Insight of Cell Injury + The most common cause of cell injury is Hypoxia. + Themost common cause of Hypoxiais ischemia + Themos sensitive cell to Hypoxiais the brain neurons ‘+ Themostresistant cello Hypoxiaisa fibroblast. Cellinjury Injury 4 Adaptation 1 fails Reversible cel jury injury continues Irreversible (cell death) cell injury ‘Types of Cell Injury omos2s There are two types of cell injury: 1. Reversible Cell Injury 2. Imreversible Cell Injury Reversible Cell Injury eoosz2 Mitochondrial Dysfunction occurs causing the decrease in ATP production, ‘The process of ATP failure includes: 1, Failure of Na’ K" ATPase Pump, NORMAL FAILURE /REVERSAL Na “ - CELLULAR 1,0 ‘SWELLING! INFLUX HYDROPIC we an CHANGE PYQ FIRST MORPHOLOGICAL, Nokia ‘CHANGE IN CEL INJURY © Thereis H20 influx. - + Itisreferredtoas Hydropic Change. + Thisis responsible for the following: © Cellularswelling © Endoplasmic reticulum swelling co Flattening of the microvil © Formation ofcytoplasmic blebs a / ii © Formation of Myelin Figures, also called Concentric Lamellation, > Composition: Phospholipids (primarily) and Ca’ 2. Anaerobic Glycolysis ‘* The pH will become acidic, causing the nuclear chromatin io clump. . Decreasein Protein Synthesis The ribosome detachment is seen, leading to a decrease in protein synthesis. © Thisisalsoassociated fatty change Irreversible Cell Injury co228 ‘Thetwodefining moments of irreversible cell injury are: 1, Severe Membrane Damage: The inflow of calcium occurs. Itcauses the activation of three enzymes: 1. Phospholipase b. Protease c. Nuclease 2. Severe Mitochondrial Damage: The calcium sits on the mitochondria causing Amomphous Flogculent Densities. (& Important Information Myelin Figures: + Myelin Figures arealso called concentric lamellation. ‘¢ Myelin figures are seen in reversible as wellas ireversible cell injuries. ‘More Myelin figures are seen in irreversible cel injury.Nuclear Changes tn the Cell Injury: ‘The three stages of nnctearehanges in cell injury are: 4 Pyknosis: The mucleus becomes stall and dark due to the nuclearehromatinedit ok condensation ryortheals: There will be Nuclear Fmagmentation, + Karyolysts: Thenneleusets dissolved, "Normal Nusieus Cell Death - Necrosis (vecteaee) Nuc tar CHANGES, NORMAL PYKNOSIS —_KARYORRHEXIS CELL Nuclear cleus chromatin | fragmentation Nuclear shrinkage Karyolysis Pyinosis—_Karyorrhexls osu Definition ‘* Misa Pathological Cell Death. ‘* Misassociated with inflammation. Microscopic Exami ‘* Itappears pink (Eosinophilic) © Amorphous + Inflammation Types of Necrosis 1. Coagul ive Necrosis: is the most commonly occurring Necrosis. ‘There is denaturation ofthe proteins. occurs in the solid organs (kidney, liver, heart) Occurrence of infarct (Wedge shaped structures) in the organs. Leading to the formation of multiple ghost cells, causing a ‘Tombstone Appearance The tissue architecture is preserved even after the death of the cells. (> important information Ghost Colts © Ghost cellsare associated with coagulative Necrosis, © Occurs on askin-generated tumor, Pilommatrixorna The row of Tombstone appears in the Pemphigus (Pemphigus Vulgaris) 2. Liquefactive Necrosh © Imosily occurs in CNS and Pancreas, ©. This occurs because they are rich in Hydrolytic Enzymes. © Itisalsocalled Colliquative Necrosis. © The issuearchitecture is not preserved. 3. Cascous Necrosis (© Associated with the high lipid content in the cell walls. (© Thereischeese-like appearance of the organs. © It is the combination of Coagulative Necrosis and Liquefactive Necrosis. © Most common examples include tuberculosis, fungal infection (histoplasmosis; coccidioidomycosisis). syphilis, etc 4, FatNecrosis: (© Itoccurs inthe fat © Itcauses the breakdown of fats into fatty acids. © AChalky White appearance is seen. © Italso occurs around the pancreas due to the presence of peripancreatic fat. ich organs .g.. breasts; omentum. etcS. Flbrinoid Necrosis: © Associated with the antigen-antibody reactions (immu complex deposition), © Someexamples are: ~ Polyarteritis Nodosa (PAN) > Rheumatic Heart Disease (RUD) > SLE ~ Malignant Hypertension (HTN) 6. Gangrene: © Blackish discoloration ofthe organs. © Foul smelling. ‘© Dry gangrene is classified as Coagulative Necrosis with a line of demarcation. ‘© Wet gangrene is classified as Liquefactive Necrosis without any line of demarcation. 