Thursday, 2 July 2015

SCIENCE

Genetic immunodeficiency diseases
CATEGORY-------------------------TREATMENT
Combined T n B cell defect
X linked SCID-------------------Stem cells ( after gene therapy) n enzymes.(normal stem cells from another person will act as an allograft)
JAK3 deficiency-----------------Stem cells
Adenosine deaminase defn--------Stem cells n enzymes.
Purine nucleoside---------------Stem cells n enzymes.
phosphorylase deficiency
MHC class 2 defn----------------Stem cells- Check
ZAP 70 kinase deficiency--------Stem cells n enzymes- Check
Recombinase activating----------Stem cells
gene deficiency
Omen syndrome-------------------Stem cells
xlinked hyper Ig M syndrome-----Stem cells
Di George syndrome--------------Gene therapy
Antibody deficiency
Xlinked agamaglobulinaemia-----Stem cells n enzyme T.K
mew:) heavy chain deficiency---Stem cells
Other distinctive syndromes with immune defects
Wiskott Aldrich syndrome-------Stem cells
Ataxia telengiectasia----------Enzyme
Bloom syndrome-----------------Enzyme
Autoimmune---------------------Stem cells
lymphoproliferative condn
Phagocyte disorders
Chronic granulomatous disease-Enzymes
Leukocyte adhesion deficiency-Stem cells
Chediak Higashi Syndrome------Stem cells
Complement disorders
Individual complement defn---Give complements deficient:).
How to increase the life span of a person?
I always thought that telomeres were related to the life span, today I read something which suggests could be right,+nce of telomerase in cancer genesis says it is an antiapoptotic gene n an oncogene, manipulate telomerase n telomeres will delay apotosis n prolong life of the cell.Take the cells of Tortoise, Elephant, Mouse n Ant n see whether there is a correlation between the lifespan n the telomeres n if there is accordingly manipulate the telomeres in human beings and one can prolong the life of a human being.
If we give telomerase to a normal person see whether the apoptosis n cell death is delayed.
How to control cancer growth?
GRowth Factor activated by activation of proto oncogenes--If this GRowth factor is different antigenically then prepare a vaccine or give abs or antagonists to control cancer growth.
How to increase height of a person?
Give growth hormone n along with it give stem cells, if required with the maturation factors, normally when we give G.H there IS accelerated growth but after acheiving a certain height that is genetically predetermined which means that, that is what the stem cell store allows will not grow further, give stem cells as well n hopefully will continue growing, give it in small doses so that there is no gigantism/acromegaly.
Also try n see whwther telomerase which is anti apoptotic in action prevents the inhibition of stem cell aging n multiplication, then stem cells may not be wanted from outside.
Folic acid n stem cell proliferation
In a fetus it is good to give folic acid , causes rapid growth of the cells i.e stem cell multplication n differentiation. In an adult also the same thing happens but the stem cells will multiply only for a fixed no of generations say around 50, This i feel is genetically determined. Rapid growth using stem cells will also mean rapid aging bcoz the stem cells will be used faster so don't take a lot of folic acid n Bcomplex it will improve brain functioning:) though, I feel it is better to use who cares about whether reserves are left or not, as u wish but too much of rough living n taking too much of Folic acid n Bcosules not appreciated live normally n take the recommended daily allowance.
Familial Cancer Syndromes with Mendelian Inheritance.
See the complete list--
T/t
1.antagonise where mutated receptors n enzymes n proteins present.
2. Give the corrected stem cells n or enzymes .
Will print out the list later.
Then came across beta catenins (in the Book of genetics in Medicine) that bind to transcription factors n activates the process n I thought if we cud antagonise the transcription then there was a t/t GI hypermotility induced n I thought in the bathroom if we inhibit RNA polymerase present in almost all the viruses then we cud prevent protein syntheis, so if we prepared a vaccine against Viral RNA polymerase cud act as vaccine against RNA, DNA n Retrovirus--The prerequisite is that the Rna polymerase has to be constant in all the viruses else make a vaccine seperately or else make an antagonist drug like Protease anta n RT n anta...
Rna Polymerase helps in the synthesis of Rna from dna or rna both.
If one antagonises this enzyme will prevent rna syntheis n thus protein synthesis .
See the list of Disorders where Gene:) affected.
Familial Sporadic
Retinoblastoma Small cell lung cancer
Li Fraumeni Syndrome Lung ca, Breast ca.
Familial breast cancer Breast cancer, Ovarian cancer
Neurofibromatosis type1 Unknown
Neurofibromatosis type2 Sporadic Shwannomas n Meningiomas
Not known Colorectal cancer
Van Hippel lindau syndrome Clear cell renal carcinoma
Hereditary non polyposis colon cancer Colorectal cancer
Tumor supressor gene gives rise to a product when the gene gets mutated then the product also gets mutated/altered.
T/t antagonise it n give the right gene product, this is when a mutation takes place in a person who has not been given a cancer vaccine.
This disorder has been categorised into two Familial n Sporadic, Familial is the one that is inherited where a mutation is passed on to the next generation n sporadic when a later mutation alters the tumor supressor gene.
GB syndrome--Several lines of evidence support an autoimmune basis for acute inflammatory demyelinating polyneuropathy.
Isolates of C.jejuni from stool cultures of patients with GBS have surface glycoprotein structures that antigenically cross react with gangliosides , including GM1, concentrated in human nerves Rest please read from Harrison:)Sorry, no time to type.
T/t--
1.Give the patient antibody against antibody, either temporary or permanent in the form of vaccine.
2.Take the plasma for plasmapheresis
3.Give Igs to supress opportunistic infections.
T/t of MND--
Pathogenesis of MND--Excitotoxic neurotransmittor such as Glutamate may participate in death of motor neurons in ALS.This may be a consequence of diminished uptake of synaptic glutamate by an astroglial glutamate transporter, EAAT2. One cellular defence against such excitotoxicity is the enzyme SOD1,which detoxifies the free radical superoxide anion.Bcoz SOD1 is mutated in some familial cases of ALS.
1.Give anti glutamate i.e glutamate antagonist.
2.Give stem cells with EAAT2 will increase the uptake of synaptic glutamate n thus prevent nerve death.
3.Give stem cells with SOD1, is mutated in some familial cases of ALS.
4.Give antioxidants.
Later read antiglutamate already in use, we are just drops humanity has been working since time immemorial.
Similarly based on the above principles ab against ab n antagonism n gene therapy of stem cells a lot of other diseases can be cured.
Treatment of Haemoglobinopathies
See the list
T/T -Irradiate the bone marrow n remove the defective stem cells n replace it with normal stem cells by genetic manipulation n replace it in the bone marrow, U will get a cure.
Today prepared Rajma n French fries got burnt bcoz of hypermotility indn once again abnormal induction went on thru out is a norm have been living with it, yesterday was a sleep indn day n made it into kitchen tidying day to bid the sleep bye, anger induction severe given to mother n me helpless.

