Pathoma Notes

General Pathology

- Increase stress : Hypertrophy : increase ptn synthesis and gene activation + production of organells like mitochondria

- Hyperplasia and hypertrophy occur together except permenant tissues like cardiac myocytes / sk. Ms / nerve

- Pathological hyperplasia  cancer except BPH

- Decrease stress ? atrophy : decrease cell number : apoptosis

- Decrease cell size ? ubiquin proteome / Autophagy : lyozomal destruction - CHANGE stress : metaplesia

- Metaplasia occurs by REPROGRAMMING of stem cells , and it’s REVERSIBLE like GERD - Apocrine metaplasia in breast ? NOT PRECANCEROUS

- ATRA = All Trans Retinoic Acid : for AML

- Myoscitis ossificans is an example of mesenchymal metaplasia

- BONE is normal and distinct separation of bone and muscle, NOT osteosarcoma - Dysplasia is REVERSIBLE

- Stress exceeds the cell ability to adapt? INJURY - Hypoxia is low oxygen delivery

- Hypoxemia is low blood oxygen

- Ischemia decrease BLODD FLOW in artery or vein ( eg: Budd Chiari Synd) - MCC of budd chiari is PRV – hypercoaggulable state in SLE

- Any Increase PACO2 like COPD  PAO2 will decrease - CO : normal PaO2 – SaO2 decreased !

- EARLY sign of CO is Headache

- Newborns are susceptible to metHB , Chocolate colored blood + cyanosis

- Ischemia : 1- damage Na K Pumb 2- failure Ca pump : increase Ca inside 3- anaerobic glycolysis

- REVERSIBLE = SWELLING : eg : loss of micro villi / membrane blebbing due to swelling / Swelling of RER  release of ribosomes  decrease ptn synthesis

- IRREVERSIBLE = membrane damage ( release of enzymes) eg : cardiac enzymes in MI and liver enzymes in LCF

- Also calcium enters the cells

- Damage of mitoch membrane and release of cyt.c - Calcium and lysozomal enzyme ? = irreversible - Cell DEATH ? = Loss of nucleus

- Necrosis = Large GROUP of cells + Inflammation / Always pathologic “not like apoptosis” - Red infarction : Loosely organized + Blood must RE-ENTER the tissue

- Liquifactive necrosis ? Enzymes

- Brain ( by microglial cells) / abscess ( neutrophils enzymes) / pancreatitis ( pancreas itself) NOT fat necrosis “ surrounding”

- Fat necrosis : Saponification in pancreatitis / breast trauma ( mass : inflammatory response : giant cells fat and calcification)

- Saponification : fat + Calcium : example if dystrophic calcification ( like psammoma bodies )

- Serum calcium is normal in dystrophic “dead tissue” Vs. metastatic calcification : calcium or po4 is High .. one of the causes is cancer but metastatic calcification itself is NOT CANCER

- Fibrinoid necrosis : malignant HTN + Vasculitis

- 30 yr old with fibrinoid necrosis ? not malignant HTN, not vasculitis : THINK preeclampsia in placental vessels ##

- Apoptosis energy dependant – maybe physiological

- Dying cells shrink : becomes eosinophilic , apoptotic bodies removed by macrophages - Caspasses break CYTOSKELETON – activates Endonucleases breaks DNA

- Fas Ligand bing CD95 (Fas receptor)  T cell selection / TNF - CD8 + also apoptosis

- Free radical has an unpaired electron on the outer orbit - O  O2-  H2 O2  OH  H2O : one electron at a time

- radiation hits water in tissue generates free radicals , hydroxyl free radicals is the MOST DAMAGING

- copper and iron also free radicals : Iron do the Fenton reaction : OH free radical - inflammation / acetaminophen

- Free radicals : Peroxidize the lipids / oxidizes Proteins and DNA (oncogenesis)

- Elimination of Free radicals : Antioxidants A,C,E / Metal carriers : transferring for Iron and ceruloplasmin for copper / ENZYMES

- SOD – catalase – GTH peroxidase

- CCL4 : in dry cleaning industry  CCl3 in P450 in the liver  decrease ptn synthesis  loss of apolipoproteins  FATTY LIVER

