disease by Dennis L Selkoe, published in Nature Magazine on 17,1060-1065(2011) published on line on September 7, 2011. Here he discusses about the gradual accumulation of Beta Amyloid deposists in the brains of humans who died without any evidence of dementia. These amyloid deposits are of the diffuse type and lacking of significant neurotic dystrophy,microgliosis and astrocytosis which represent in alzheimeer's disease.
      2. The Pathogenesis of Alzheimer's Disease: Re-evaluation of the "Amyloid Cascade Hypothesis" by R.A. Armstrong , Int J of Alzheimer's Disease; 2011:2011:630865 published on line on Feb 11. 2011 . The Amyloid Cascade Hypothesis proposes that the depositon of B-Amyloid is the initial pathological event in alzheimer's disease leading to the depositon of senile plaques and then to neurofibrillary tangles ,death of neurons and ultimately dementia. In his re-evaluation of the pathology of alzheimer's disease ,his objections are: That Senile Plaques maybe reactive products resulting from neuro-degeneration in AD rather than being it's cause. There is no generally accepted mechanism to explain how the deposition of B amyloid leads to neurofibrillary tangles. He proposed modification of the amyloid cascade hypothesis: that the essential trigger mechanism to the development of AD is aging of the brain and associated risk factors such as head trauma,vascular disorder and systemic disease. That senile plaques and neurofibrillary tangles develop independently from each other  especially in late onset AD,that in transgenic experiments ,the effect of the transgene will be aged dependent, indicating that there was loss of pyramidal neurons in the hippocampus CA sectors at sites devoid of plaques deposition.
      3. Reimagining Alzheimer's disease-an age based hypothesis by Karl Herrup,Department of Cell Biology and Neurosciences ,published The Journal of Neuroscience , December 15, 2010, 30(50):16755-1672 . He postulates that in alzheimer's disease,there are at least 3 stages of the disease .(a) precipitating injury that begins the pathogenic process. (b) then starts the chronic inflammatory process that adds further injury to the brain cells which are already affected with aging. (c)this further leads to cellular injury to the brain cells leading to dying and dead cells.
     4. In oxidative stress,mitochondrial dysfunction and aging by Hang Cui,Yahin Kong,Hong Zhang, they challenged the free radical theory of aging the fact that  Superoxide dismutase and catalase have increased oxidative damages in mice but with a normal life span. Also over expression of the antioxidants catalase and Superoxide dismutase do not extend the life span.
.     Another mechanism explaining the Pathophysiology of Alzheimer's Disease and other Neurodegenerative Disorders are the Decreased levels of Cell Specific Carbonic Anhydrase. These leads to the decreased level of intra cellular ZINC which leads to APOPTOSIS. Intra cellular Zinc depletion induces caspase activation as indicated by the following steps:
1. Pre-caspase is activated 2. Caspase is released 3.Programmed cell death(apoptosis) occurs 4.Apoptosis related events occurs resulting in 5. Dead cells and dying cells(neurons-brain) 6. Neurofibrillary tangles (remnants of cytoskeleton),Tau proteins(remnants of nuclear proteins of brain cells)
     Also  Decreasing the  levels of cell specific carbonic anhydrase enzymes  triggers an immune reaction. The cells try to defend themselves by producing cell specific carbonic anhydrase enzyme antibodies. These immune cells also produce reactive oxygen which leads to oxidative stress.Decreased levels of cell specific carbonic anhydrase enzymes results to the  decreased level of hydrogen ions needed  to neutralize these reactive radicals including reactive oxygen. They bind with almost all molecules in the tissue of a subject. These reactive oxygen binds with the cell wall membrane making it permeable, allowing  toxic materials and substances enter the cell causing death and destruction of the cells. As a result of these events, they lead to: In the brain ,neurofibrilarry tangles, tau proteins, intracellular B amyloid proteins. They occur in specific cells, in specific tissues fueled by specific carbonic anhydrase enzymes which are decreased as a result of oxidative stress and or normal aging. These events are repeated to other normal cells over and over and it spreads to others, just like a wild fire. In normal aging the sequelae of aging are diffusely scattered deposition of senile plaques and less involvement of neurons,while the opposite are true with the sequelae of oxidative stress and  transmission of defectivel linked cel specific carbonic anhydrase enzymes.l 
       All of the unexplained pathophysiology on the hypothesis of aging,alzheimer's disease and almost all diseases of mankind could be explained by cell specific carbonic anhydrase enzymes. You need hydrogen ions produced by cell specific carbonic anhydrase enzymes  inorder for the antioxidants superoxide dismutase, catalase, gluthathione peroxidase and others to work as antioxidants to form superoxide, hydroxyl ions,hydrogen peroxide and finally water as the final product and hydrogen ions to fuel all cellular activities including all enzymatic activities. 