7. Zenker's Degeneration: © Itisatype of Coagulative Necro: © Itoceurs in typhoid or Enteric fever. © Itisa complication seen in the skeletal muscles: — Rectus Abdominis — Diaphragmatic Muscle McQ: Q. Myelin figures are derived from? Cytoplasm Nucleus ‘Cell Membrane Ribosomes: ae oe A61-YEAR-OLD female patient presents with left-sided chest pain radiating to the Jeft arm and jaw, The patient explains that the pain has increased severely over the past 40 minutes. She is immediately rushed to the hospital. Cardiac ‘enzymes are elevated. The patient was admitted and started on thrombolytic therapy. However, on the fifth day of observation, she suddenly collapses und dies. Which of the following Necrosis are you most likely to find in the heart of © this patient? emmemmmmenmmamcconeencane 3 4, Liquefuctive Necrosis b, Congulative Necrosts ©. PatNecrosis , Fibrinold Necrosis Q. AA5-yeur-old female patient complained of being hit in the chest by a football while passing by a garden 4 weeks back. Initially, her loft breast was tender and swollen, But aver the weeks, the tenderness has subsided, However, she now notices a lump in the peri-arcolar region which is firm to hard in consistency, Radiological investigations reveal calcific deposits. Which of the following best describes the phenomenon above? 8, Liquefaetivenecrosis b, Coagulative necrosis ©. Fatnecrosis 4d. Fibrinoid necro ono Cell Death—Apoptosis Definition: + Apoptosisis a greek word hat means "falling off.” © Itis both physiological as well as pathological cell death. Mitochondria play a pivotal role in apoptosis. © It is a programmed cell death, now known as Caspase Dependent Programmed Cell Death. ATP Usage: ‘© There willbe the usage of ATP. © Occurs asin Active Process Inflammation: ‘© Noinflammation will occur. 3 Examples of Apoptosis ‘+ Physiological Apoptosis (© Organogenesis (Embryogenesis), For example, fingers andhand formation. © Neutrophils Clearance ~ o Endometrial Shedding + Pathological Apoptosis © Councilman Bodies, seen in viral Hepatitis (Hepatitis C- Virus) © Civatte/ Colloid/ Cytoid Bodies, seen in Lichen Planus. EB Important information Chemotherapy: © Itcauses cancer cell death ‘© W’sacombination of Apoptosis (80%)and Necrosis(20%). | |Caspase oui ‘+ Itconsists of Cysteine Residue. © Whreaks afer aspartic acid residues. * MisanEnzyme, Mechanism of Apoptosis, ‘The mechanism is classified into two processes. 1, Initiation It is dependent on Caspase 8, 9, and 10, There are two pathways toapoptosis initiation, a, Extrinsic Pathway: i, Ihappenson the surface of the cell ii, The cell wanting to die will have CD95 / Fas, and the supporting Tell will have CD9S Ligand /Fas Ligand. ili, I leads to the occurrence of Trimerisation of CD95/ Fas iv. The Fas Associated Death Domain (FADD) will activate Procaspase 8, 10 into Caspase 8, 10. The process is inhibited by FLIP (ant molecule) Vi, Itisalso called Death receptor pathway. b. Intrinsic Pathway: i. Itisalsocalled Mitochondrial Pathway ii, Ithappens within the cell. occurs when the cells undergo stress. iv. The stress is detected by the stress sensors: BIM, BID, BAD,NOXAand PUMA. v. The sensor increases the pro-apoptotic factor and decreases the anti-apoptotic factors. vi. The Apoptosome activates Procaspase 9 into Caspase 9. vee i PYq ca aportosome "me ae wrt Factor Proc z © ps3 * BCI2 * BAC * MCII * BAX © BCIXL 2. Execution: © Moccursafterthe Initiation process. ‘+ Itisdependent on Caspase 3, 6,and 7. ‘© Mactivatesthreeenzymes: © Phospholipase © Protease E> important Information Endonuclease: © Ibreaks the DNA after 180-200 bp ‘© Iis called Internucleosomal Cleavage Once the execution takes place, the cell falls off into small