- Reperfusion injury : return of O2 and inflammatory cells = free radicals : in cardai

catheterization

- Amyloid : misfolded protein that deposits in EXTRACELLULAR space (outside)  damage - Multiple proteins not one kind  all are B-pleated sheet configuration

- Tends to deposit around blood vessels ( see image) SYSTEMIC AMYLOIDOSIS :

- Primary amyloidosis : AL chain due to plasma cell dyscriasis : increase Light chain > heavy chain

- Secondary Amyloidosis : SAA = systemic derived amyloid associated

- APR “ chronic inflammation” = malignancy / RA / familial mediterranian fever ? - FMF : dysfunction of neutrophils : episodes of fever and inflammation  involves

serosal surface ( pericardium / peritoneum)  APR is SAA  deposit as amyloid - Findings : Nephrotic / restrictive CM / tongue enlargement / HSM / intestine

enlargement and malabs

- AMYLOID CANNOT BE REMOVED LOCALIZED AMYLOIDOSIS :

- Single organ

- Non-mutated transthyritin : Senile cardiac : Asymptomatic and 25% in people >80% - Mutated ? FAMILIAL AMYLOID CARDIOMYOPATHY : restrictive / African Americans - NIDDM – excess insulin  Amylin which is derived from insulin  deposit

- Alzheimer : AB amyloid protein  derived from amyloid precursor ptn present on chr 21 ( early onset)

- Dialysis ? B2 microglobulin ( in joints) : MHC1 support ## - Calcitonin in medullary thyroid : WITHIN tumor  biopsy ---

- Inflammation is due to 1) Infection 2) Tissue Necrosis - Goal is eliminate infection OR remove necrotic debris - inflammation is Innate : limited specificity

- Toll like Receptors ? on innate immunity cells : recognize PAMPs [ pathogen associated molecular pattern] : example is CD14 recognize LPS

- TLR activation  up-regulation of NF-kB

- VD occurs at arterioles , permeability is at capillary end - PGE2 – FEEEVER and pain

- Diagram : LTC4 , LTD4 , LTE4 : VC and bronchospasm : increase permeability

- Mast cells activated by : 1) tissue trauma – C3A, C4A , IgE

- Mast cells : 1) PREFORMED histamine 2) LATE RESPONSE by Leukotrienes - C5a , C3a mast cell degranulation

- C5a  chemotactic for PNL , C3b  opsonins

- Hageman factor : from liver : from inflammation : coagulation and DIC - Dolor via PGE2 and bradykinin

- Rubor and calor : from VD : histamine / PGs / bradykinin

- Tumor : histamine and tissue damage : from post capillary venules

- Fever : MACROPHAGES : IL1 and TNG increase COX activity In hypothalamus  PGE2  increase set point

- 1) margination : slowing blood flow AT POSTCAPILLARY VENULES - 2) Rolling : sialyl lewis x and selectins :

- P-selectins from Weibel Palade bodies “ VWF + P-selectin” - E-selectins : upregulated by TNF and IL-1

- 3) firm Adhesion : CAM : cellular adhesion molecules bing Integrins on leucocytes - CAM : activated by TNF , IL1

- Integrins activated by LTB4 and C5a

- LAD ? lack of CD 18 ni nutrophils to clear the tissue and fascilitate umbilical cord separation  delayed

- Increased circulating neutrophils ? normally 50% are stuck in the vessels of the lung ( called marginated pool _ , in LAD : marginated pool will be released in the blood - Recurrent bac infection that Lack pus bcz no PNL

- 4) Transmigration : POST CAPILLARY VENULES - 5) chemotaxis : C5a IL8 LTB4 and bacterial product - 6) Phagocytosis : enhanced by opsonins

- Pseudopods from neutrophils or macrophage : form Phagosome  moves ( in a road of trafficking by microtubules) to fuse with Lysozome  Phagolysozome

- Chediac Higashi : no microtubules  no phagolysozomes - Nutropenia dt failure of division and cytokinesis

- Giant granules in leucocytes : piling up bcz they cannot migrate to periphery - Defective primary hemostasis : platelets migration

- Melanocytes : can form pigment , but it cannot be moves to keratinocyes ! ( one melanocyte = 25 keratinocytes) so it’s partial