Tuesday, 30 June 2015

29.6.15 n 30.6.15 Science

29.6.15 n 30.6.15
Memory cells produced in an autoimmune pt against an antigen cud be given as a vaccine against a particular antigen in a normal person, i.e we will introduce the ag i.e normal protein, polysacharide, fat(+protein) n nucleic acid (+protein) of the body altered somewhat n produce abs n collect the memory cells n introduce it into another person.

Memory cells cud  act as passive immunity in serious conditions like needle stick injury with a dangerous virus.

In hybridoma technology we fuse a tumor cell with a ab producing B cell, here we will fuse a stem cell with a ab producing B cell, will produce abs just like hybridoma technology the benefit being can be used inside the body when difficult to locate memory cells will act like passive immunity, helpful against dangerous infections.

Stem cell + B cells against self modified ags will augment ab production  for long this is for faster ab production.

In case of liver failure or cirrhosis try giving liver cells into the liver they like stem cells have the ability to regerate liver to some extent.

Convert stem cells into beta cells now introduce it into the pancreas of a pt with Diabetes or old pt  with an aging body.

Fuse stem cell with hormone producing cells or else convert stem cells to endocrine cells n treat conditions like dwarfism-gh, acromegaly--somatostatin, menopause--follicular cells n corpus luteum cells to be fused with diff stem cells n produce oestrogen n progestrone everyday but with no gap in between as happens in a normal cycle, same for adrenal hormone deficiency, Stem cell + prolactin releasing cells for prolactin release find out whether a single dose of prolactin is sufficient for milk release or a sustained release wanted for sustained release, in the case of latte this will do.

Deficient blood clotting Fator gene into the liver cells thru a viral vector. Check.

Make an antibody against an antigen on supressor T cells n then the body will get hyperimmune n one will be able to create a vaccine against so many conditions, or else to make the condition temporary use T supressor cell antagonist.

Hepatic porphyrias ---------------Deficient enzyme
AlA dehydratase deficiency--------ALA dehydratase
Acuteintermittent porphyria-------HMB synthase
Porphyriacutanea tarda------------Uro decarboxylase
Hereditary coproporphyria---------COPRO oxidase
Variegate porphyria---------------PROTO oxidase

Erythropoetic porphyrias
X linked sideroblastic anaemia----ALA synthase
Congenital erythropoetic porphyria-UROsynthase
Erythropoetic protoporphyria-------Ferrochelatase

Give the deficient gene for the enzyme thru a viral vector and create a vaccine with the accumulated porphyrin as the antigen
egs see below.
pORPHYRIA------------------Increased porphyrin
ALA dehydratase deficiency--------------PROTO
congenital erythropoetic porphyria------URO1
Erythropoetic protoporphyria---------PROTO-9

Hyperuricaemia

Inborn errors of purine metabolism
Enzyme--------------------------------------------Activity
Hypoxanthine phosphoribosyltransferase---------Complete n partial deficiency
Phosphoribosylpyrophosphate synthase-----------Overactivity
Adenine phosphoribosyltransferase--------------Deficiency
Xanthine oxidase-------------------------------Deficiency
Adenylosuccinate lyase-------------------------Deficiency
Myoadenylate deaminase-------------------------Deficiency
Adenosine deaminase----------------------------Deficiency
Purine nucleoside phosphorylase----------------Deficiency

Disorder---------------------------Enzyme deficiency
Mucopolysaccharidosis
MPS1 Hurler--------------------Alpha-L-Iduronidase
MPS3A sanfilippo A----------------Heparan -N-Sulphatase
MPS3B sanfilippo B----------------N-acetyl-alpha-glucosaminidase
MPS3c sanfilippo c----------------Acetyl -CoA:alpha-glucosaminide N-acetyltransferase
MPS3D sanfilippo D----------------N-Acetylglucosamine-6-sulfate sulphatase
MPS4A morquio(136)----------------N-Acetylgalactosamine-6-sulfate sulphatase
MPS6B morquio(136)----------------Beta galactosidase
MPS6 maroteaux Lamy(136)----------Arylsulphatase B
MPS7(136)------------------------Beta glucuronidase

GM2 Gangliosidosis
Tay Sach's disease--------------Beta Hexosaminidase A.
sandhoff's disease-------------Beta Hexosaminidase A n B.

Neutral Glycospingolipidosis
Fabry's disease-------------------Alpha-Galactosidae A
Gaucher disease-------------------Acid beta-Glucosidae
Niemann Pick disease--------------Sphingomyelinase

Glycoproteinosis
Fucosidosis----------------------Alpha fucosidase
Alpha-mannosidosis---------------Alpha mannosidase
Beta--mannosidosis---------------Beta mannosidase
Aspartylglucosaminuria-----------Aspartylglucosaminidase
Sialidosis-----------------------Neuraminidase

Mucolipidoses(MLM
ML2, I cell disease--------------UDP-N-Acetylglucosamine-1-phosphotransferase
ML3,Pseudo-Hurler polydystrophy--UDP-N-Acetylglucosamine-1-phosphotransferase

Leukodystrophy
Krabbe's disease---------------------Galactosylceramidase
Metachromatic leukodystrophy---------Arylsulphatase A
Multiple sulphatase deficiency-------Active site cysteine to C alpha--formylglycine-converting enzyme