PARKINSON'S DISEASE- It is a neurodegenerative disorder of the central nervous system resulting from the death of specialized neurons producing Dopamine. These specialized neurons are found in the substantia nigra located in the midbrain. The substantia nigra is fueled by Carbonic anhydrase enzyme II(CA-II). They are characterized by abnormal movements such as rigidity,shaking,problem walking,gait. Later in life they have dementia and other mental problems. There is abnormal accumulation of proteins- alpha-synuclein later forming Lewy bodies in the neurons.Any conditon or disease that  decreases the  level of Cell specific carbonic II (CA-II) such as some pesticides increases the risk of Parkinson's disease.

MULTIPLE SCLEROSIS--this is a disorder characterized by demyelinization of the axons of the brain and the spinal cord. It is mostly an inflammatory disease which could also be classified under Neurodegenerative disease.As a result, the Brain and Spinal cord cannot communicate with each other. The myelin sheath serves as a means of conducting nerve impulses between them. The Oligodendrocytes are the myelin forming cells of the Brain and the Spinal cord. They are mostly found in the white matter of the Brain and Spinal Cord. Cell Specific Carbonic Anhydrase II (CA-II) mostly fuels the Oligodendrocytes and the white matter. Any disease or condition that affect Carbonic anhydrase Enzyme II(CA-II) increases the risk of having a Neurodegenerative Disease which includes Multiple Sclerosis. 

AMYOTROPHIC LATERAL SCLEROSIS(Lou Gehrig's Disease). This is a Neurodegerative Disease affecting the Upper and Lower Motor Neurons in the motor cortex of the brain, brain stem, and in the ventral horns of the spinal cord.  They are characterized by progressive weakness, spasticity,muscle atrophy, fasiculations, dysphagia,respiratory compromise. Sensory and mental functions are rarely affected. Prior to the death of the Neurons, proteinous inclusions containing ubiquitin accumulates in the axon and in their cell body. The are thought to be caused by mitochondrial dysfunctions due to oxidative stress caused by deficiencies of  Superoxide Dismutase activity and  mutant SOD1 toxicity, program cell death. The Neurons are fueled mostly by Cell Specific carbonic anhydrase enzyme II,IV,VII. They are fatal ,and live for only a few years.

HUNTINGTON'S DISEASE

    It is a neurodegenerative disease which is mostly inherited and born with a defective gene. They manifest mostly in the middle ages. They are characterized by involuntary motor activities and later mental and cognitive impairments. They are also found to have inclusion bodies  in the form of huntington's bodies consisting of  nuclear and neutrophil aggregates in the cerebral cortex and striatum. As with the other neurodegenerative diseases they are produced as a result of mitochondrial dysfunctions, oxidative stress, apoptosis. The affected regions of the brain are fueled by Cell specific Carbonic anhydrase enzymes II, IV, VII. At present their is no cure for this condtion.

PATHOPHYSIOLOGY OF ALZHEIMER'S DISEASE AND OTHER NEURODEGENERATIVE DISEASES

(A). PRIMARY deficiency of Cell Specific Carbonic Anhydrase Enzymes due to defective gene-linked Cell Specific carbonic enzymes.(B) Secondary Deficiency of Cell Specific Carbonic Anhydrase enzymes due to:(1) Neurotoxic material such as lead,iron,aluminum(2) infections that alter the blood- brain- barrier(3) Amyloid deposits that alter the blood-brain-barrier.(4) other conditions or diseases that alter the blood-brain-barrier that displaces the Zinc from Cell Specific Carbonic Anhydrase Enzymes resulting to the Decreased level of Cell Specific Carbonic anhydrase enzymes. This results to the decreased production of hydrogen ions(H+) needed to fuel  all cellular activities.                     