- Peripheral neuropathy : cannot maintain integrity of periphery dt decrease moving - 7) destruction of phagocytosed material : oxygen dependant and oxygen independent - HOCL “ bleach” is the product of MPO

- Most bacteria have H2O2  can be used by MPO in CGD - Except catalase +ve : destroy H2O2

- -ve Nitroblue tetrazolium test : No NADPH = No Blue color

- MPO deficiency ?? Asymptomatic but maybe candida infection / NbT test is POSITIVE - O2 independent : enzymes like Lysozyma and MBP “less effective”

- 8) Resolution : PNL die via apoptosis and form Pus

- 9) the phase of Macrophages ( 2-3 days) via the same ways  phagocytosis : PRIMARY MECHANISM is Enzymatic killing by Lysozymes

- Release cytokines:

- Resolution by IL-10 and TGF B

- Continue : IL-8  recruit MORE neutrophils  so there maybe ACUTE inflammation for 8 weeks : there’s still neutrophils

- If it cannot handle it ?? summon lymphocytes and chronic inflammation

- Granuloma = epithelioid histiocytes [ macrophages with abundant pink cytoplasm] - NOT NECESSAIRELY : giant cells / rim of lymphocytes

- Non caseating : foreign material “ wood – breast implant” / sarcoidosis / Beryllium in NASA / Crohn / Cat-Scratch ( stellate shaped granuloma )

- Caseating Granuloma : do AFP stain look for TB / GMS stain to look for fungus - Granuloma = macrophage + TH1

- Macrophage secrete IL-12  TH1  Inf gamma  convert macrophage to histiocytes

- SCID : cytokine receptor def / ADA / MHC II - Stem-cell transplant ##

- Bruton’s :Bacteria / enterovirus / giardia - CVID : risk of autoimmune

- WASP gene = Wiskot Aldrich Syndrome Protein

- Lebman sacks ? SLE : vegetations on BOTH sides of the valve : characteristic - SLE : Pancytopenia

- FALSLY elevated PTT :  the patient is actually hypercoaggulable - DVT and Budd chiari / stroke / placental thrombosis

- Can’t chew a cracker “dry” / dirt in my eye / dental caries : Sjogren Synd - Anti-SSA and Anti-SSB : anti Ribonucleoprotein

- Sjogren associated with RA

Sjogren  Parotitis  risk of B-Cell Lymphoma ## Unilateral swelling late in the disease course

- Scleroderma ? No peristalsis  solids and liquids

- Serum antibodies against U1 ribonucleoprotein ? MIXED CT DISORDER

- Healing = Regeneration (same tissue : depend on type of tissues) + Repair ( scar) - BM stem cells ? CD34+

- Stable tissue : Liver and kidneys

- Permenant tissue ? ONLY REPAIR by fibrous scar in ms / cardiac / neuron - Repair ? permenant tissue / stem cells have been damaged

- Bone = type one / Cartwolage = type two - Regeneration and repait ?? Paracrine signaling - FGF ? Angiogenic ## and skeletal development - Vit C : important of cross linking between hydroxyl - Hypertrophic scar : excess SCAR tissue

- Keloid : WAYY out of proportion to the wound  ear lobe  type III

NEOPLASIA

- Unregulated, irreversible and monoclonal [ proved by G6PD isoforms on chromosome X / androgen receptor isoforms]

- Polyclonal = hyperplasia

- Clonality of B cells is by light chain , kappa or lambda ( polyclonal : the K:L is STILL 3:1 ) - K:L is 20 : 1 ?? MONOCLONAL  lymphoma

- Both benign and malignant are monoclonal - Lymphocytes  NO BENIGN

- Lung cancer is the most killer dt no improvement in screening - 30 divisions occur before clinical symptoms

- With each division  mutations  more aggressive - Depend on site : eg : pancrease is late : worst prognosis - Carcinogens are agents that damage DNA

- Grains in Africa ? aspergillous  aflatoxins

- Arsenic ? Sq cell carcinoma of Skin / Lung cancer “ cig smoke” / angiosarcoma of liver - Most important carcinogen in cig smoke is Polycyclic hydrocarbon

