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Degradation of Purine Nucleotides

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Degradation of Purine Nucleotides

CATABOLISM OF PURINE NUCLEOTIDES

  • Human catabolises purine to uric acid.
  • In higher primates, Allantoin by enzyme uricase is the end product.
  • Adenine nucleotides catabolism- liver, heart muscle, Skeletal muscle, GIT mucosa.
  •  Guanine nucleotides catabolism- liver, spleen, kidney, pancreas, GIT mucosa.
  •  First metabolic product of purines is Xanthine.

Exam Important

  1. Human catabolise purines (adenine and guanine) to uric acid.
  2. First metabolic product of purines is xanthine.
  3. In non primate mammals, uric acid is converted to water soluble  allantion by enzyme uricase.
  4. The end product of purine catablism is uric acid, which is excreted.
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Degradation of Pyrimidine Nucleotides

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Degradation of Pyrimidine Nucleotides

CATABOLISM OF PYRIMIDINE NUCLEOTIDES

  • Cytosine and Uracil to Beta Alanine — CO2, NH3
  • Thymine and β- aminoisobutyrate — CO2, NH3
  • The end products are highly water soluble.

Exam Important

  1. The end products of pyrimidine catabolism are highly water soluble. E.g. CO2, NH3,  β- aminoisobutyrate, beta alanine.
  2. Pseudouridine is excreted unchanged as it cannot be catabolized in human.
  3. Humans have no enzyme that can catabolise pseudouridine derived from degradation of t-RNA.
  4. There is no energy generated in pyrimidine catabolism.
  5. The end products of pyrimidine catabolism is CO2 and H2O.
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Steps Of Protein Synthesis (Translation)

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STEPS OF PROTEIN SYNTHESIS (Translation)

TRANSLATION 

  • Translation is the process in which the genetic information stored in DNA is passed on to mRNA where it is translated into proteins.
  • Translation occurs in ribosomes.
  • mRNA is translated from its 5’ end to its 3’- end (51 à 31 )
  • 4 letter language information from nucleic acids to 20 letter language proteins.

STEPS OF PROTEIN SYNTHESIS-

  1. Activation of Amino acid
  2. Initiation
  3. Elongation
  4. Termination

1. Activation of amino acid (charging of tRNA)

  • Activation of amino acids takes place cytosol.
  • Each of the 20 amino acids covalently attached to the respective tRNA, by the ATP as two high energy phosphate bond catalyzed by aminoacyl tRNA synthase (AAS) so called as charging tRNA.
  • AAS is identified by DHU arm and is considered as proofreading mechanism of translation.
  • Aminoacyl tRNA synthase – are specific for particular amino acids and tRNA.
  • They are responsible for high fidelity of translation of genetic message.
  • Implements genetic code by acting as molecular dictionaries.
  • 2 ATPs are required for this reaction.

2.  Initiation- is a multi process stage.

  • It is facilitated by accessory proteins called Initiation factors (IF) and for eukaryotic initiation factor (eIF).

a) Ribosomal dissociation–

  • Two initiation factors(eIF3 & eIF-1A) binds to 40S subunit of eukaryotic ribosome (80S).
  • 80S ribosomes disassociates into 40S and 60S subunits.

b) Formation of 43S preinitiation complex–

  • A ternary complex containing met- tRNA1 and eIF-2(controlling factor in eukaryotes) bound to GTP attaches to 40S subunit to form 43S preinitiation complex.
  •  AUG serves as initiation codon for protein synthesis and codes for methionine

c)Formation of 48S Initiation complex-

  • The binding of mRNA to 43S preinitiation complex results in the formation 48S initiation complex is facilitated by 7- methyguanylate cap at 51 –end of mRNA.
  • In Eukaryotes, Kozak consensus sequence surrounds AUG and determines the initiating codon of mRNA.
  • In Prokaryotes, a sequence of nucleotide bases on mRNA called as Shine- Dalgarno sequence (SD sequence). It is located -6 to -10bp from AUG codon. (purine rich)

d) Formation of 80S initiation complex-

  • 48S initiation complex + 60S subunit = 80S initiation complex
  • 3 sites on 80S Ribosome- A site, P site, E site.

3. Elongation-

  • Catalyzed by proteins called as elongation fators.
  • Has 4 steps-

a) Binding of aminoacyl tRNA to the A-site-

  • Elongation factor EF-1 helps in binding of tRNA.

b) Peptide bond formation-

  • The methionine of tRNA of P- site is transferred to the new amino acid on tRNA of A-site to form peptide bond catalyzed by peptidyl transferase (a ribozyme).

c) Translocation-

  • It requires elongation factor eEF2 (translocase) and hydrolysis of GTP.