     CELL SPECIFIC CARBONIC ANHYDRASE ENZYMES ARE ALSO IMPLICATED
                                       IN CANCER
         Cell specific carbonic anhydrase enzymes are: Aside from producing Hydrogen ions that fuels all cellular activies, 1/2 for cell division and 1/2 for all other cellular activities, they are also growth factors, growth factors of stem cells and or precusors of cells.Cell Specific Carbonic anhydrase Enzymes existed in bacterias even before the telomerase enzyme evolved.The enzyme Telomerase has been found beginning with eukaryotes such as  plants and mammals.Cell Specific Carbonic Anhydrase Enzymes and Telomerase are markedly increased during fetal development and peaks during fetal maturation then they progressively decrease in level. The enzyme telomerase are not expressed in somatic cells except in stem cells and germ cells and tissues that needs replenishing.The cell specific carbonic anhydrase enzymes fuels the telomerase to produce telomeres. Decreased cell specific carbonic anhydrase enzymes results to decreased production of hydrogen ions needed to produce ATP(adenosinetriphosphate), to fuel the telomerase to produce telomeres hence no replication of the telomeres. Both  Cell Specific Carbonic Anhydrase Enzymes and Telomerase are implicated in aging and in Cancer. Cancers maybe due to Primary  Gene Mutation (Hereditary) and Secondary Gene Mutation(oxidative stress). These mutant genes produce either excessive or decreased  production of cell specific carbonic anhydrase enzymes. Cancers are divided into: Well differentiated forms and Undifferentiated forms. Well differentiated forms- are due to excessive production of cell specific carbonic anhydrase enzymes, while Undifferentiated forms are due to decreased production of cell specific carbonic anhydrase enzymes, the cancer cells are unable to mature because of lack of hydrogen ions to fuel their cellular activities.The use of cell specific carbonic anhydrase enzyme inhibitors for the treatment of cancers  are just beginning.Elevated levels of Cell specific carbonic anhydrase enzyme VII has been associated with cancer of the brain- astrocytomas,oligodendrogliomas,mixed oligoastrocytomas and are potential prognostic markers in gliomas-by Fatemeh Bootorabi, Joonas Haapasalo and et al-- Institute of Medical Technology and School of Medicine, University of Tampere, Tampere, Finland.

EXAMPLES OF COMPOUNDS THAT ARE KNOWN TO INCREASE THE PRODUCTION OF THE REQUIRED CELL SPECIFIC CARBONIC ANHYDRASE ENZYMES INCLUDE BUT ARE NOT LIMITED TO:

1. Acetylcholine--------------------------------------------increases the production of CA-II,CA-IV
2. Histamine ----------------------------------------------- increases the production of CA-I, II,IV
3. Serotonin--------------------------------------------------increases the production of CA-I,II
4. Zinc----------------------------------------------------------increases the production of CA-VI
5. Growth Hormones--------------------------------------increases the production of CA-II,CA-III
6. Sex Hormones------------------------------------------Increases the production of CA-III
7. Vitamin D3 and 1,25 dihydroxyvitamin D3 -- Increases the production of CA-II
8. L and D Phenylalanine------------------------------ increases the production of CA-I,II,
   V(A),VII
9. NSAID(non steroidal anti-inflammatory)-------increases the production of CA-I, CAII
10. Androgens including DHEA(dehydroepiandrosterone)- increases the production of CA-II, CA-III
11. Selective Serotonin re-uptake inhibitors which include sertraline,fluoxetine,citalopram-- increases the production of
     CA-I,CA-II
12. and others

EXAMPLES OF COMPOUNDS THAT ARE KNOWN TO DECREASE THE PRODUCTION OF THE REQUIRED CELL SPECIFIC  CARBONIC ANHYDRASE ENZYMES INCLUDE BUT ARE NOT LIMITED TO:
 
 Benzene Sulfonamides and it's derivatives-- inhibit CA-II, IV, V, acetazolamide and its derviatives,phosphonates , cyanides-are universal cell specific carbonic anhydrase enzyme inhibitors,azide derivatives and others.

The medical community has been using animals in Clinical trials for the treatment of neurodegenerative disorders. These clinical trials have been a failure due to the fact that the blood-brain barrier of animals are incomplete compared to that of humans where their blood-brain barrier is complete. This means to say that in animals the compounds used in clinical trials readily passes the blood brain barrier of animals hence they are able to exert their effects on the the targeted substances. These toxic substances readily passes out of the blood brain barrier where it is open.While in humans these compounds used in clinical trials are unable to pass the blood- brain barrier hence they do not have any effect on the targeted toxic substances located in the brain cells.

Aside from their other functions,CELL SPECIFFIC CARBONIC ANHYDRASE ENZYMES passes  the blood-brain barrier and into the cell. Hence they are able to exert their effects inside the blood- brain barrier and inside the cell itself.