- Naphthylamine : in cig smoke : urothelial carcinoma of the bladder - Nickel  lung cancer

- AML / CML / papillary carc of thyroid : Ionizing radiation  hydroxyl free radicals - NON-Ionizing radiation ? UVB  BCC / Sq cell carcinoma / melanoma

- Proplem in Xeroderma

- myc translocated to ON location  macrophage eating dying cells  starry sky - cyclin D  Mantle cell lymphoma : G1  S

- expansion of the mantle : region next to the follicle - CDK-4  melanoma

- Hyperchromasia : increase nucleus

- The ABSOLUTE DIFFERENCE is that benign tumors NEVER METASTASIZE - Immunohistochemistry : antibody that bind the cell to identify it - Like “ keratin / vimentin / …..

- Used to classify tumors

- Chromogranin : good : carcinoid / bad : Small cell carcinoma

- Downregulation of E-Cadherin : attached to laminin and destruct BM - BM : collagen 4 + laminin

- Attach to fibronectin then BV/ lymph

- Omental cacking : very thick in ovarian cancer ---

BLOOD

- VC of vessel : sympathertic and Endothelin release - VWF : Weibel Palade bodies

- Qualitative ?? NO PETICHIEA - ITP = IgG against GP IIB/IIIA

- Spleen makes antibodies, and they coat platelets, then macrophages ALSO in the spleen eat them

- Chronic ITP : eg SLE / women in child bearing age - ITP : increase magakaryocytes ( to compensate)

- ADAMTS 13 : cuts down VWF polymer into monomers  deficient in TTP ( autoantibodies / autoimmune in adult female )

- Abnormal platelet adhesion  PLATELET microthrombi

- E.coli O157:H7  verotoxin damages endothelial cells and damages ADAMTS 13 - Qualitative : BSS – Glanzman – aspirin – Uremia “ decrease function”

- BSS : platelets are lacking GP – 1B  platelets live shorter  mild thrombocytopenia  compensatory increased size of platelets “ Big suckers”

- Distinguish between hemophalia : mixing study : adding normal plasma : if corrected PTT then it’s hemophilia not coagg factor inhibitor

- VWF deficiency : abnormal ristocetin test

- Desmopressin increase release of VWF from W-P bodies

- LCF : 1) decrease production of coagg factors, 2) decrease epoxide reductase = decrease activation of Vit K

- Large volume transfusion = dilution of coagg factors

- Heparin complex with PF4  forms Abs  destroyed  fragments can activate other platelets  coagulation

- Adenocarcinoma  mucin  activate coagg cascade

- D-Dimer : is the split product of fibrin ( which means there were excess fibrin)

- Plasmin cleaves Fibrin AND fibrinogen AND /knocks out coagg factors AND block platelet aggregation

- Radical prostatectomy ??  release of urokinase  anticoagg - Liver cirrhosis ??  decrease antiplasmin anticoagg

- Increased fibrinoGEN split products BUT NOT D-DIMERES ( bcz no fibrin ) - D_DIMERS is the difference between it and DIC ###

- ANTEMORTUM CLOT : 1) attached 2) lines of zhan - Endothelium releases Heparin Like Molecule “ HLM”

- Endothelium releases thrombomodulin : modulates thrombin that it can activates protein C ##

- Vit B12 deficiency can lead to thrombosis dt increased homocysteine

- Protein C&S deficiency : skin necrosis with warfarin  usually knocks out C & S faster and elrllier that 2,7,9,10 , so there will be INCREASED coagg factors  coagulation and thrombosis  this is why we give heparin

- In AT III def : you give HIGH DOSES of heparin to activate the limited AT III  then give coumarin to maintain and stop heparin then

- Atherosclerotic embolus : cholesterol crystals “picture” - Caisson’s diseases = gas embolus causing BONE NECROSIS

- Amniotic fluid  baby skin gets shed off periodically so the amniotic fluid embolus will contain keratin debris and squamous cells ## picture

- PE is usually silent 1) dual blood supply 2) small and self resolve

- Symptoms ? 2) large or medium sized artery 2) pre-existing Cardiopulmonary problems ( dual blood supply is not protective )