Disorders of Neutral Lipids
Wolman  disease---------------------Acid lysosomal lipase
Cholesteryl ester storage disease---Acid lysosomal lipase
Farber disease----------------------Acid ceramidase

Type/Common name--------------------Basic defect
Liver glycogenoses
Ia/Von geirke disease --------------Glucose-6-PO4tase
Ib----------------------------------Glucose-6-PO4tase translocase
3a Cori/Forbes----------------------Liver or muscle debranching enzyme
3b----------------------------------Liver debranching enzyme
6/Hers------------------------------Liver phosphorylase
9/Phosphorylase kinase defn---------Liver phosphorylase kinase
Glycogen synthase deficiency--------Glycogen synthase
9/Fanconi or Bickel-----------------Glucose transporter 2
Disorder associated with------------Branching enzyme
 liver cirrhosis4/Anderson

Muscle glycogenosis

Disorder with muscle
 energy impairment/Mcardle----------Muscle phosphorylase
7/Tarui-----------------------------Phosphofructokinase-M subunit
Phosphoglycerate kinase defn--------Phosphoglycerate kinase
Phosphoglycerate mutase defn--------Phosphoglycerate mutase-Msubunit
Lactate dehydrogenase defn----------Lactic acid dehydrogenase-Msubunit
Fructose 1,6 biphosphate -----------Fructose 1,6 biphosphate aldolase A
aldolase A defn
Pyruvate kinase defn---------------Pyruvate kinase-Muscle isozyme
Muscle phosphorylase---------------Muscle specific phosphorylase kinase
kinase defn 
Disorders with progressive skelet--Lysosomal acid alpha glucosidase
-al myopathy n or cardiomyopathy
2/Pompe

Cardiac phosphorylase-------------Cardiac specific phosphorylase kinase
kinase deficiency

Galactose disorders
Galactosemia with uridyl---------Galactose 1-Po4 uridyl transferase
 transferase deficiency
Galactokinase deficiency--------Galactokinase
Uridine diphosphate -----------Uridine diphosphate
galactose 4-epimerase----------galactose 4-epimerase
deficiency

FRUCTOSE DISORDERS
Essential Fructosuria-----------------Fructokinase
Hereditary fructose intolerance-------Fructose 1-phosphate aldolase B
Fructose 1,6 Diphosphatase defn-------Fructose 1,6 diphosphatase

Inherited disorders with Amino acid catabolism
Condn---------------------------------Enzyme defect
Phenylketonuria type1-----------------Phenylalanine hydroxylase
Phenylketonuria type2-----------------Dihydropteridine reductase
Phenylketonuria type3-----------------6-Pyruvoyl-tetrahydropterin synthase
Malignant hyperphenylalaninemia-------GTP cyclohydrolase
Hyperphenylalaninaemia----------------Pterin-4alpha-carbinol-amine dehydratase
Tyrosinemia type1---------------------Fumarylacetoacetate hydroxylase
Tyrosenemia type2---------------------Tyrosine transaminase
Tyrosenemia type3---------------------4-Hydroxyphenylpyruvatedioxygenase
Hawkinsinuria-------------------------4-hydroxyphenylpyruvatedioxygenase
Alkaptonuria--------------------------Homogentisicacid oxidase
Albinism------------------------------Tyrosinase
Tryptophanuria------------------------Unknown
Xanthurenic aciduria------------------Kynureninase
Histidenemia--------------------------Histidine ammonia lyase
Urocanic aciduria---------------------Formiminotransferase

Glycine imino acids
Hyperglycinemia-----------------------Glycine cleavage
Sarcocinemia--------------------------Sarcosine dehydrogenase
Hyperoxaluria type1-------------------Alanine;glyoxylate amino transferase
Hyperoxaluria type2-------------------D-Glyceric acid dehydrtogenase/glyoxylate reductuse
Hyperprolinemia type1-----------------Proline oxidase
Hyperprolinemia type2-----------------Pyrroline dehydrogenase
Hyperhydroxyprolinemia----------------Hyperhydroxyproline reductase
Iminopeptiduria-----------------------Prolidase

Sulphur containing
Hypermethioninemia--------------------Methionine adenosyl transferase
Homocystinria-------------------------Cystathionine beta synthase
Homocystinuria------------------------5,10-Methylene tetrahydrofolate reductase
Homocystinuria n methyl---------------Cobalamin reductase
malonic acidemia(cb1C,-D)
Homocystinuria n methyl---------------lysosomal efflux
malonic acidemia(cb1F)
Homocystinuria(cb1E,-G)---------------Methionine synthase n MS reductase.
Cystathioninuria----------------------Cystathionase
Cystinosis----------------------------Lysosomal efflux
S-Sulpho-L-cysteine,sulfite,----------Sulfite oxidas...
thiosulfaturia


T/t of Genetic conditions of Enzyme deficiency n excess.
When enzyme is deficient thru a transdermal patch or i.v pass it in2 the blood circulation bcoz all cells lack this enzyme now here is the point antibodies circulating in the circulation enters the cells easily so I feel even the enzymes can  n if this works shud then be a cure,( had come across two children suffering from Leukodystrophy  son  n daughter of a dear sister, we can give them enzymes from outside and give antibodies against the stored material by making it antigenic :) or give the gene 4 the enzyme thru a virus n make antibodies against the accumulated material.

When enzyme in excess thru a transdermal patch pass the antagonists to be used according to the extent of supression wanted.


Inherited  defects of membrane transport
See the list what we can do is that we will transport genes thru viral vectors that will replace the defective transporters.
where there are receptors involved on the cell surface can do nothing if less in amount if in excess we can give antagonists.

See the complete list in Harrison, was searching 4 this last week n God sent the charts in Harrison-Medicine, printed it out yesterday night n today afternoon.
T/t of Wilson's n Hyperoxalurea.
wilson's disease--In this condn there is deficiency of ceruloplasmin n the level of Copper is high.
We treat this condn similarly that is replace Ceruloplasmin n chelate the Copper.