 


                                                 TO BE CONTINUED


Parma, Ohio
December 28, 2010
"The United States Patent and Trademark Office just issued U.S. Patent # 7858602
Therapeutic and Prophylatic Uses of Cell Specifc Carbonic Anhydrase Enzymes in Treating Aging Disorders due to Oxidative Stress and as Growth Factors of Stem Cells". This patent deals with almost all diseases of mankind including Alzheimer's Disease. Restrictions were made by the Patent Examiner so Alzheimer's Disease was elected. This is about the Use of vitamin D3 in treating alzheimer's disease.Divisional U.S. application #12/928,145 -but not yet published was applied for other diseases  and mixture of compounds for almost all the diseases of mankind.

November 1, 2010
Parma, Ohio-- The United States Patent Office just issued a NOTICE OF ALLOWANCE -- THERAPEUTIC AND PROPHYLACTIC USES OF CELL SPECIFIC CARBONIC ANHYDRASE ENZYMES IN TREATING AGING DISORDERS
DUE TO OXIDATIVE STRESS AND AS GROWTH FACTORS OF STEM CELLS.
U.S. Patent application # 11/801,870
This can  be viewed at http://www.uspto.gov

Parma, Ohio June 3, 2010
          The United  States Patent Office just published  U.S. Patent Application# 12/655,783,Therapeutic and ProphylacticUses of Cell Specific Carbonic Anhydrase Enzymes for the Treatment of Aging, Disorders of Aging, Cancer, as growth Factors of Stem Cells and as an Alternative to Stem Cell Therapy.
         It can be viewed at http://www.uspto.gov
         Increase or decreased  levels of carbonic anhydrase enzymes are associated with Cancer and aging due to the fact that hydrogen ions produced are used for:1/2 for cell division and 1/2 for all other metabolic activities. In cancer there is an increased or decreased  levels of carbonic anhydrase enzymes because of gene mutation. They are  primary(hereditary)andSecondary(oxidative stress). Decreased levels results to undifferentiated forms of cancer because they need fuel (hydrogen ions) to differentiate while increased levels results in differentiated forms of cancer.
     Aging is further divided into primary(hereditary) and Secondary(accelerated aging ).Primary aging is caused mainly in the inherent  progressive decreased activities of the genes that regulates the cells.While secondary aging is mainly caused by oxidative stress.Oxidative stress is mainly caused by environmental factors such as toxic materials, ionizing radiations or any disease or condition that alters the cell wall membrane and the vascular endothelium. These altered conditons allows the entry of subtances that will dispalce the Zinc from  cell specific carbonic anhydrase enzymes leading to their decreased levels hence leading to cellular death.
     Compounds that stimulates the production of carbonic anhydrase ezymes are used.Such compounds are: example Vitamin D3, Growth hormones,androgens,NSAID and others.But one has to assay which carbonic anhydrase enzymes are found to be decrease level in the tissue of  a subject.
      I have been taking compounds  such as Vitamin D3 in high doses(therapeutic and non toxic doses )for the treatment  of Aging and they work. Vitamin D3 produces carbonic anhydrase enzyme II that is found in almost all tissues but most of all in the Brain, Bones and Kidneys. They act as growth factors too.
 
Parma, Ohio June 25, 2007
The United States Patent and Trademark Office issued a Notice Of Allowance for U.S.
Application # 10/858,091"TREATMENT OF AGING DISORDERS IN HUMANS".
         This invention is about the Use Of 1,25-dihydroxyvitamin D3 for the Treatment of Alzheimer's Disease, Dementias and Neurodegenerative Diseases in Humans.1,25-dihydroxyvitamin D3 is not a Vitamin but actually is a hormone made by the actions of sunlight  and the skin and then made into the active form by the kidney.This hormone produces Cell Specific Carbonic Anhydrase Enzyme 2 which produces hydrogen ions needed to fuel the ion pump that maintains the cell wall membrane,fuels all other cellular functions and  the hydrogen ions produced as anti-oxidants.
        U.S. Application # 11/801,870  was filed on May 12, 2007  --
" THERAPEUTIC AND PROPHYLACTIC USES OF CELL SPECIFIC CARBONIC
ANHYDRASE ENZYMES FOR THE TREATMENT OF AGING DISORDERS DUE TO
OXIDATIVE STRESS AND AS GROWTH FACTORS OF STEM CELLS"
      This application is a continuation -in-part- of U.S. patent # 6821997 which deals with the uses of Cell Specific  Carbonic Anhydrase Enzymes,substances that increases the production of cell specific carbonic anhydrase enzymes which includes Vitamin D3,sex hormones, NSAID,androgens,and others in the therapeutic and prophylactic treating of aging disorders which includes alzheimer's disease,parkinsons disease,lou gehrig's disease,osteoporosis,arthritis,immune disorders,neurodegenerative disorders and others.This patent also deals with the uses of cell specific carbonic anhydrase enzymes as growth factors of stem cell in treating diseases.
     This patent application can be viewed at http://www.uspto.gov.    Parma,Ohio,  November 24,2004