- Spiral CT : vascular filling defects in lung / Doppler in DVT / D-Dimers elevated - Hemorrhagic bcz second blood supply “ blood re-enter” / loosely organized tissue - Saddled embolus ? saddled to occlude BOTH branches of PA : electomechanical

dissociation ( there’s contraction bubt no blood is pumped) ANEMIA:

- Ferroportin is the iron regulator NOT intestinal cells - For every 3 TF  one carries Iron

- TIBC : how much TF – saturation : how many TF carrying Iron

- Decrease ferritin \\ always increased TIBC “ the liver senses and produces more transferring”

- Increased TIBC / BUT decrease saturation

- INITIALLY normocytic anemia : good RBCs but few of them - Pica : psychological drive to get iron : chewing on dirt - IDA : INCREASED FEP free erythrocyte protoporphyrin - They will give you a lymphocyte to compare size - ACD ?? increased ferritin / ergo : decreased TIBC

- Decrease serum iron / decreases saturation / increase FEP - Sideroblastic = decrease protoporphyrin

- Ringed sideroblast : Iron is present in MITOCHONDRIA - Congenital : ALAS def

- Acquired : Alcoholism ( mitochondrial poison) / Lead ( ALAD and ferrochelatase) / Vit B6 ( ALAS )

- High ferritin bcz macrophage will eat all the iron from the sideroblast ( SAME IRON PROFILE as hemochromatosis)

- Thalassemia carries protection against pl. falciparum - Normally 4 alpha alleles on chr 16

- Knock out 2 near genes ? cis [ worse] [ in Asians] [ ass with severe thalassemia in offspring] [ high rate of spontaneous abortion]

- Knock out2 genes opposite ? trans [ less severe] [ Africa]

- 3 gene deletion ? no problem in foetus  after that  risk of HbH  tetra beta Hb damages RBCs

- 4 gene deletion  tetramer of gamma chain  lethal in utero

- B- thalassemia : alpha tetramers damages RBCs  destruction In the spleen - NO HBA  there’s HBA2 and HBF

- Macrocytic anemia : one less division

- Hypersegmented neutrophils = greater than 5 lobes - Vit B-12 bind to ( R-Binder) from salivary gland

- Vit B-12 released in intestine by protease of pancrease and bind Intrinsinc factor - Complex goes to ileum and absorbed

- Parietal cells = Proton Pumps / Pink “ not like blue chief cells” / Pernicious anemia - Vit B12 def in pancreatic deficiency ? not released from R-Binder

- Methyl-malonic acid accumulation in B-12 ?  neuropathy and SCD - Reticulocytes = RNA in cytoplasm

- A decreased RBCs mass may induce falsly increased Reticulocytes  so corrected reticulocytes

- Corrected = Reticulocytes X hct/normal hct

- Intravascular ? bing to haptoglobin and send it back to spleen to re-use  so decreased haptoglobim “ but it’s not enough”

- Hemoglobinemia / Hemoglubinuria / hemosedrinurea “ tubular cells contain iron – die and slough off – days over  urine”

- Spherocytosis : inherited defects in membrane teathering protein : spectrin / Ankyrin / band 3.1

- Increased RDW / parvo B19 crisis

- Splenectomy : anemia resolves but spherocytes PERSIST / howell jelly bodies - HbS POLYMERIZE in acidosis / dehydration / hypoxia  this is not covalent binding - HbF prevent against sickling  so use Hydroxyurea

- Extravascular hmolyisis / intravascular bcz membrane damage - Target cells bcz membrane damage  blebs

- Sickling is usually reversible  if irreversible  vaso-occlusive crisis

- Maybe : Acute chest syndrome : occlusion of pulmonary vessels : aggravated by pneumonia “ classic finding – most common cause of death “

- Gross hematuria and ptn urea ?  think renal papillary necrosis - Sickle cell trait ? 55% HbA and 43% HbS and 2% HbA2

you need MORE than 50% HbS to sicke  so they don’t sickle

but in EXTREME HYPOXIA they can sickle  microscopic hematuria  eventually decreased ability to concentrate urine

- Metabisulfite test : screen for HbS : +ve for BOTH trait and diseases - HbC  LySine