Primary Hyperoxaluria--The enzyme deficient is  hepatic peroxisomal enzyme  alanine:glyoxylate amino transferase, 
Book says that t/t is combined liver n kidney transplant, In liver condn see if transplant of a few liver cells is going to decrease the load to some extent but this cannot be the complete t/t so what I wished to say was that  give a drug n let  it passs thru the circulation n enter every cell bcoz when we give an antagonists like tyrosinase antagonist  they will enter every cell, but exert their effect only in the melanocytes, so it was with antibodies they enter every cell so if we give the enzyme that is deficient thru the circulation it should take care of the deficiency.

 Earlier had mentioned about genetic disorders where abnormal proteins were formed it was imp to prepare n give antagonists at a very early stage this would work for enzymes it is better to create a vaccine n give abs instead for enzymatic proteins.

Difficult  to say whether will work for structural proteins for eg- Osteogenesis imperfecta n Ehler Danlos Syndrome  where deletion or point mutation causes reduced amount of normal collagen or normal amount of abnormal collagen if abs given will remove abnormal proteins n if correct proteins provided thru viral vectors or thru circulation wonder whether will work the t/t should start as early as possible bcoz would lead to accumulation of abnormal structural proteins if at all the protein is antagonised later.

In a child born with respiratory distress syndrome bcoz of deficiency of surfactants, one could give sufactants thru a narrow tube passed into the lung after the suction of mucous thru a mucous sucker.


There was hypertorture today being killed God is sleeping, but work had to go on tho my hands were trembling bcozof torture n father in pain similarly, today prepared, rice, paneer, bhindi n dal n it coincided with sister's arrival cooking ats as a stress releaser, mother prepared namkin peetha for the evening aftar:).29-6-25


One can givestem cells after gene therapy i.e for the enzyme/protein  deficienct give the gene mising for the enzyme along with the regulatory gene, if all the regulatory genes not known then take a normal stem cell from another person n antagonize i.e  delete the gene responsible for the gene recognition as foreign.
Today slept the whole day got up at 4:00pm n fed my bunnies n tidied things n had bath n aftaar n got a sinlge thought bcoz hybridoma tech page was open in sisters book of medical genetics:) 30-6-15.


Science 28.6.15

28.6.15
Vaccine against obesity--Triacylglycerol cud be used as an antigen  and antibodise prepared against it. One cud use enzyme inhibitors i.e enzyme antibodies against

enzyme antigen that help in synthesis of fatty acid, cholesterol n triacylglycerol.Also cud be used vaccine against LDL though enzyme inhibitor against cholesterol is

sufficient. Had prepared ab against triacylglycerol but at the last moment had not mentioned it, so mentioning now. The other fats are essential n we cannot make

antibodies against them.


Immune tolerance is bcoz of three factors
1.Clonal deletion of activated induced cell death-
One of the mechaniosms to prevent uncontrolled  T cell activation during a normal immune  response involves apoptotic death of activated Tcells by Fas Fas ligand

system.Lymphocytres as well as many other cells express Fas CD95 a member of the TNF receptor family.Its expression is upregulated in ag-activated Tcells.  The ligand

for fas (CD95) a membrane protein that is structurally homologous to cytokine TNF is expressed cheifly on T lymphocyte.The engagement of Fas Fas L, coexpressed on

activated Tcells dampens the immune response by inducing apoptosis of activated Tcells, such activation induced cell death also underlies the peripheral deletion of

autoreactive Tcells.

So Fas causes the depletion of Tcells n thus controls an autoimmune process.  We can try n give Fas +ve stem cells from outside can act as a drug like steroids in an

autoimmune pt.

If we take two strains of mice, lpr mice with mutation in the Fas gene n gld mice with defective Fas L, Mice of these two strains are prone to develop severe

autoimmune sisease resembling SLE in contrast suffer from generalised lymphoproliferation.
Genetic correction of autoimmune process by replacing Fas -ve with Fas +ve genes.

If we need to augment a vaccine formation i.e ab formation against say a fat vaccine if we give this Fas neg stem cell from outside will augment ab formation during

the acute phase after vaccination. If we give a vaccine against Fas ag the pic will be that of the mice above with SLE n lymphoproliferative condn.

2.Clonal anergy--This refers to prolonged or irreversible inactivation of lymphocytes induced by encounter with antigens under certain conditions. Activation of Tcells

requires two signals,recognition of peptide ags in association with self MHC molecules on the surface of ag presenting cells  and a set of second costimulatory signals

provided by the ag presenting cells.To initiate second signals , certain T cell associated molecules such as CD28, must bind to their ligands(called B7-1 N B7-2) on

antigen presenting cells.If antigens is presented by cells that do not bear CD28 ligand, negative signal is delivered n the cell becomes anergic.i.e B7-1 is

costimulatory to the immune system.

Another Vaccine against autoimmune condns--
So to make a vaccine against autoimmune condition make a vaccine with altered B7-1 ag to some extent i.e partially altered B7-1, ab formed will cross react with B1-7

will decrease the costimulatory signal n the autoimmune cond be cured.

3.Peripheral supression of Tcells--Although the above 2 are the main mechanisms of self tolerance,is beleived that  additional mechanisms must also exist.Supressor T

cells have a ability to downregulate  the function of other autoreactive Tcells.There is some evidence that peripheral supression of autoreactivity may be mediated in

part  by the regulated secretion of cytokines. Cytokines produced by T helper2 cells(eg-IL-4, IL-10,TGF-beta, can down regulate the T helper 1 response.

Mechanism of autoimmune disease
Breakdown of Tcell anergy--Tcell anergy can be broken if these antigen producing cells can be induced to express costimulatory molecules such as B7-1 and to secrete

cytokines such as IL-12 that stimulate the generation Th 1 cells . Upregulation of costimulator molecule B7-1 has s been noted in Multiple sclerosis, in which Tcells

attack the myelin sheath of the nerve fibres.Similar indn of B7-1 has been noted in the synovium of pts with Rheumatoid arthritis n in skin of pts with Psoriasis. Vac

with altered B7-1 ag will work
A demo of autoimmunity--Bcoz the transgeneic mouse are born with viral ag for all practical purpose this viral protein is treated as self antigen  n there is no

autoimmune response aginst it, if the transgenic mice is made to express both the viral protein n B7-1 under the insulin promoter however coexpression of the viral ag

n B7-1 on the pancreatic beta cells occurs.This breaks down peripheral tolerance n T cell mediated injury to the islet cell occurs.