4. Termination-

  • Stop codon is in the A site now.
  • In eukaryotes, one single releasing factor, eRF.
  • In prokaryotes, 3 releasing factors- RF- 1, RF-2, RF-3.

Exam Important

  1. Translation occurs in ribosomes.
  2. mRNA is translated from its 5’ end to its 3’- end (51 à 31 )
  3. AAS is identified by DHU arm and is considered as proofreading mechanism of translation.
  4. Aminoacyl synthase implements genetic code by acting as molecular dictionaries.
  5. Two initiation factors(eIF3 & eIF-1A) binds to 40S subunit of eukaryotic ribosome (80S).
  6. AUG serves as initiation codon for protein synthesis and codes for methionine
  7. Shine- Dalgarno sequence located -6 to -10bp from AUG codon. (purine rich).
  8. 3 sites on 80S Ribosome-
  • A site- new aminoacyl tRNA binds
  • P site- growing peptidyl chain present
  • E site- deacylated tRNA present.
  1. 2 ATPs are required for activation of amino acid.
  2.  There is no tRNA for hydroxyproline and hydroxylysine.

 

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Acute myeloid leukemia (AML)

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Acute myeloid leukemia (AML)

ACUTE MYELOID LEUKEMIA (AML)

  • AML is a heterogenous disease characterised by infiltration of malignant myeloid cells into blood, bone marrow.
  • AML is due to inhibition of maturation of myeloid stem cells due to mutations.
  • Seen in mainly in adults (50 years).
  • Chromosomal mutations in AML are
  1. translocation t (8: 21) & t (15: 17)
  2. Inversion  16 or t (16: 16)

Etiology-

  • Hereditary – Down syndrome, Klinefelter’s Syndrome, Patau Syndrome.
  • Radiation
  • Chemical- smoking

Pathogenesis-

  • t (8: 21) disrupt the RUNXL gene & Inv (16) disrupts the CDF1β gene both have good prognosis.
  • t (15: 17) (acute promyelocytic leukaemia-M3) have good prognosis.
  • Gene mutation encoding components of cohesion complex.
  • Most common congenital AML (in infants) are AML M5 (acute monocytic leukemia)
  • Most common AML in children is AML M7 (acute megakaryoblastic anaemia)
  • Most common translocation- MLL gene rearrangements on chromosome 11q.
  • Monosomy is associated with a poor prognosis. 

Clinical features-

1. Due to bone marrow failure-

  • Anaemia
  • Bruises, petechiae, bleeding from gum
  • Infection
  • Fever

2. Due to organ infiltration-

  • Pain & tenderness of bones
  • Lymphadenopathy, enlargement of tonsils
  • Splenomegaly
  • Hepatomegaly
  • Gum hypertrophy
  • Chloroma

Investigations-

1. Blood picture-

  • Anemia
  • Thrombocytopenia
  • WBC increased

2. Bone marrow examination

  • Cellularity- marrow is hypercellular but blood tap or dry tap is seen.
  • Leukemic cells- Blast cell count >20% (WHO)
  • Dyserythropoiesis, megaloblastic features & ring sideroblasts are common.
  • Megakaryocytes.

3. Cytochemistry-

  • Myeloperoxidase- Positive in immature myeloid cells containing granules & Auer rods (most definitive sign of myeloid differentiation)
  • Cluster of Auer rods called as Faggot.
  • Auer rods, distinctive needle like azurophilic granules,they are particularly numerous in AML with the t (15: 17) (acute promyelocytic leukaemia-M3).
  • Non specific esterase (NSE)- positive in monocytic series (M3, M4 & M5)
  • Investigation of choice is flow cytometry.

Treatment-

  • Blood transfusion & platelet transfusion.
  • Cytotoxic drug therapy- most effective treatment of AML is cytosine, arabinoside, anthracyclines.
  • Promyelocytic leukemia (M3)- tretinoin orally
  • Bone marrow transplantation.

Exam Important

  • AML is due to inhibition of maturation of myeloid stem cells due to mutations.
  • Seen in mainly in adults (50 years).
  • Chromosomal mutations in AML are
  1. translocation t (8: 21) & t (15: 17)
  2. Inversion  16 or t (16: 16)

Pathogenesis-

  • t (8: 21) disrupt the RUNXL gene
  • Inv (16) disrupts the CDF1β gene.
  • Gene mutation encoding components of cohesion complex.
  • Most common congenital AML (in infants) are AML M5 (acute monocytic leukemia)
  • Most common AML in children is AML M7 (acute megakaryoblastic anaemia)
  • Most common translocation- MLL gene rearrangements on chromosome 11q.