bodies called apoptotic bodies. These apoptotic bodies give an "Bat me" signal to Macrophages, causing Phagocytosis. Efferocytosis + The apoptotic bodies giving the eat-me signals, expressed in the form of Clq, Thrombospondin, and PS (Phosphatidy! Serine) In the normal cell, the Phosphatidyl Serine is present in the inner leaflet, butsin-the: apoptotic cell, the Phosphatidy! Serine comes out?" ‘© There is Phosphatidyl Serine Flipping. ‘* Theflipping is knowns the signal given to the Macrophage. ‘One major defect of fipping is Scott Syndrome. * The Macrophage engulfs the apoptotic bodies, which is called Efferocytosis. 13810 Defectsin Efferosome * SLE * COPD © Bronchiectasis, © Cystic fibrosis EE Important Information ‘Survival of Cancer cells: ‘+ Cancer cells express CD47 to Macrophages. * Cd47isa"Donot Eat me" Signal. Update Robbins 10c- * Proapoptotic molecules [BAC, BAX, BCLXS}: BH |-3 Anti-apoptotic molecules [BCL2, MCLI, BCLXL}: BH | -4 * Stress sensors [BIM, BID, BAD, NOXA, PUMA]: BH 3 only. + SMAC/DIABLO: Proapoptotic onsnss * Glucocorticoids: Proapoptotic * Sex Steroids: AntiapoptoticIdentification of Apoptosis ours? Marker: Annexin V (marker for testing PS flipping) Molecular Marker: CD95/Fas Microscopic Examination: Nuclear Chromatin Condensation. (The cytoplasm will be pink and Nucleus will beblue, along with cellularshrinkage) ‘Stain: Tunel Stain (TdT dUTP Nick End Labelling) © Positive: Apoptosis © Negative: Necrosis Gel Electrophoresis: Step Ladder Apoptosis BD important Information ‘© Step Ladderis seen both in Apoptosis and Necrosis. Bywesoget mea? PREVIOUS YEAR QUESTIONS ° Q. Whatis the first change in the cell injury? Mitochondrial Dysfunction Q. Whichis the first morphological change in the cell injury? The cellularswelling or Hydropic Change. Q. Whatis the composition of Myelin Figures? Primarily made up of phospholipids and a calcium. F presence of Q. What is the composition of Amorphous Flocculent Densities? Calcium. . The injury with which the Amorphous Flocculent Densities are associated? ‘ Irreversible Cell Injury. . The three stages of nuclear change in the cell injury? Pyknosis Karyorthexis Karyolysis. Q. What is the most common type of Necrosis? Coagulative Necrosis Q. Which are the most common organs affected by Coagulative Necrosis? Heart Q. Which necrosis happens inside the pancreas? Liquefactive Necrosis Q. Which necrosishappens around the pancreas? Fat Necrosis Q Zenker's Degeneration be seen in which skeletal muscles? Rectus Abdominis Diaphragmatic Muscle+ ‘ewer Cell Deaths Necroptosis Pyroptosis Ferroptosis Anoiki Necroptosis Necrosis + Apoptosis makes Necroptosis 090.22 Definition: Caspase independent programmed cell death Necrosis: + Morphology © Inflammation Apoptosis: © Programmed cell death Necroptosis: + Physiological ‘©. Growth Plate Formation in Human Body + Pathological ‘© Reperfusion Injury (MI) Updates: Robbins 10th Edition Programmed Necrosis (New terminology to necroptosis) cmv «It does not undergo apoptosis due to the presence of caspase inhibitors. ‘+ Iundergoes necroptosis (caspase independent) Mechanism of Necroptos © 1-2-3death © Step 1: TNF comes andbindto TNF receptor © Step 2: due to binding trio occurs -RIPK 1, RIPK 3 (RECEPTOR INTERACTING PROTEIN KINASE,) PROCASPASE8 © Step 3: MLKL phosphorylation which results in Cell Death Pyroptosis Pyromeans Fever + tosis means cell death. ‘Associated with microorganisms. Examples: ‘© Initially studied for Shigella an salmonella 2 NEWER CELL DEATHS Bacteria enters the body Binds to NOD Receptors (gest activated) 1 Inflammasomes tL activates CASPASE I—+activates IL-1 — fever 4 5 } Cell death un Anoikis ‘Type of apoptosis - why isitdifferent? + Lackofnatural environment Example: © Cells keptinan unnatural environment-cell dies. oonn27 Q Choose the incorrect statement about Necroptosis ? a. Isitacaspase independentcell death b. RIPI&3is formed ¢. Caspase8isrequired 4. Growth plate formation follow necroptosis. Q Choose the incorrect statement about pyroptosis ? a, Seeninresponse