The United States Patent and Trademark Office issued U.S. Patent # 6821997

 "THERAPEUTIC AND PROPHYLACTIC TREATMENT OF AGING AND

DISORDERS OF AGING IN HUMANS" including Alzheimer's Disease.This patent deals with the use of one or more
compounds in in delaying and  treating conditons of aging in Humans at the cellular level.  Examples of these compounds are: Zinc,Sex Hormones, Androgens including DHEA, NSAID , Vitamin D,Growth Hormones, Selective Serotonin reuptake inhibitors like fluoxetine ,citalopram, sertraline and others.These compounds  are given in combination with each other,in order  to raise the level  of Carbonic Anhydrase Isozymes that are present in decreased amounts in the tissue of the  a patient.

This  patent   can be viewed at http://www.uspto.gov

 

                                      For more information about the Treatment of Aging Disorders
                                      contact,

                                      KINSMAN MEDICAL CLINIC
                                      3345 East 55th Street
                                      Cleveland, Ohio 44134
                                      Tel. 216-441-4432
                                      
                                      Victorio C. Rodriguez M.D.

                                      E-Mail- victorio.rodriguez@sbcglobal.net

 -------------------------------------------------------------------------------------------------------------------------------------------------------------

Parma, Ohio

December 17, 2013

It has been 1 year ago  since I had an acute elevated ST myocardial infarction(heart attack) while I was sleeping. Miraculously I woke up, if not I should have been dead.

Let me tell you my story:

 I was a medical officer with the 1/501-101st Airmobile Division, stayed with the division  stationed near the demilitarized zone in  Vietnam from 1969-1970. We were not aware that we were exposed to Agent Orange with it's toxic effects.

My health problems started in the late 1980's. Because of my health problems the following events began:

C-28-365-780

7913-----20%--  Diabetes Mellitus (02/28/2006)

8521----20%---Peripheral Neuropathy-left lower extrimity(02/28/2007)

8521----20%-- Peripheral Neuropathy-right lower extrimity(02/28/2007)

7099-7006 --10%-- Ischemic Heart Disease(04/19/2010)

Total rating 60%

Problems with the Cleveland Veterans Regional Office, Dr. Murray D. Altose- Head of VISN 10 (veterans Integrated Service Network) arose, so complaints were filed AGAINST THEM  with the Office of the Inspector General, Department of Veterans Affairs on October 22, 2013, and was assigned Case# 2014-00651-HL-0102 on November 18, 2013.

This is the case: VIOLATION OF MY DUE PROCESS RIGHTS UNDER THE 5TH AMENDMENT OF THE U.S. CONSTITUTION BY WITHOLDING CARDIAC MRI ORDERED BY MY PRIMARY VA PHYSICIAN RESULTING IN ACUTE  ELEVATED ST MYOCARDIAL INFARCTION WHICH I ALMOST DIED.

                                                   TEXT OF THE COMPLAINTS:            

RE: COMPLAINTS AGAINST DR. MURRAY D. ALTOSE

       HEAD OF VISN 10(VETERANS INTEGRATED SERVICE NETWORK)

       DEPARTMENT OF VETERANS ADMINISTRATOR

       SERVICE LINE MANAGER FOR TERTIARY MEDICAL/SURGICAL CARE

       CHIEF OF STAFF, LOUIS STOKES CLEVELAND VETERANS MEDICAL CENTER

       CASE WESTERN RESERVE SCHOOL OF MEDICINE, CLEVELAND, OHIO

                              

       Dear Sir/Madame,

 

       I am filing complaints against Dr. Murray D. Altose for flagrant violation of my DUE PROCESS RIGHTS under the 5th amendment of the U.S. constitution. In re: Cushman V. Shinseki.

       This letter will tell you the events that harmed me(in case I die of sudden cardiac death),had harmed or will harm other veterans.