B7-1 will increase ab formation

Failure of activation induced cell death--Persistent activation of potentially autoreactive T cells may lead to their apoptosis by Fas Fas ligand system.Defects in

this pathway may lead to apoptosis or may allow persistence and proliferation of autoreactive T cells in the peripheral tissues.

Fas -ve will stimulate ab formation

Failure Of T cell mediated supression- Loss of autoregulatory or supressive T cells can limit the function of autoreactive T n B cells n can lead to autoimmunity.

T supressor antagonistor depletors  will augment immunity.

Molecular mimicry--Some infectious agents share epitopes with self antigens.
eg-1.Rhd-streptococcal M proteins cross react with cardiac glycoproteins.
2.Multiple  sclerosis, viral  peptides cross react with myelin basic protein.


Cross rkn augments immunity.


Polyclonal lymphocyte activation--Several micro organisms n their products are capable of causing polyclonal activation of B cells.The best investigated among this grp

is bacterial lipopolysaccharide (endotoxin) which can induce mouse lymphocyte to produce  anti DNA, antithymocyte and anti red cell antibodies in vitro. In addition

certain other bacterial prdts can bind to n activate a large pool of CD4 +T lymphocyte in an antigen independant manner. Bcoz they stimulate all T cells they are

called superantigens

Make the vaccine highly immunogenic.


Release of sequestered antigen--Any self antigen that is completely sequestered during development is likely to be viewed as foreign if introduced into the circulation

and an immune response develops.Spermatozoa n ocular ags fall under this category.Post traumatic uveitis and orchitis after vasectomy pbly results from ags normally

sequestered in the eye n testis .The mere release of ags is not sufficient to cause autoimmunity , inflammation associated with tissue injury is essential for

upregulation of costimulatory pathways that are critical for induction of immune response. I feel that ag ab interaction is followed by complement n neutrophil induced

phagocytosis n release of mediators of inflammation, but if there is associated inflammation that will attract the Tn B lymphocyte n augment the ab formation.

So when creating a vaccine, try to create a localised inflammation the ab response will be better, all the factors being discussed will increase the ab formation

against the vaccine.


Exposure of cryptic self n epitope spreading--T cells cud cause autoimmune disease if the cryptic epitopes are somehow presented to them in an immunogenic form.
Thus it is postulated that regardless of initial trigger of an autoimmune response (eg--infection with a cross reacting microbe, release of sequestered antigen,

failure of supressor T cells)the progression n chronicity of the autoimmune response is maintained by recruitment  of autoreactive T cells that recognize normally

cryptic self determinants.
All these factors will augment an immune response against the vaccine being planned on the principle of cross reactivity.
Similarly the above factors can be controlled to decrease the immunity to prevent a host vs graft rkn.

Vaccines cud be prepared against many autoimmune conition some of them have been listed here.
Single organ or cell type
Probable
Hashimoto's thyroiditis
Autoimmune haemolytic anaemia
Autoimmune atrophic gastritis of pernicious anaemia
Autoimmune encephalomyelitis
Autoimmune orchitis
Goodpasture's syndrome
Autoimmune thrombocytopenia
Insulin dependant D.M
Myasthenia gravis
Graves disease

Possible
Primary biliary cirrhosis
Chronic active hepatitis
Ulcerative colitis
Membranous glomerulonephritis

Systemic
Probaqble
SLE
Rheumatoid arthritis
Sjogren's syndrome
Reiter's syndrome


Possible
Inflammatory myopathies
Systemic sclerosis
Polyarteritis nodosa
Add further
Onecan use their abs as antigens n create vaccines, the Fc portion of their abs will be modified n thus made antigenic.

vaccine against Amyloidosis --Of two types systemic (generalised) n localised, take the amyloid protein n convert it into an antigen n then make antibodies against it,

Alzheimer's is also an eg of localised amyloidosis.
If nO antibody formation takes place against altered antigen then try giving costimulatory molecule B7-1 if works all alone or with the ag on the Tlymphocyte whatever

way it works, same for principle to be followed 4 other vaccines as well, but if there is development of an autoimmune condition then give an antagonist n maintain a

rt balance of increased immunity but no major autoimmunity.



This Rakshas Hitler went on with constant neck pain, phobias, dirty images,extreme painful itching feeling of hot n cold leaves no stone unturned to hurt n disturb n

torture me whatever I say is less, he hurts me to such n extent that it would have been better he was put behind bars n whipped continuously for 14 years all this to

stop me same happened yesterday n I tried to sleep to escape this neg Hitler, father cried in constant pain the whole day. God stop him or he will destroy the world.

Saturday, 27 June 2015

Science.

Why antibodies not formed against fetus in the mother Embryologist Ronald W.Dudek from Brody school of medicine said  in his book said  that
1.the syncytiotrophoblast cells lining the villous chorion lack major histocompatibility complex MHC antigens n they do not evoke n immune response.
2. Decidual cells within endometrial stroma secrete prostaglandin E2,which inhibits T lymphocyte activation.

Every cell on our body has a MHC antigen which is unique only identical twin share MHC antigens, OK,
Next point that prostaglandin E2 inhibits T cell activation cud mean that givin Aspirin or NSAIDS cox 2 inhibitors that inhibit prostaglandin secretion during autoimmune conditions, on one hand decreases signs of inflammation which is bcoz of release of mediators of inflammations from different WBCs and on the other hand by inhibiting prostaglandin synthesis they activate T cells n augment the autoimmune process, so one needs to check out whether NSAIDS are really doing some good to the patient n then continue with the drug weighing the pros n the cons.

Another point struck to me was that the blood cells of the mother are not carried across the placenta into the fetus so the T cells (helper n cytotoxic ) are not sensitized by the fetal antigens n they are not able to activate the B cells of the mother n so no antibody formed against the fetus.