toshigella b. TLRisused c. Caspase | is required d. ILL activated Cell Injury - Cellular Adaptations © Hypertrophy © Hyperplasia ©, Atrophy © Metaplasia © Dysplasia- PRECANCER Healthy cll HypertrophyHypertrophy + When the size of cells is increasing but the number remains same Hyperplasia + Number of cells increases, size remains same Differentiation between Hypertrophy and Hyperplasia Basic Difference Increase in Size of cells Increase the number of cells Mechanism Increase in -Transcription _« Happens by Factors division/mitosis *GATA4 Increases the number of NFAT cells * MEF 2 Are being elevated. + More RNA + More Protein Hence the size increases: *DNA —___ RNA Teascripion — Protein ‘Common Examples are: Common examples of hypertrophy and hyperplasia are 1. Gravid uterus shows hypertrophy (more commonly) as well asbyperplasia 2. Breast development during puberty and pregnancy shows both hypertrophy as well as hyperplasia (more commonly) Examples of Hypertrophy (only) 1. Bodybuilders- Skeletal Muscle Hypertrophy 2. Obstruction Proximal o Obstruction Q. How will the body adaptto obstruction? Answer: The body is going to adapt o hypertrophy. Example: Aortic stenosis — left ventricular hypertrophy Examples of Hyperplasia (only condition) For Females Endometrial Hyperplasia © Increased Estrogen i responsible, Q..Name one condition whereestrogen increases? Ovarian Tumors -Granulosa Cell Tumor Produces estrogen —> it will cause endometrial hyperplasia —+ Riskof Endometrial cancer type 1 For Males * BENIGN PROSTATIC HYPERPLASIA © Now called Nodular Hyperplasia of the Prostate © Testosterone <> DIIT - Dihydotestosterone (metabolite) —> hyperplasia F inhibits Finasteride Atrophy © Cellsize decreases + Cellnumberdecreases Mechanism of action UPP- UBIQUITIN PROTEASOME PATHWAY. Examples: + Disuse Atrophy ~ Fracture —» cast for six weeks —+ muscle atrophy + Denervation Atrophy © Polio * Ischemic Atrophy © Senile» Alzheimer’s Disease + Malnutrition + Endometrial atrophy © Lessofestrogen More estrogen + endometrial hyperplasia + Endometrial Cancer Less estrogen —sendometrial atrophy + Endometrial Cancer Type 2 Type | © Worst prognosis Metaplasia Allcellular adaptations are Reversible. Toughest to revertis Atrophy. Q. What metaplasiais, # 100%reversible # Onetissue another tissue 6 Epithelial = epithelial © Mesenchymal Sii@tinchymal Mechanism of action ‘+ Reprogramming of the Stem Cells. Examples: + Epithelial toepithetial Q. Most common metaplasia 1) Squamous metaplasia- most common condition Pseudostratified ciliated columnar epithelium Chronic Smoker Vitamin A (deficiency/excess) \d result) epithelium squamous (2) Barrett's Esophagus - Precancerous adenoca esophagus (cancer) Squamous epithelium ——> intestinal columnar epithelium noma of the 1 Contains goblet cells Alcian blue positive (special stain) Q. Hallmark of Barrett Esophagus © Gobletcells Q. Wheredo you see Mesenchymal metaplasia Breast is one such organ where all Myositis(muscle) + ossificans(calcium/bone) Muscle changes to bone—voccurs dueto trauma 1 the adaptation happens. In Puberty & Pregnancy Hypertrophy and Hyperplasia both occurs, M/Cis hyperplasia. ‘Atrophy occurs in postmenopausal occurs —+ old age ladies Metaplasia- © Squamous Metaplasia of the lactiferous Ducts (SMOLD) © Most commonly seenin chronic smokers female MCQs Q. Allare true for meta a, Slow growth b, Reversible with treatment c. Irreversible except? 4, Canbe precancerous Seyret ‘istopathological difference between Barrett's epithelium and gastric mucosa? a. Barrett's mucosa is acidic and stains alcian blue po b. Barrett's isalkaline and stains prussian blue positive cc. Barrett's alcian blue negative becauseitsneutral d. Gastrie mucosa is alkaline andstains aleian blue positive Q. A47-year old man visits an outpatient clinic with complaints of heartburn and chest pain for the past 6 months. His pain is retrostemal and was initially only associated with intake of solid foods, but it now occurs with liquid as well. Antacids don't relieve his pain