- PNH : ACQUIRED defect of myloid stem cells ( RBCs / granulocytes / platelets)  GPI protein which fixes CD55 (DAF : Decay Accelerating Factor) and CD59 ( MIRL :

Membrane inhibitor of Reactive Lysis )

- Shallow breathing at night  resp acidosis  complement activation - Sucrose test : SCREEN : activate complement and induce hemolysis

- MCC of death : thrombosis  bcz destruction of platelets  fragments activate coagg pathway

- AML develop in 10% ( it’s easy to acquire new mutation im myloid stem cells) - African G6PD : mild decrease / Mediterranean : marked decrease of enzyme - G6PD will not be available for the whole life of RBCs

- Heinz Preparation ? used to show hemoglobin aggregates  SCREENING - Bite cells ? macrophages will take a bite with Hb Aggregates

- Warm IgG antibodies ? lose excess membranes  SPHEROCYTOSIS !

- SLE / CLL / drugs 1) penicillin : antibody binds to it 2) methyldopa  forms antibody - IgM ? cold agglutinin  fixes complement  MAC

Mycoplasma / IMN

- Direct coombs : does the patient has RBC ALREADY coated ? indirect : does the patient have Antibodies in the serum ?

BLOOD CELLS

- Neutropenia : from drugs  Rx is GM-CSF or G-CSF

- Neutrophilic leukocytosis ? infection / tissue necrosis / cushing

- Immature neutrophlis in left shift ? decreased CD16 ( which is the Fc receptor) which means they are not functional correctly

- Eosinophilia ? allergy / parasitic infestation / HODGKIN’s ?? By IL-5 ## - Basophilia ?  associated with CML ###

- Lymphocytes Leukocytosis ?  viral infection / Bordetella Pertussis ?? exception bcz it produce Lymphocytosis blocking factor  inhibit Lymphocytes from entering LNs  remain in the blood

- Generalized LAD in IMN ? T cells  in para-cortex - Splenomegaly ? in PALS

- Atypical lymphocytes : 1) much bigger nucleus than adjacent RBCs 2) abundant blue cytoplasm  resemble monocytes

- Spleen rupture  avoid sports for 1 year - Rash with PCN

- Dormancy in B-cells

- Blast = large / little cytoplasm /punched out nucleus ( nucleolus) - MPO crystallize to form Auer Rods  marker for myeloblasts - tDt is a marker for Lymphoblast ( dna polymerase  in the nucleus ) - B-ALL  CD 10 / 19 / 20 / 22

T-ALL CD2  CD 8 ( NO CD 10 ##)

- T-ALL  Thymic mass “ lymphoma” Teenagers - Acute monocytic leukemia ?  GUMS ##

- Acute Megakaryoblastic Leukemia  lack MPO  Down’s Syndrome before the age of Five ##

- Myelodysplastic syndrome  blasts less than 20% with cytopenias - CLL : B lymphocytes  CD-5 ( normally on T not B ) and CD20

- CLL  can transform to diffuse large B-cell lymphoma ( enlargement of LNs and Spleen )

- In HCL  Splenomagealy is due to expansion of RED PULP Dry tap ? bcz BM is fibrosed

No LN enlargement ( bcz TRAPPED in BM and in Red bulp) - Respond to ADA (-) = Cladribine ( 2-CDA)

- Adult T-cell Lymphoma  there’s RASH nad Lytic bone lesions with hypercalcemia ( don’t jump to MM)

- Neoplastic T- cells in epidermis  in mycosis fungoides is called Pautrier microabscesses

- Spread to the blood  Sezary syndrome  ceribriform nuclei

- MPD  all myeloid cells increase  but one in particular increases more

- CML  BASOPHILS ##

- In CML  the mutation MUST be in a stem cell .. so the mutation maybe in the

Myelocytic stem cell  AML (2/3) / OR it can be in Hematopoeitic stem cell  ALL (1/3) ie : Both can be correct

- CML chch : 1) LAP negative [ bcz they are inactive] 2) Basophils 3) t(9;22) - PRV  thrombosis  Budd-Chiari

- PRV : mat cells  itching after bathing “ classic” - Thrombocytosis : maybe ETC / IDA

- RARELY leukemia and RARELY fibrosis

- No significant risk of hyperuricemia “ just pieces of cytoplasm “ - IMF  PDGF  Megakaryocytes