Creation of vaccine How? Body elicits an immune response against any foreign antigen, any altered protein can act as an antigen and cross reaction can take place so chances are high the vaccines will work, we need to alter the structure of a protein that was constant or try altering it by adding foreign proteins.
Thena thought came that antibody synthesis starts in the fetal body by around the time the haematopoetic system develops which is followed by the development of the T n B cells n it is then the antibody synthesis begins as well, the antibody is made up of two chains heavy chain which is longer n a light chain has two parts constant n variable, the variable part keeps changing according to the antigen the B cell is senitized to n the body accepts this level of change  after fetal life ends no str in the body changes after fetal life thus. In Rheumatoid arthritis antibodies Ig M is formed against Ig G (Rh factor) Autoantibodies develop against the Fc portion of autologous Ig G, they are Ig M may be of ther classes as well. Abs not formed normally bcoz Fc constant even during fetal life, so if we have to make the antibody against the antibody will we will have to alter the Fc portion not the Variable portion, Ok.

Fetal Vaccine--I had been dreaming of this vaccine since ages, wonder will work, the body recognises all the antigens present in it b4 the formation of the immune process as self, at this stage if we give all the exogenous antigen associated with an autoimmune condition i.e micro organism single n mutlicellular that makes the body cross react against self antigens( endogenous antigens are the body's own antigen that have been altered or mutated bcoz of radiation, mutagens or toxins following an infection)n see wether the body recognises them as self and does not mount an immune response against them then we can create a vaccine against autoimmune conditions caused by an exogenous ag, Vaccine will have to be given USG guided. We can also give MHC antigens present in major organs from siblings in case the child needs a transplant later. Hope this works.

Hints from immunodeficient conditions.
SCID--severe combined autoimmune condition, here adenosine deaminase is deficient, this is responsible for accumulation of deoxyadenosine n its derivative which are particularly toxic to immature lymphocytes especially  of  T cell lineage, there is greater reduction of T than B cells.
So for the treatment of host versus graft rejection and autoimmune conditions one could use ADA antagonist instead of steroid which lowers the lymphocytes, bcoz steroid use is associated with a lot of side effects buffalo hump n S.E related to abnormal metabolism of fat n carbohydrate n other S.Es, they will be gone only those related to immune supression will be left.

X linked agamaglobulinaemia of Bruton:)-- In Bruton agamaglobulinaemia, B cell maturation stops after rearrangement of heavy chain genes. Bcoz light chains are not produced, the complete immunoglobulin molecule containing heavy n light chain cannot be assembled n transported to the cell membrane .Free heavy chains are found in the cytoplasm. This block in differentiation in due to mutations in cytoplasmic tyrosine kinase.Prophylactic i.v Ig therapy allows most individuals to reach adulthood. Give normal stem cells with growth factors that give rise to B n Tcells.
If one tries tyrosine kinase antagonist this will prevent antibody formation n cud be helpful in autoimmune condn n organ transplants.

Isolated IgA deficiency- IgA deficient are also deficient in Ig G2 N IgG4. The IgA deficient patient has  a high frequency of respiratory tract allergy n a variety of autoimmune conditions.
Why?Bcoz Ig A acts as a mucosal barrier against foreign proteins and antigens, it could be speculated that unregulated absorption of foreign protein antigens triggers abnormal immune responses in vivo i.e excess of foreign antigens entering the body n too much of Ig G, M, D, E produced, the latter takes part in allergies.In asthma an allergic condition the exposure to toxins is increased bcoz of inflammation of the resp tract n presence of high amount of Ig E mounts an ag ab rkn followed by release of mediators of  inflammation. Asthma is like an autoimmune condn where ag ab rkn takes place n the ab is Ig E. Had found the two conditions associated in a friend of mine.
The molecular basis of this condn is still elusive. In most pt the no of Ig A +ve B cells is normal but only few of them can be induced to transform into Ig A Plasma cells.Serum antibodies to IgA is found in 40% of the patients. So prepare a vaccine:).When transfused with blood containing normal Ig A some of the pts develop severe even fatal anaphylactic rkn, when an ag ab rkn due to IgE spreads systemically leading to vasodialation n shock k.a anaphylactic schock.
This condn clearly presents out how autoimmune condn n allergy condn cud have risen, excess of ags n abs:).

Hyper IgM syndrome--T cell disorder in which functionally abnormal T cells fail to induce B cell to make antibodies of isotype other than IGM. Ig M n Ig D antibodies are produced first folowed by the sequential formation of Ig G, A, E formation. This orderly appearance of antibody types during an abnormal immune response is called isotype switching.
The mutation in either CD40L or CD40 prevents the T n B cell interactions necessary for isotype switching. Give normal stem cells as above n see whether things normalise.

Wiskott Aldrich Syndrome-The thymus is morphologically normal atleast early in the couse of the disease,  but there is progressive secondary depletion of Tlymphocytes in peripheral blood and in the paracortical (thymus dependent) areas of the lymph nodes, with variable loss of cellular immunity. Pts do not make antibodies to polysaccharide ag n response to protein ag is poor. Ig M is low, Ig G is normal, IgA n Ig E is elevated, one ab depressed others there is a compensatory increase. One cud create a clone zygote n grow the zygote till one gets stem cells in a test tube n differentiate them using different factors n transplant them to pts instead of bone marrow.