anymore. He is worried about the pain as it is getting worse.physical examination including abdominal examination isnormal. He has lost 2.7 ka(6 Tbs). Laboratory investigation reveals.: Hgb-10gm Platelet count- 168 * 10.9/ L. Esophagogastroduodenoscopy reveals an exophytic mass in the lower third of the esophagus. Which of the followingis the mostllikely diagnosis in the patient? ‘Squamous Cell Carcinoma Leiomyoma Gastric Uleers . ‘Adenocarcinoma pes%&Q CROSS WORD PUZZLES e Crossword Puzzle Across 3, Initially studied for Shigellaand salmonella 4. Allcellular adaptations are REVERSIBLE. Down 1, When the size of cells is increasing but the number remains same 2, Number of cells increases ,size remains samePigment Melanin © Presentin, skin, hair & eyes, + Inthebrain, melaninis present inthe substantia nigra 008s & Important Information * InParkinson's disease, there is a decrease in dopaminergic neurons, which causes a decrease in dopamine and ‘melanin, causing the appearance of a pale substantia nigra, Melanin Stain ‘+ Inthe skin, there is a brownish stain around the basale layer, whichis called stratum basale. ‘© The blackish color image representation of the melanin stain is knownas the Masson Fontana Silverstain. 3 | INTRACELLULAR ACCUMULATIONS + The bluish color stain isknownas the Schmorl stain. ‘© The best stain that we have for melanin is the Dopa Oxida Itisalso knownas the enzyme histochemical stain. ‘+ Immunohistochemistry -HMB 45 and $100. * Itconsists ofany existence ofhemorrhage orhematoma. * Yellow. Brown, refractile (Shiny) © Perl's stain or Prussian Blue stain can be seen. * Itconsists of Fe3+ # In the case of any iron overload, Hemosidetin will b appearing. E> Important Information 's stain will done forFe2+Lipofuscin or ipochrome: moxso ‘¢ Itisalso definedas wear and tear pigment: © SenileAtrophy © Brownatrophy ‘Atelltale sign of free radical injury (morein oldage) If a free radical injury increases, lipofuscin will increase because free radicals do ligid peroxidation, which causes the formation of lipofuscin. «As it is present around the nucleus, it is also called perinuclear, Q. What arethe special stains? Oilred O, ZN stain (Acid Fast) Certain criteria regarding pigments: + Copper: ‘©. Increased copper will cause Wilson's disease. © The special stain that is related 10 copper is Rhodanine and Rubeanic acid. © However, Rhodamine is related to mycobacterium TB (Buuorescent) © The copper-associated protein is ceruloplasmin. Orcein stain is related to ceruloplasmin, It is the stain for the HBsAgand Elastin © Hemati ‘© Italso shows Hamazoin, which comes up in the di ase of malaria * Anthracotic pigment: © This pigment consists of carbon. © Therefore, individuals that smoke a lot show these varieties of pigment. mogentisic acid: © Wis also a black-colored pigment that gets deposited in the disease of Alkaptonuria, Lipids: ‘= The most common organ where the fat will get deposited is, the fatty liver/steatosis. ‘When the fat gets deposited in the heart, itis called the tigered effect or tabby cat. ‘Some conditions for the deposition of fatin the heart are: © Cellinjury © ARVCM (Arthythmogenic right ventricular cardiomyopathy) © Diphtherial Myocarditis, In the case of atherosclerosis, some empty spaces can be seen in the image. These empty spaces are called cholesterol clefts. InH& Esai @ Due to the processing with alcohol, the fat is washed off, which causes the formation of Cholesterol Clefis. ‘The tiny yellow color dots are called Cholesterolosis of the gallbladder, It is also called the strawberry gallbladder, ‘© Italso shows foamy macrophages. ‘Therefore, the representation where mg has engulfed all the cholesterol. nDosily seen inalcoholic liver disease wosed of eytokeralin 8/8, © Multiple myelom Stains fortipids: > They are Thered color stain is called the oil red O The black colorstain is called Sudan Black B The orange color stain is called Sudan 4, One of the other stains is knownas the osmium tetroxide. Cryostat or frozen section machine. This