Investigations-

  • Leukemic cells- Blast cell count >20% (WHO)
  • Dyserythropoiesis, megaloblastic features & ring sideroblasts are common
  • Myeloperoxidase- Positive in immature myeloid cells containing granules & Auer rods (most definitive sign of myeloid differentiation)
  • Cluster of Auer rods called as Faggot.
  • Non specific esterase (NSE)- positive in monocytic series (M3, M4 & M5)
  • Investigation of choice is flow cytometry

Treatment-

  • Cytotoxic drug therapy- most effective treatment of AML is cytosine, arabinoside, anthracyclines.
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Sjogren syndrome

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SJOGREN’S SYNDROME

SJOGREN’S SYNDROME

  • Sjogren’s syndrome is an autoimmune disorder associated with parotid glands.
  • It is characterised by lymphocytic infiltration of salivary and lacrimal gland.
  • It affects women more (40- 60 years)
  • Associated with HLA- B8 & DR3.
  • Associated with RA, SLE, and primary biliary cirrhosis.

Clinical Features-

  • Dry eyes ( keratoconjuctivitis sicca)
  • Xerostomia
  • Vaginal dryness
  • Raynaud’s phenomenon
  • Lymphoma
  • Splenomegaly

The development ofLymphomas in patients with Sjogren syndrome is suggested by : –

  • Persistent parotid gland enlargement
  • Purpura
  • Leukopenia
  • Cryoglobulinemia
  • Low C4 complement levels

Investigations-

  • Schirmer test- for flow of tear
  • ESR elevated
  • Biopsy- The earliest histological finding in both the major and minor salivary glands is periductal and perivascular lymphocytic infilteration which eventually becomes extensive
  • Autoantibodies- RF, ANA, anti- Ro (SS-A), anti- La (SS- B)

Treatment-

  • Lubricants for dry eyes.
  • Xerostomia- saliva forming lubricants
  • Corticosteroids for extraglandular & musculoskeletal deformities.

Exam Important

  • Sjogren’s syndrome is an autoimmune disorder associated with parotid glands.
  • It is characterised by lymphocytic infiltration of salivary and lacrimal gland.
  • It affects women more (40- 60 years)
  • Associated with HLA- B8 & DR3.
  • Associated with RA, SLE, and primary biliary cirrhosis.

Clinical Features-

  • Dry eyes ( keratoconjuctivitis sicca)
  • Xerostomia
  • Vaginal dryness
  • Raynaud’s phenomenon
  • Lymphoma
  • Splenomegaly

The development ofLymphomas in patients with Sjogren syndrome is suggested by : –

  • Persistent parotid gland enlargement
  • Purpura
  • Leukopenia
  • Cryoglobulinemia
  • Low C4 complement levels

Investigations-

  • Autoantibodies- RF, ANA, anti- Ro (SS-A), anti- La (SS- B)
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Glucose-6 -phosphate dehydrogenase deficiency (G6PD)

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Glucose-6 -phosphate dehydrogenase deficiency (G6PD)

GLUCOSE-6 –PHOSPHATE DEHYDROGENASE DIFICIENCY ANAEMIA (G6PD)

  • Hereditary disorders of red cell interior are of 2 types-

1. Red cell enzyme defects (enzymopathies)

  • Defective red cell metabolism involves 2 pathways-
  1. Defect in hexose monophosphate shunt- E.g. G6PD deficiency.
  2. Defect in Embden- Meyerhoff pathway- E.g. Pyruvate kinase deficiency

2. Disorders of haemoglobin (Haemoglobinopathies) 

G6PD-

  • G6PD gene is located on the X- chromosome & its deficiency.
  • Sex- linked trait affecting males and femal are carriers.
  • Normal G6PD variant- Type B & Type A+
  • Most common & significant variant A- type found in dark males.
  • A- type G6PD variant protects against malaria.
  • Abnormal protein folding leads to G6PD loss.
  • Haemolytic attacks due to oxidant stress-
  1. Drugs- antimalarial (Pyrimaquine), sulphonamides, vitamin K.
  2. Ingestion of Fava beans (favaism)
  3. Infections

Pathogenesis-

  • In G6PD deficient cells oxidant will denature globin of haemoglobin to form Heinz bodies.
  • To detect Heinz bodies stain, crystal violet is used.
  • Macrophage will remove Heinz bodies & bite cells are formed.

Clinical features-

  • Acute haemolytic anaemia
  • Acute renal failure
  • Neonatal jaundice

Lab findings-

1. During period of acute haemolysis,

  • Rapid fall in haematocrit value.
  • Formation of Heinz bodies is visualized by crystal violet called Heinz body haemolytic anaemia.