1. He willfully denied the life saving medical diagnostic test -CARDIAC MRI(magnetic resonance imaging of the heart) which was ordered by my VA primary physician. His action resulted in failure to diagnose and treat, resulting to an acute elevated ST myocardial infarction which I almost died.

    This I have property rights--7099-7006--rated -10% for ISCHEMIC HEART DISEASE(04/19/2010)

2. He wilffuly denied the Gastro-intestinal consult to Cleveland Clinic ordered by VA  N.P. Gildone because of my colonic neuropathy which was causing my abdominal distention and shortness of breath.

(1) This Cardiac MRI was ordered by Dr. Knappenberger, my VA primary physican because of persistent left sided precordial chest pain which I have been complaining to the Veterans Administration since my agent orange registry examination in 2007. Had the Cardiac MRI been done earlier, it would have diagnosed the coronary artery disease that had been causing my left sided chest pain.This coronary conditon would had been treated accordingly before I had the heart attack.

          I was diagnosed having diabetes mellitus  type II  in the late 1980's . I was only made aware about Agent Orange when I saw an advertisement  in an RTA bus late 2006. This AD was informing Vietnam Veterans having diabetes mellitus urging them to register for Agent Orange examinations. So on February 28, 2007 I went for Agent Orange registry examination at the Brecksville VA here in Brecksville , Ohio.   

         Physician Assistant Birdsell  performed the Agent Orange Registry examinations . I informed him about my persistent  left sided precordial chest pain. I also informed him that I am a practicing family physician for the last 37 years. So aside from all the other laboratory tests, he ordered an EKG. He informed me that the test was read as normal inspite of the fact that there were Q waves present.I informed my VA primary physicain, Dr. Knappenberger and VA about this matter.

          Stress Test was done which was read as normal. I told my primary physician and the Veterans Administration that this stress test was not accurate in diagnosing coronary artery disease. I told them that former President Clinton had a normal stress test but he had coronary by pass surgery.

          I had another C-P examination ordered by VA which was done by nurse practitioner Reed on April 19, 2010. She ordered another EKG which showed post myocardial infarction age undetermined. The  Veterans Administration gave me 10% compensation rating for ischemic heart disease

          Again I told Dr. Knappenberger that I was still having precordial chest pain. I told him that EKGS do not confirm or are diagnostic as to the state of my coronary arteries and to the heart as a whole. I recommended doing Cardiac MRI which was being done at Cleveland Clinic. I explained to him the reasons why, so Dr. Knappenberger ordered it. This test would  tell what is causing my persistent left sided chest pain, the state of my coronary arteries and to the state of my heart as a whole. 

        In response to the Cleveland Regional Office action dated January 26, 2011, RE:325/211/AZ, I explained to VA why I can not do other cardiac tests. I requested that I should be referred to Cleveland Clinic for Cardiac MRI.

         Again, in my response to the Cleveland Veterans Regional Office action dated May 5, 2012, in RE:325/213/Mng, I adamantly requested Cardiac MRI. I indicated that I have medicare part A and B, that the cost of the test should be paid by VA and Medicare. I also wrote that the Veterans Administration will be accountable if something happens to me.

         Inspite of all these pleadings, the Cardiac MRI which was ordered by my primary physician was denied by  Dr.Murray D. Altose(Head of VISN 10- a lung specialist).

         On December 17, 2012, I had an acute elevated ST myocardial infarction(heart attack) while I was sleeping. Miraculously, I woke up. My wife drove me to Parma Community General Hospital, Parma, Ohio which was only about  2 miles from home.

         Dr. Jamie Cohen did an emergency Cardiac Catheterization showing complete obstruction of the mid left anterior descending coronary artery, severe hypokenisia, ejection fraction of 30%. He inserted 2 bare metal cardiac stents. 

         Since then on, I was hospitalized 4 more times at Parma Community General Hospital: July 19, 2013 for chest pain, August 1, 2013  for chest pain wherein I had another Cardiac Catheterization showing stenosis of the proximal left anterior descending artery with an ejection fration of 50%., August 25, 2013 for chest pain and palpitations, and lately on october 9, 2013 for dizzines and markedly elevated blood pressure and precordial chest pain. 

          (2) The COLONIC NEUROPATHY (under appeal--CUE-Clear and Unmistakable Error- in RE: Cushman V. Shinseki) causing my abdominal distention and shortness of breath has been going on for years. I have been evaluated by physician assistans,residents,GI consultants here at Louis Stokes  VA hospital. My abdominal distention and shortness of breath persisted so I requested an out of network institution which is the cleveland clinic. N.P. Gildone ordered the consultation request to Cleveland Clinic Hospital  but Dr. Murray D. Altose denied the request

           Because of these actions by Dr. Murray D. Altose, who did not call nor examined me, my medical conditions had markedly worsened,my mortality and morbidity,the risk of sudden cardiac death had markedly increased.