Science

Went thru lessons in Immunity at night tht abt  the diff types of hypersensitivity reaction n whether things wud work or not etc
In the morning thought about Asthma vaccine, then went on with the cleaning of my room n bathing too much of indn of itching was being produced then fed my bunnies n self then prepared rice, khade masoor ki dal for the first time, aloo ki sabzi n chokha put up clothes for washing, washed some dishes, then started my run to the bathroom bcoz of indn of inc GI motility:)  n thought about vaccine against organ transplant,torture continued painfully the whole day n relief as usual were my bunny kids ten born in the last 12 days,two opened their eyes two days back, three mothers n ten kids , two passed away.Love feeding them thru their mothers, Feel so good watching them Blackie for eg fed the kids yesterday night when I took her out of her home to feed the kids, ten kept together in a big letterbox she pulled the green blouse from a basket n when I came back found it inside the box felt so cute little creatures have instincts like human beings they also peep inside n watch the little ones off n on like me, I love Blackie a bit more so one day two days back  when I gave her kheer n she was lost instead all others ate I had a new realization I watched her and smiled, similarly felt good when I washed the face of my now going to be 2 mnths old kid:), she had had mango n totally dirtied her face, pets n children bring happiness I feel too happy taking care of the newborns specially n saving their lives only drawback is that they love paper n have eaten up a lot of my books n everyday my daily workout begins with cleaning the room messed up by them which keeps me alert:).The whole day diff thoughts came up vaguely but finally have summarised them in this chart they fitted here.

Types of hypersensitivity reaction--Type1 Anaphylaxis
Prototype disorders-- some forms of asthma
Immune mechanism--Formation of Ig E antibody-->immediate release of vasoactive amines n other mediators from basophils and mast cells followed by recruitment of other inflammatory cells.

What I thought 2day morning--

Vaccine against asthma--Take Ig E or Leukotrienes n modify its structure by adding foreign protein n see if antibody formed against the combination if formed will act as a vaccine against asthma.


Types of hypersensitivity reaction-Type2
Prototype disorders--Autoimmune haemolytic anemia,Erythroblastosis foetalis, Goodpasture syndrome
Immune mechanism--Formation of Ig G n Ig M--Binds to ag on target cell surface.--Phagocytosis of target cell or lysis opf target cell by C8, 9 fraction of activated complement  or antibody dependant cellular cytotoxity.

What I thought 2day afternoon--

Vaccine against haemolytic anaemia n Erythroblastosis foetalis -- In haemolytic anaemia n erythroblastosis foetalis antibodies are formed against blood cells n they cause haemolytic anaemia n there is no cure n the person n the foetus both suffer. Use the antibody formed against the blood cells  as antigen n make a vaccine i.e abs against those abs . If the vaccine not possible then make an antibody antagonist that will save the life of the fetus.
What happens in Erythroblastosis foetalis--Mother is Rh -ve n the father is Rh +ve the child is also Rh +ve when the 1st child grows in the uterus there is no problem if the mother hasn't received Rh +ve blood earlier, when the foetus is delivered some of the fetal blood from the placenta:) enters the maternal circulation n causes the formation of antibody, to prevent this if the mother has already been given  Rh immunoglobulin that will bind with Rh ag n prevent further ab formation but if not, abs will be formed and in the next pregnancy these antibodies will go n react with the Rh+ve blood cells n causes haemolysis n there is no treatment. So we will try the antibody antagonist till the child is delivered:), vaccine can be tried b4 pregnancy or during the first Rh +ve pregnancy. These should work if these don't work then go for traditional management i.e repeated transfusion thru the cord until child reaches the stage of extrauterine viability.

Vaccine against blood transfusion reactions--Give a small amount of blood of the other group other than O,small amount of antibody will be formed use it as antigen n make antibodies this will prevent a transfusion reaction when blood of diff grp is given during a emergency.


Vaccine against all autoimmune condn follow the same rule--Similarly make abs against the abs against lung n kidney formed in Goodpasture's syndrome or make an antagonist against the antibodies. Rheumatoid arthritis surprisingly is the condition where antibodies are formed against antibody so we can create abs against abs cud be then produced in large amounts by hybridoma technology n given to pateints here n in so many other conditions.


Types of hypersensitivity reaction-Type3
Prototype disorders- SLE, Arthus reaction, Serum sickness.
Immune mechanism--Antigen antibody complexes-->Activated complement--->attracted neutrophils------>release of lysosomal enzymes and other toxic moieties.

Types of hypersensitivity reaction-Type4
Prototype disorders- TB, cancers, Transplant rejection, Contact Dermatitis.
Immune mechanism-Sentized Tlymphocytes--->release of lymphokines n T cell mediated cytotoxicity

To augment the treatment of cancers n TB give lymphokines--Also try Mycobacterial  DNA polymerase antagonist to counteract TB, bcoz the mycobacterias are  very slow dividers taking from 8-42 days for one division that is why take 9 mnths to two yrs for cure. TRY the above two will decrease the duration of therapy they are also very susceptible to radiations from the Sun, try n see if NaPo4 especially with radioactive P works esp for life threatening MDR tb.

Next thought about this in the bathroom death n activation of apoptosis gene n thought apoptosis ags released n the dead cells cleared, but what happened in a RTA esp if the body was crushed n the heart still alive n then struck vaccine that prevented organ rejection wonder will work
vaccine for organ rejection--Give small amout of the organ's antigen n that will elicit an antibody response.Create an antigen out of that antibody n that will act as the vaccine.

Thought about giving a genetically engineered bacteria that produced all the enzymes that cud be helpful in pateints with indigestion or pancreatitis. 

Thursday, 25 June 2015

Some science .

Vaccine against brain stroke--Thought about this on the night of 23rd, pts after valve surgery take anticoagulants to prevent thrombus formation bcoz if the blood cells due to damage when they pass thru artificial valves gets thrombosed then the clot formed may cause paralysis if lodged in the brain, if we create a vaccine against thrombin then we could prevent clot formation,the protein thrombin to be taken partly or whole n some foreign antigen joined to it, similar to what nature produces in RHD an autoimmune condn. Streptococcus has an antigen that resembles Mprotein present in the heart  of an RHD pt i.e a foreign streptococcal ag + a human Mprotein antigen, abs formed will cross react with the Mprotein present in the heart.

Prothrombin --------in +nce of Prothrombin activator+Ca---------> Thrombin
Fibrinogen --------thrombin------>fibrinogen monomer---Ca----->Fibrin fibres-----(Fibrin--> activated fibrin stabilizing factor13a)-->Cross linked fibrin fibres.