- Splenomegaly and extramedullary hematopoeisis  leucoerythroblastic smear “ no control of size and more immature cells in blood”

- Extramedullary is not sufficient

- Teardrop  stretch as they try to leave BM LYMPHADENOPAHY

- Paracortex hyperplasia in viral / follicles in RA and early HIV - LNs draining cancer ?? Sinus histiocytosis

- Lymphoma  lymph cells that form a mass - Small lymphocytes = well differentiated

- In follicular lymphoma : the follicles contains cells that may fail somatic hypermutation – they need apoptosis but BCL-2 anti apoptotic

- Translocate from chr 18 to Ig heavy chain on chr 14 - Rituximab  anti CD-20

- Can progress to large B-Cll lymphoma “ enlarging LN”

- Anti-apoptotic = no macrophages in follicles to clear the failed cells ( no tangible body macrophages”

- Region immediately adjascent to follicle ?  Mantle cell lymphoma

- Marginal zone lymphoma  associated with chronic inflammatory state [ hashimoto / sjogren / h,Pylori ]

- C-myc drives peoduction and growth  translocated to Ig heavy chain on chr 14 - Diffuse large  no follicle or whatever diffuse

- Sporadically or progressed from follicular - B symptoms are due to cytokines ##

- Nodular sclerosis : neck or mediastinal LNs in females - RS cells in spaces  lacunar cells

- Mixed cellularity : EOSINOPHILS  called in by IL-5

- MM  high serum Il-6 often elevated : important growth factor for plasma cells - MM activates RANK receptors in osteoclasts

- Normal serum ptn electrophoresis : the spike is LESS than Albumin – in MM : in SPEP [Serum Protein Electrophoresis] : M spike is higher than Albumin and narrow - Usually IgG or IgA

- Increased IgG  decrease charge between RBCs  stick together  Roleaux formation - Primary AL Amyloidosis bcz extra light chain

- MGUS in elderly  may develop MM

- Waldenstrom macroglobulinemia  this Is Lymphoma  macro bcz IgM is large - Viscocity of the blood increases but no lytic bone lesions or kidney

- ttt with Plasmaphoresis

- histiocytosis : CD 1a+ and S100+

- people’s name = malignant / malignant = skin rash / 2 people = less than 2 yrs / three people = more than 3 yrs

-

CVS

- Intima “Endothelium on BM” / Media “ sm.ms” / Adventitia : CT - Vasculitis : 1) NS symptoms 2)ischemia

- Ischemia bcz 1)inflammation = tissue factor = thrombosis 2) heal by fibrosis - Giant cell arteritis : classically ESR is > 100

- Giant cell arteritis : Granulomatous “ giant cell”

- It’s segmental  so you do biobsy  even if it’s negative it doesn’t exclude - Takayasu ? LESS than 50 yrs old

- Medium vessels = muscular artery “ supply organs like Renal artery” - PAN : fibrinoid necrosis  fibrosis  form NODES

- String of pearls appearance ? varying stages ( aneurism / fibrosis / aneurism / firbosis / ….)

- A kid with MI ? think Kawasaki - Rx ? Aspirin and IVIG  NO steroids

- This is interesting bcz the C/P looks like viral illness and you shouldn’t give bcz Rye’s syndrome

- Aspirin bcz inhibits COX and inhibit aggregation and protects them from thrombosis in coronaries

- P- ANCA = perinuclear anti nutrophils cytoplasmic antibody - C-ANCA = cytoplasmic Anti nutrophils cytoplasmic antibody

- Wagners = Microscopic Polyangitis except : 1) P-ANCA 2) no nasopharynx 3) no granuloma

- Churg Vs Microscopic both have P-ANCA BUT Churg strauss : 1) eosinophilia 2) granuloma 3) Asthma

- Follows URT infection  because it generates IgA ##

- RAS in old male ? atherosclerosis / in female : Fibromuscular dysplasia - Atherosclerosis : Intima of small and large sized vessels

- Artriolosclerosis : narrowing of small Bl.Vs - Monkeberg : Media

- Rupture atherosclerotic plaque occurs at the neck ##

- Hyaline artrioloscleorosis : proteins : pink staining ( DM / benign HTN) - Glomerular scarring : due to hyaline nephroscleorosis