machine is used for the identification of the oil red. Iso knownas the tumor of plasmacells. >It is caused due to the increased production of antibodies. > Russell bodies are intracytoplasmic collections of immunoglobulins > Dutcher bodies are intranuclear collections of immunoglobulins © Crooke Hyaline Change: Protein: 028-7 * Thereare two conditions of protein accumulati © Eitherthere will bean accumulation of too much protein, © However, there must be another condition which is called > Itis seen in the pituitary gland. the misfolding protein. > Itis caused due to Cushing disease ‘+ Someexamplesare: — Itis composed of cytokeratin, ee ee ae te: Peery Parent ras g protein.) LDLRe Alzheimer’s disease AATD (Hypercholestrolemia Abeta (Alpha t Deficiency) CFTR (Mutation.) Prion disease PrP protein Tay Sachs Disease Retinitis pigmentosa (Hexosaminidase deficiency. ) ——<—$SS— 880 O8ee&& Important Information © The alpha-1 deficieney causes patuneinar enphyxernn in the lungs (Caused due to the delicieniey of the protein.) and eirshosis in the liver (Caused due t0 th protein), misting omasar lyeogen will be accuntilatedonly in the enseof © Glycogenstorage disease, ‘© Diabetes Mellitus, (Diabetic nephropathy.) => Glycogen goes into the PCT (Proximal convoluted ‘Tubule), then itis called an Armani Ebstein Lesion, ‘© Somespecial stains are: > PAS (Perlodic acid Schiff) = lewillbe pinkin color. > PAS + Diastase Sensitive shows that if you add the diastase, the glycogen will vanish. Hence, the pink color will disappear. Calcification: + Typesof calcification: ©. Dystrophiccaleification: —~ Dead or degenerating tissues are seen. — There will bea normal blood calcium levels. > Some examples: * Dead Parasite + 1B + Atheroma + Monckeberg Sclerosis: © Itisalsocalled calcific medial degeneration. © Ithappens in the tunica media. © Calcium oceurs blue in color. © IMoccurs only as an old age phenomenon and there is no clinical significance, o Psammoma Bodies: Stains for calcium: © Von Kossa: Itwill give usablack color. is present asaconcentriclamellations, tshowsan onion peel appearance. “The psammoma bodies areseen in => Papillary Carcinoma > Protactinoma + SomatoStatinoma >» Serous Ovarian Tumor > Meningioma > Mesothelioma Metastatic calcification. — Seen in normal tissues. + The blood calcium level is elevated > The most common organ affected due to metastatic calcificationis the lungs Some Examples: = Hyperparathyroidism: It occurs due to the increase ofthe parathyroid hormone, Caused by the increase inthe calcium = Cancer: RCC and Breast cancer shows an increase of calcium. + Vitamin D intoxication + Milkalkali syndrome. = Multiple myeloma: It shows bony lytic causing the increase of calcium level in the blood. Sarcoidosis: It shows non-caseating granuloma, causing the increase of vitamin D3. Henceforth, increase in the calcium level. oosiso2 CROSS WORD PUZZLES Crossword Puzzle Across 3. He is said to contributions are as follows: 4, Thisis caused by integrins in Leukocytes. Integrins be the father of modern Pathology. His Down 1. Vasoconstriction (First event, Transient event | seconds, Reflex) 2, Leukocytes Mediated. Injury: It i Leukocytes by releasing Enzymes. lasting for few s done by WBCs. and© Alvanin Red S ‘© ltwill giveusa red color. used to represent when the minute amount of calcium is present. = Calcein + AZANstains: (9. Itisused for differentiating between andosteoid. the mineralized bone Onc-liner: Q. What isthe first plac ‘Ans. Mitochondria (However, in the history of kidney deposition, ‘goes into the basement membrane) ce of deposition of thecalcium? the calcium MCQs: Q. Elderly female patient presented othe outpatient department with the presence of @ lump in the right breast measuring Sadem, The lump was firm to hardin consistency. The right axillary group of lymph nodes is also palpable and shows the presence of tumor deposits. There is the deposition of an tmorphous material noted which stains positive with von Kosst stain, Which of the following statements is