2. Between the crises- red cell survival is short.

 Diagnosis–

  • MRT, Fluorescent screening test, ascorbate cyanotic screening test.
  • Direct enzyme assay in red cells.

Treatment-

  • Prevention of haemolytic anaemia
  • Blood transfusion rarely.

Exam Important

  • Hereditary disorders of red cell interior are of 2 types-
  1. Red cell enzyme defects (enzymopathies)
  • Defective red cell metabolism involves 2 pathways-

a) Defect in hexose monophosphate shunt- E.g. G6PD deficiency.

  • G6PD gene is located on the X- chromosome & its deficiency.
  • Sex- linked trait affecting males and femal are carriers.
  • A- type G6PD variant protects against malaria.
  • Abnormal protein folding leads to G6PD loss.
  • Haemolytic attacks due to oxidant stress-
  1. Drugs- antimalarial (Pyrimaquine), sulphonamides, vitamin K.
  2. Ingestion of Fava beans (favaism)
  3. Infections

Pathogenesis-

  • In G6PD deficient cells oxidant will denature globin of haemoglobin to form Heinz bodies.
  • To detect Heinz bodies stain, crystal violet is used.

Clinical features-

  • Acute haemolytic anaemia
  • Acute renal failure

Lab findings-

  1. During period of acute haemolysis,
  • Rapid fall in haematocrit value.
  • Formation of Heinz bodies is visualized by crystal violet called Heinz body haemolytic anaemia.
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Healing of specialised tissue (fracture healing)

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Healing of specialised tissue (fracture healing)

HEALING IN SPECIALIZED TISSUES

Fracture healing-

  • Healing of fracture by callus formation depends on-
  1. Traumatic/ pathological
  2. Complete/ incomplete
  3. Simple/ compound 

Healing of any fracture takes place by-

  1. Primary union of fracture
  2.  Secondary union (more common)- it is described under 3 heading-

a) Procallus formation- it is as follows

  1. Hematoma formation
  2. Local inflammatory response- fragments of necrosed bone are scavenged by macrophages & osteoclasts
  3. Ingrowth of granulation tissue- soft tissue callus formed
  4. Callus composed of woven bone & cartilage

b) Osseous callus formation-

  • Callus formation takes place- 4 to 12 weeks

c) Remodelling

  • Osteoblast & osteoclast removes necrotic content, which results in remodelling of the united bone end into compact bone.

Exam Important

  • Healing of any fracture takes place by-
  1. Primary union of fracture
  2.  Secondary union (more common)- it is described under 3 heading-

a) Procallus formation- it is as follows

  1. Hematoma formation
  2. Local inflammatory response- fragments of necrosed bone are scavenged by macrophages & osteoclasts
  3. Ingrowth of granulation tissue- soft tissue callus formed
  4. Callus composed of woven bone & cartilage

b) Osseous callus formation-

  • Callus formation takes place- 4 to 12 weeks

c) Remodelling

  • Osteoblast & osteoclast removes necrotic content, which results in remodelling of the united bone end into compact bone.

 

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Stem cells

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Stem cells

STEM CELLS

  • Stem cells has major 2 properties-
  • Self renewal
  • Asymmetric replication (stochastic differentiation) 

Types of Stem cells-

1. Embryogenic stem cells (ES cells)-

  • They are pluripotent (generate all cell lineages)
  • Isolated from normal blastocysts
  • Most undifferentiated stem cells.

2. Adult stem cells

  • Also called as tissue stem cells.
  • Adult stem cells occur in specialized micro environmental within organ called stem cell niches.
  • Adult stem cells are-

a) Liver stem cells-

  • At canals of Hering
  • Forms bipotent progenitor called oval cells.

b) Skin stem cells-

  • Forms bulge stem cells.

c) intestinal crypt epithelium-

  • Located above Paneth cells.

d) Skeletal muscle

  • Located at basal lamina of myotubules.
  • Called as satellite cells.

e) Cornea

  • Located limbal stem cells.

f) Bone marrow

  • Pluripotent
  • Marrow stromal cells

g) Brain

  • Located at dentate gyrus
  • When stem cells transforms to form cells characteristic of other tissues, the process is called as trans differentiation.