           If this happened to me, what more for those veterans who might have been denied these life saving tests, procedures and or treatments by Dr. Altose. How about the care of other veterans from other VISN (Veterans Integrated  Service Network). I would not be surprised if this is happening to them too.

           VISN 10 and others are responsible for providing oversight and management, taking responsibility for the regional budget for the activities of the Veterans Health Administration,balance the budget at the end of the fiscal year. These may explain the actions of Dr. Altose.

           DEATHS OF  VETERANS IN VA FACILITIES, BONUSES OF VA EXECUTIVES ARE PRESENTLY BEING INVESTIGATED.

         Also, I made the VA aware, that I a licensed practicing family physician for 41 years that my opinions,statements should be taken into consideration as in RE: Espiritu V. Derwinski 2 Vet. 492(1992). These were all ignored and fell to deaf ears.

        For the sake of my fellow veterans and me, I am requesting full investigation of this matter. Those who had caused harm by witholding life saving procedures and or treatment should be dealt accordingly.

                                                                             Respectfully,

                                                                             Victorio C. Rodriguez M.D.

                                                                             Vietnam Veteran/bronze star medal

                                                                              C-28-365-780

                                                                              (O)-216-441-4432

                                                                               E-mail--victorio.rodriguez@sbcglobal.net

Copies:

Office of the Special Counsel

U.S. Dept. of Justice

Office of the Inspector General, Dept. of Veterans Affairs

Service Center Manager Cleveland Veterans Regional Office

Senator Bernie Sanders- Chairman of the Senate Veterans Affairs Committe

Representative Jeff Miller- Chairman of the House Veterans Affairs Committee

                                                             END OF TEXT   

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PARMA, OHIO

FEBRUARY 14, 2014

RE: VA MANAGEMENT ACCOUNTABILITY ACT OF 2014

I fully support this accountability bill of Congresman Jeff Miller and Senator Marco Rubio.

Aside from firing and demoting after granting them DUE PROCESS, if they are found to have commited criminal offenses they should be sent to PRISON.

This bill should contain which are criminal offenses, offenses like witholding life saving procedures and or treatment resulting to injury or death of the patient.

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Parma, Ohio

 May 27, 2014

REVISITING THE DECENTRALIZATION OF THE VETERANS HEALTH ADMINISTRATION INTO THE VETERANS INTEGRATED SERVICE NETWORKS. THE ROLE OF THE VETERANS INTEGRATED SERVICE NETWORKS AS AUTONOMOUS ENTREPRENUIAL ENTITIES IN DELAYING THE DIAGNOSIS AND TREATMENT RESULTING TO THE DEATHS OF VETERANS.

                It has been 7 months ago when I filed with the VA office of the inspector general Case# 2014-00651-HL-0102

against Dr. Murray D. Altose- Head of VISN 10, the Veterans Administration/Cleveland VA Regional Office for flagrantly

violating my 5th amendment DUE PROCESS RIGHTS by witholding the CARDIAC MRI which was ordered by my

primary physician Dr. Knappenberger. This resulted in the delay in diagnosing the state of my coronary arteries,

delaying the proper treatment of my Ischemic Heart Disease resulting to an Acute elevated ST Myocardial Infarction 

which I almost died in my sleep. Miraculously, I woke up.

                In 1995, congress approved the decentralization of the Veterans health Administration upon the

recommendation of Dr. Kiser into 21 Veterans Integrated Service Networks(VISN). These are autonomous integrated

service networks whose functions are: They are given budgetary,oversight, management decisions,empower to plan for

the care, for all the needs of more veterans at a low cost at their assigned location and jurisdiction for all

VA Medical Centers,clinics and others. They are clones of the Veterans Health administration and are autonomous from

 the VHA and from each other. Aside from these,they can join Union,the National Association of VA Physicians and

dentists,with performance bonuses. So you can not just fire them.

                  The Veterans Integrated Service Networks are composed of: As head-Regional Director; Board Members

composed of other Directors. They are the top brass of each Veterans Integrated Service Networks(VISN).

 They decide all activities of each VISN, present and future. They have their own laws.