incorrect regarding the same? a. Grossly calcium appears ch b. Von Kossa gives black color to calc c. Stains for picking up minute quanti alizarinredS 4. The fist site of deposition of calcium is the endoplasmic reticulum : incolor jum ities of calcium include alky whi ans:d, The firs site of deposition ofcalejumis the endoplasmic eticulum J with « pizenented lesen sd suale patient presented vy of the lesion “dx em on the right cheek. A biops I cells with prorninent nucleoh diagnosis of Q.ASA-yenro mensring stuns the presence af atypical Histopathological Mitotic figures are noted. inatignant melanoyyinde: Which of the following cannot be sed for thedingnosis? 8, Masson Fontan ssi ¢, HIMB4S 4d. Masson trichrome ‘Ans: d, Masson trichrome Q. Incorrect about the pigment shown. b, Formeddue tol ¢. Canbepositive for il red O 4. Seenmore commonly in infants ‘Ans: d. Seen more commonly in infants Q. Which OF The Following Stains Is Best Suited For The Diagnosis OfGlycogen? a OilredO b. Perl'sstain c, PAS d. Congored ‘Ans:c, PASPremature Ageing ome Werner Syndrome or Adult Progeria Laminopathy Syndrome Occurs in erin adulthood CCaltracewsora accu it ‘ty indo patients ate which Later onset Early Childhood Onset = disease DNAHelicase LMNA(LaminA)gene — ERCC defect defect where the nucleus is gene defect not developed properly Medical Therapy for Hutchinson Gilford Syndrome: Lonafarnib - A famesyl transferase inhibitor is under trial It is supposed tocorrect the nucleus. Note ‘Adult progeria syndrome MEN (Multiple Endocrine under premature ageing. Neoplasia) | Syndrome Q. Wemer Syndrome is defect in? a, DNAHelicase b. NERgenes c. MMR genes d. Allofthe above Q. Hutchinson-Gilford Progeria syndrome is due to the mutation in? 2. KeratinA b. Keratin B nemeecupmencnmanarsc SF 4. LaminB jieal Injury won enuse of ageing © Mostco Free Radical = Also! ‘= They are of three types: is ROS (Reactive Oxygen Species) © Superoxide nsrunpa © Hydrogen peroxide i? © Hydroxyl (most potent free radical) # Allofthem eause lipid peroxidation © Lipofuscin pigment is generated, a tell-tale sign of free radical injury. 0, Fenton's RXN Toxins Poisons so Ferrous Ferric Reperfusion |Dismutase Fe" Fe Injury 0, S22, 1,0, => on Superoxide Hydrogen Hydroxyl peroxide Oxygen —> Superoxide due to the environmental chemicals, soxins, poisons, and reperfusion injury. Superoxide —» Hydrogen Peroxide by Superoxide Dismutase (SOD). Hydrogen peroxide —r Hydroxyl (most potent) and the reaction iscalled Fenton's Reaction. # InFenton’s Reaction the ferrous ion — ferricion. Free Radical Injury Protection © Dietshould have antioxidants like vitamin A, C, and. ‘= Transport proteins Transferrin - Transports Fe ©. Ceruloplasmin- Transports Cu © Protective Enzymes Free radical injury - Protection? 0, SOD, H,0,——>0H Catalasé\ [Glutathione peroxidase HO HO 0, 0, 9 7%Q > cROSS WORD PUZZLES e (Crossword Puzzle TTT) ‘Across 3. Adult progeria syndrome under premature ageing 4. Reactivate telomerase Down 1, Wemer Syndrome is defect in 2. Dropsdown immediately? Q. Allare features of reversible cell injury EXCEPT? (AUMS 2019) A. Endoplasmic reticulum swelling, B, Densedeposition of mitochondria C. Bk formation D. Detachment of ribosome Q. Awedge shaped are in the adrenal gland is affected. On HPE nucleus is not seen but cellular outlines are intact. Which type ofnecrosisisbeingdescribed? __ GIPMER ~ Nov - 2018) ‘A. Coagulative av a B. Liquefactive CC. Fibrinoid D. Caseous Q. BCL2proteinis located in which of the following site? ~ GIPMER ~ May - 2018) A Cell membrane B. Mitochondria ©. Nucleus D. Cytosol Q. APAF 1 is involved in the activation of which of the (AIMS ~ June -2020) PREVIOUS YEAR QUESTIONS following caspases A. Caspase 8 B. Caspase? ©. Caspase3 D. Caspase 10 . Staining of lipids is best seen in which of the following conditions? (INICETNov2020) ‘A. Frozen ection B. Liquid paraffin . Formalin fixed D. Kamovsky stain Q Dystrophic calcification seen in which of the following conditions? (AIMS - May-2019) A. Myositis ossificans