Try thrombin or other elements involved in the intrinsic n extrinsic pathway, there will always be danger of haemorrhage has positive as well as negative effects one will have to werigh the pros n cons n take the vaccine, in an adult after around 35 the chances of injury n fall leading to bleeding is not that high so the vaccine cud be taken around middle age post surgery, else one could try it in old age as one takes aspirin to prevent an infarction but chances of haemorrhage will always be there, the pic will be similar to middle n old age Haemophilia.

In case of a severe bleed one cud give the thrombin or the element used in excess from outside the abs will not be able to counteract things that fast, wow!

Vaccine against MI (Heart Stroke)-- Similar vaccine to be used in old age n in pts with Familial Hypercholesterolaemia give it during the teens try it with the vaccine  for BP. In this condn the LDL receptors are lacking there4 the LDL level is very high n that leads to accelerated atherosclerosis n premature MI in very early life. Thought about this yesterday evening:)had gone to sleep after thinking about brain stroke n then got busy with the day's work.

Vaccine against embolism--Pulm n otherwise--Similar to above.


Yesterday morning thought about treatment for Lactose intolerance, give Lactobacilli else give a bacteria with genetically engineered enzyme lactase into the gut.

Thought about a vaccine against RHD--collect Streptococci n sepaerate the ag that resembles Mprotein n see if there is a common ag in all the strains of streptococci if there is then the vaccine may work, at the moment it seems will not work, else there wud have been immunity after a a few attacks maximum, thought this yesterday morning was happy then thinking would work:).

Snake, scorpion n poison vaccines--Similarly try after joining to a foreign antigen try bovine antigen:).

Try Digoxin vaccine in patients with heart failure bcoz digoxin abs are used to treat digoxin poisoning.

At around 8 at night yesterday came this--
Vaccine against autoimmune condition---Treatment of Rheumatoid arthritis, Myasthenia gravis, SLE...
Modify the antibody slightly that is responsible 4 attacking the target tissue will act as antigen n then make antibodies, in an antibody there is a variable region n a constant region the, the difference in abs is bcoz of the variable region one will take the variable region n exclude the constant region join it to a foreign protein n make an antigen if the constant region taken could cross react with other abs, bcoz that is constant for all antibodies.
Will recheck if I get time else later plz bear with me.
Horse antibody is like human antibody IF Ab's protein vary then will act as antigen  n antibodies will be formed just like bovine insulin.If we alter the antibody structure partially will act as an antigen n if given in adequate amount will elicit antibody formation n destroy the antibodies formed in the autoimmune condition.Two years back had mentioned about antibody formation against antibody but how was not that clear, Had it been clear then would have given an idea about vaccine synthesis, just hope things work now.

So the summary is Half human protein half foreign protein or else alter half human protein will act as a vaccine against self antigens.

Vaccine against Prion disease--Antibodies against prion disease to become antigen n antibodies formed will prevent progression of this disease.

Vaccine against Obesity--Thought today.
The diff classes of lipids are Fatty acids, triacylglycerol, phospholipids, Glyco n Sphingolipids, Steroids n Vitamins A,D,E,k.

The body needs fat in the form of essential fatty acid, phospholipids that helps in the formation of various leukotrienes, Prostaglandins, thromboxanes, Glycolipds n Sphingolipids  for nervous tissue formation, Steroids for hormone synthesis,
One cannot make a vaccine against fat ingested (all forms essential n needed for some imp work) n will be too much to be taken care of by the antibodies.

See the chart of Fatty acid synthesis, we can create enzyme inhibitors n inhibit each enzyme in the diff steps n see if they work. Inhibit any one of the enzymes like Acetyl 2 Co-A-ACP-transacylase inhibition of  the first step or try  Malonyl CoA transacylase ....Try Acetyl Co-A carboxylase vaccine naturally inhibited in the body by Fatty acyl CoA. There are few more enzyme that cud be inhibited.

StepEnzymeReactionDescription
(a)Acetyl CoA:ACP transacylase
Acety-CoA ACP transacylase.png
Activates acetyl CoA for reaction with malonyl-ACP
(b)Malonyl CoA:ACP transacylaseCenterActivates malonyl CoA for reaction with acetyl-ACP
(c)3-ketoacyl-ACP synthase
3-ketoactl-ACP synthetase.png
Reacts priming acetyl-ACP with chain-extending malonyl-ACP.
(d)3-ketoacyl-ACP reductase
3-ketoacyl-ACP reductase.png
Reduces the carbon 3 ketone to a hydroxyl group
(e)3-Hydroxyacyl ACP dehydrase
3-hydroxyacyl-ACP dehydrase.png
Removes water
(f)Enoyl-ACP reductase
Enoyl-ACP reductase.png
Reduces the C2-C3 double bond.
Abbreviations: ACP – Acyl carrier protein, CoA – Coenzyme A, NADP – Nicotinamide adenine dinucleotide phosphate.
Synthesis of Triacylglycerol
Inhibit Acyltransferase or Phsphatase, these are the two enzymes used in the 4steps of Triacylglycerol synthesis. This synthesis takes place in the int lumen n liver,( instead of inhibiting the synthesis it wud be better if the fatty acid in any form is not consumed in excess amount).In that way we reduce the fatty acid n triacylglycerol load n by inhibiting the fatty acid synthesis from the acetyl co A n TAG synthesis we Inhibit fat entry into the body n thus control obesity. LDL vaccine also going to be protective.

(Acyl transferase also helps in the conversion of  cholesterol to Cholesteryl esters. This step is insignificant, in the +nce of esterase will revert back to cholesterol:)
So vaccine for obesity inhibits, fatty acid synth, Triacylglycerol syntheisis n Cholesterol synthesis or LDL antagonist:).

This reminds me had mentioned about Lipoprotein lipase that helps in triacylglycerol degeneration pbly two yrs back a step towards weight decrease.

Vaccine for hair removal in females:) not the scalps- The adrenal cortex in the females produce testosterone this is responsible for pubic n axillary n times slight mustache growth:). Adrenostenedione forms testosterone, we can give adrenostenedione vaccine or a testosterone vaccine cud be of help in females suffering from acne but would not be liked by female athletes bcoz testosterone is an natural anabolic steroid, increases strength cud be given during convalescence n kidney failure.