                   As I see them from my research, they formulate their own rules and regulations as to what to do in their

own jurisdiction. The  Regional Director of the VISN can withhold life saving procedures and or treatments as

exemplified in my CASE wherein my primary physican ordered Cardiac MRI but was wihtheld.Luckily, I was getting

copies of my medical records showing the name who was withholding them.

                Administrative  VISN  Meetings are not accesible by Freedom of Information Acts. This is because of

Exemption 5 of FOIA. For VA to be really transparent,  Congress should amend the FOIA.

                 Lately, much has been written about DEATH PANELS, I would not be surprised if the VISN Administrators

did not sign orders for it , such was the case of Dr. Murray D. Altose (head VISN 10) for flagrantly withholding,

 intentionally denying the Cardiac MRI ordered by my Primary Physician because of MY persistent precordial

chest pain, with ISCHEMIC HEART DISEASE.

                   VISN ADMINISTRATORS SHOULD BE INVESTIGATED FOR CRIMINAL ACTIVITIES, IF CONGRESS

CAN GET THEIR DELIVERATIVE ACTIVITIES RECORDS WHICH ARE EXEMPTED FROM FOIA -EXEMPTION 5.

                 The President should sign an executive order as recomended by a member of congress  to address

these serious allegations against the Department of Veterans Administration, then have the full congress act on this

executive order.      

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PARMA, OHIO

JUNE 1, 2014

DELAY,DIAGNOSIS, TREATMENT  AND DEATH OF VETERANS

ERIC SHINSEKI TAKES THE FALL

Comments by the Editorial Board of the New York Times -- May 30, 2014

These are my findings:

          As always, it is a shame when the Head of a  Department has to take the fall, when some terrible scandal

of great magnitude such as  what has been happening to the Department of Veterans Administration.

          The case of the Veterans Administration is an exceptional case in as much as the life and death of  Veterans are 

at stake .

          Congress seems to have dementia wth regards to what has been happening to the Department of Veterans

Administration since the Decentralization of the Veterans  Health Administration in 1995 into 21 autonomous Veterans

 Integrated Service Networks(VISN). These VISN"s started with a bang but as Dr. Kizer said lately

( if I am not mistaken),are prone to abuses,graft and corruption. Such were also the findings of the Office of the

Inspector General which they shared with Congress for such a long time. Some members of congress tried to pass bills

addresing these issues, but there were not much interest in them.

-----------------------------------------------------------------------------------------------------------------------------------------------------------------

Parma, Ohio

June 16, 2014

The Veteran's Access to Care through Choice,Accountability, and Transparency Act of 2014

              I have been practicing Family Medicine for the last 42 years. These are my comments with regards to the

above proposed bill by Senator McCain and Senator Sanders.

              First of all , this bill should not be hurriedly passed just to appease the wraths of the Veterans who were

pracitically ignored by Congress with regards to the activities of the Department of Veterans Affiairs. This bill

should contain all what has to do to prevent  the abuses of the Department of Veterans Affairs,to criminally punish and or

prosecute those who causes injuries and or death of veterans.

----------------------------------------------------------------------------------------------------------------------------------------------------------------

Parma, Ohio

June 28, 2014

FRIENDLY FIRE,DEATH, DELAYS,AND DISMAY AT THE VA--

                               BY

SENATOR TOM COBURN(CNSNews.com)

        Senator Coburn and staff's one year investigations of the Veterans Administration are so well documented exposing the Veterans Health Care System rewarding employees for deleting records, ignoring criminal behaviors.   Veterans are dying because of long waits and inappropriate care, while congress looks the other way around.

        These investigative findings deals a fatal blow for the existence of the Veterans Administration.

        I read the report of Senator Coburn and Staffs. The investigative reports on VA is so disgusting , that congress should start finding a replacement for the VA.

TO BE CONTINUED

     

MAY 16, 2014

                  I agree with Columnist Col. Jack Jacobs, U.S. Army Retired ,Military Analyst, NBC, MSNBC. Awardee 2010

Colby Award. Keep the Veterans Administration. Have the Veterans Health Administration and the Veterans Integrated

Service Networks merged with Medicare and Medicaid and some fine tuning.

                 As to VA Secretary Shinseki, he should stay. He has done lots of things for the Veterans. He has to have

congress give him the absolute power to fire and hire.

                  Congress created the VISN, they should be the one to fix it.

           Col. Jack Jacobs column--published on May 16, 2014, VAWATCHDOG.ORG

                                              

 

                                                  


 
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