B. Paget's disease C. Metastasis D, Sarcoidosis+ Auto ="Selfand Phagy = "Eating." © Other name: Cell Cannibalism. ‘¢ AJapanese scientist named "Yoshinori Ohsumi”, (© Gaveall the mechanisms of autophagy in2016. © Receiveda Nobel prize for the discovery. Examples of Autophagy enous © Senile © Malnutrition © Cancers Neurodegenerative Conditions © Alzheimer's disease © Parkinson's disease ‘Types of Autophagy Four types of mechanisms for autophagy: 1. Macro-Autophagy 2. Micro-Autophagy 3. Chaperone Mediated Autophagy (CMA) 4, Mitophagy General outline of Macro-Autophagy Refer Image 4.1 1. Macro-Autophagy 009500 + Autophagosome formation occurs. fh is the autophagy in which the phagophore or jon occurs? Q. Whie ‘aulophagosome or the plate formati “Answer: Macro-Autophagy ULKL COMPLEX» BECUN-L APSeL 3 =APLS 4 | AUTOPHAGY AND FREE RADICAL INJURY B + Eating of Endoplasmic Reticulum and Ribosomes occurs = ULK1 COMPLEX starts the formation of the plate called Phagophore. ‘© Plate will gradually elongate and become bigger. © BECLIN-1 helpsinelongation. ‘= LC3 (Light Chain 3) completes the full plate formation and now the plate is called Auto-Phagosome (APS). «= Auto-Phagosome fuse with the lysosome to form ‘Autophagolysosome (APLS). ‘© Finally, all the substrates are broken inside the APLS. Complexes Involvingin Macro-Autophagy ULK1 + BECLIN-1 — Le3 Q. Whatis the marker of Autophagy? Ans.LC3 + Advanced Points ‘© mTOR decides the fate of autophagy. (© Ata well fed stage mTOR is activated and it will inhibit ULKI. ‘©. Inmalnutrtion, mTOR is inhibited © mTOR& 1/Autophagy. 2, Micro Autophagy :1000 ‘© Simplest process. «© Direct uptakeby lysosomes via endocytosis. 3. CMA ‘© CMAstands for Chaperone Mediated Autophagy. + Chaperon corrects misfolded protein. Examples of Chaperone «© HSP (Heat Shock Proteins) Mechanism of CMA. ‘© Chaperone binds with misfolded protein. + The complex enters the lysosome via LAMP 2A (Lysosome ‘Associated Membrane Protein 2A) for autophagy. Q. LAMP2Ais used in which mechanism? ‘Ans. CMA 4, Mitophagy 071636 © Atypeof Macro-Autophagy. © Autophagosome formation. © Only eating ofmitochondriaoccurs. $_‘= Old mitochondria are represented by PINK and PARKIN moleculesontheirsurface. + Hiconfirms catingup of old mitochondria Important LC3 (Light Ch Marker of autophagy Most important gene for ATGI autophagy SCIAEHUSE FISK to get tuberculosis (TB) ATGS gene mutation Increased risk of Crohn's Disease (Inflammatory Bowel Disease) ATGIOL gene mutations Cellular Ageing coats Causes of Cellular Ageing: © Free jury (via chemicals, poisons and pollution) is themost common cause of ageing. Telomere shortening © Insulinresistance © DNArepairdefects ‘Telomere Shortening co2s83 © Thousands of telomeres are present at the terminal end of chromosomes from human birth. ‘* Onetelomere sequence: TTAGGG. ‘© With each cell division, telomeres become shorter, thus ageing occurs. * Thiscanbe prevented by "Telomerase". «Telomerase isa RNA Dependent DNA Polymerase enzyme. «Telomerase is very famously known as "Immortality Gene” Telomeres -S@e ae a ‘c= 9000 32S ATTN INAS canes 00000000- Pi Cot ion TWonee sfonenioa Dorit have telomerase? Germ cell 7 ‘Stem eels Telpmere length. ——> Growth arrest “4, Cell divisions ———_—> een) ne eat ‘Somatic cell Drops down Stem cell Gradual decrease Germ cell No change Maximum telomerase activity is seen Cancer cell Reactivate telomerase ‘Survive longer Hayflick Limit ‘* Acell undergoes 40-60 cell divisions beforeit gets old. ‘In some books 60-70 cell divisions are the average cell divisions performed before ageing of cell How to Protong Lifespan? # SIRT Genes (SIRT 1-6) produces SIRTUIN proteins in the + human body. © SIRTUIN proteins are the histone deacetylases. ‘© High levels of SIRTUIN proteins can show anti-ageing properties. Role of SIRTUINS + Promote cell repair, therefore, being used in cancer treatment ‘© Used in the treatment of diabetes as it increases insulin sensitivity How to Increase SIRTUINS Levels * Caloriedeficit ‘© Redwine consumption a