Exam Important

Stem cells has major 2 properties-

  • Self renewal
  • Asymmetric replication (stochastic differentiation)

Embryogenic stem cells (ES cells)-

  • They are pluripotent (generate all cell lineages)

Adult stem cells

  • Also called as tissue stem cells.
  • Adult stem cells are-

a) Liver stem cells-

  • At canals of Hering
  • Forms bipotent progenitor called oval cells.

b) Skin stem cells-

  • Forms bulge stem cells.

c) intestinal crypt epithelium-

  • Located above Paneth cells.

d) Skeletal muscle

  • Located at basal lamina of myotubules.
  • Called as satellite cells.

e) Cornea

  • Located limbal stem cells.

f) Bone marrow

  • Pluripotent
  • Marrow stromal cells

g) Brain

  • Located at dentate gyrus
  • When stem cells transforms to form cells characteristic of other tissues, the process is called as trans differentiation.

 

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Urolithiasis

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urolithiasis

UROLITHIASIS

  • Urolithiasis/ nephrolithiasis is the formation of urinary calculi at any level of urinary tract.
  • Most common location of calculi arise in the kidney.
  • More common in males.
  • Seen in 2nd to 3rd decades of life.
  • They are characterised by colicky pain (renal colic) & hematuria.

Types of Urinary Calculi-

  • There are 4 types of urinary calculi-
  • 90% Idiopathic
  • Most common abnormality found in standard investigation – hypercalcemia
  • Calcium oxalate – most common (70%)
  • Struvite stones – 15%
  • Calcium phosphate – 10%

a) Calcium stones-

  • Most common of all calculi
  • Most common cause is hypercalciuria with or without hypercalcemia
  • They are radioopaque stones.

b) Mixed (Struvite) stones-

  • Made up of magnesium- ammonium- calcium phosphate so often called as struvite or triple phosphate stones.
  • Caused due to infection of urinary tract with organism as Proteus so called as infection induced stones.
  • ‘Staghorn stones’ is an example of struvite stone.

c) Uric acid stones-

  • Made of uric acid.
  • They are radiolucent.
  • Caused by hyperuricaemia and hyperuricosuria as primary and secondary gout.
  • Hyperuricosuria is the most important factor for the production ofuric acid stones.

 d) Cystine stones-

  • Formed in acidic urine due to genetic defect of metabolism.
  • They are yellowish and waxy.

Exam Important

  • Gastrointestinal disorders predisposes to urolithiasis -short bowel syndrome.
  • Gallstones and kidney stones are known complications of IBD
  • 90% Idiopathic
  • Most common abnormality found in standard investigation –hypercalcemia
  • Calcium oxalate – most common (70%)
  • Struvite stones – 15%
  • Calcium phosphate – 10%

 

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Granulocyte Stimulating Factor (G-Csf)

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GRANULOCYTE STIMULATING FACTOR (G-CSF)

GRANULOCYTE COLONY-STIMULATING FACTOR

  • Granulocyte-colony stimulating factor (G-CSF or GCSF)/Colony-Stimulating Factor-3 (CSF 3).
    • A glycoprotein that stimulates bone marrow to produce granulocytes and stem cells.
  • Produced by endothelium, macrophages, and other immune cells in response to cytokines.
  • Recombinant G-CSFs include filgrastim, lenograstim, nartograstim & pegfilgrastim.
  • Normally present during pregnancy. 

Actions of G-CSF:

  • White blood cells
    • G-CSF-receptor present on precursor cells of bone marrow.
    • Initiates proliferation & differentiation into mature granulocytes. 
    • Stimulates survival, proliferation, differentiation and function of neutrophil precursors & mature neutrophils.
  • Hematopoietic system
    • Potent inducer of hematopoietic stem cell mobilization from bone marrow into bloodstream.
  • Neurons
    • Can also act on neuronal cells as neurotrophic factor.

Medical use:

  • Treatment of chemotherapy-induced neutropenia.
    • Also indicated for Kostmann’s syndrome (severe congenital neutropenia).
  • Used before blood donation.
    • Used to increase hematopoietic stem cells quantity in donor blood, before collection by leukapheresis.
    • This is particularly useful during hematopoietic stem cell transplantation.
  • During stem cell transplants
    • Given to receiver during hematopoietic stem cell transplantation, to compensate for conditioning regimens.
  • Fastens wound healing:
    • Systemic injection of G-CSF mobilizes hematopoietic stem cells to wound site and accelerate healing by clearing granulating bed.
  • Acts as reliable biomarker for Early-Late Onset Neonatal Sepsis (EOS).

Exam Important

  • Drug of choice for Neutropenia due to cancer chemotherapy is Filgrastim.
  • G-CSF stimulates production of a wider variety of hematopoietic stem cells.
  • Filgrastim is used in treatment of Neutropenia.
  • Treatment in a child with recurrent severe bacterial infections and diagnosed of having Kostmann’s syndrome is G-CSF.
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