- Hyperblastic : smooth muscle hyperplasia  flea bitten kidney and ARF - Aortic dissection : 1) damage to intima 2) blood goes into media

- Need per-existing weakening of media and a lot o stress “ eg : HTN in proximal Aorta” - HTN = narrowing of vasa vasorum

- Aneurism  sisrbts laminar blood flow  activates coagg cascade - >5 cm aneurism  RUPTURE

- Triad of ( hypotention / pulsatile abd mass / flank pain) - Usually dt atherosclerosis of Abd aorta

- Angina = REVEERSIBLE injury “ no necrosis”

- Unstable angina  INCOMPLETE occlusion of coronary a.

- MI : complete occlusion > 20 minutes ( thrombus of pirenzimital ) - Fibrinolysis --. Calcium enters the cell  contraction bands - You only get fibrinous pericarditis with TRANSMURAL infarction

- Necrisos  dark coloration / inflammation  yellow / granulation  red / fibrosis and scar  white

- Fetal Alcohol Syndrome  VSD  cri du chat

- Paradoxical embolus : from Right side  ASD  Left side - PGE : KEEps PDA open

- TGA  meternal Diabetes

- Infantile coarctation : associated with PDA , occurs proximal to PDA - Presented with lower extremity cyanosis / Turner Syndrome

- Adult coarctation : distal to ductus artriosus : hypotention in low etremitis  and bicusbid aortic valve

- RF = molecular mimicry against M protein and endocardium - Erhtyema marginatum : red at the margins

- Scarring of the valve  fish mouth appearance

- RHD Vs wear and tear AS stenosis : 1) in RHD there’s ALWAYS MS 2) RHD there’s fusion of the valves

- pulmonary congestion  hge  macrophages  HF cells are in the lung - septic embolization in SBE  jenway and osler / ACD

- Trans-eophageal-echo -> TEE : see vegetations in SBE - Sterile vegetations  hypercoagg state or adenocarcinoma - Libman sacks ? MV  regurgitation

- DCM  pregnancy

- Myocarditis can cause DCM - Ttt : Transplant only

- Congenital HOCM -- > AD : genetic mutations in sarcomere proteins - HOCM : myocardial fibrils with disarray

- RCM = CHF “ blood accumulated backwards”

- Heart is permenant cells , so the only tumor is mesenchymal “ myxoma” - Rhabdomyoma is a hamartoma

- Metastasis is more common than primary tumors  pericardium  pericardial effusion - - - - - - - GI :

- Behchet syndrome : apthus ulcers + genital ulcers after viral infection : no etiology known

- Hairy leukoplakia ? on the lateral side NO dysplasia - True leukoplakia is dysplasia vs candidiasis : scrab test

- Erythroplakia : vascularized leukoplakia [ more suggestive to dysplasia] - Pleomorphic adenoma = stromal + epithelial

- MW syndrome : painful hematemesis

- Esoph varices ? painless hematemesis : MCC of death in cirrhoso [ with DIC] - Chronic gastritis is type IV HPY , pernicious anemia is type II HPY !!!!! - Celiac disease : DQ2 and DQ8

- Celiac is IgA deficient because it’s deposited and form dermatitis - EATL : enteropathy associated T cell lymphoma : associated with celiac - pANCA : think about UC

- smoking increases risk of chron’s and protects from UC

- RECTAL SUCTIO BIOBSY : not normal mucosal biobsy in hirchsbrung . to be able to truly look at ganglia

- Aspirin : decrease COX , decrease adenoma carcinoma sequence - Sessile is more dangerous and villous is more dangerous

- Pancreas : Liquifactive necrosis + fat necrosis of the surrounding adipose tissue - Hypocalcemia dt use of calcium in saponification

- Pancreatitis  Shock dt digestion of Bl.Vs  hge and shock

- Chronic pancreatitis ? no elevated enzymes  all cells are destroyed - Pancreatic adenocarcinoma  DUCTAL carcinoma

- Thin elderly male that suddenly developed DM ? think cancer pancreas - Estrogen stimulate HMG coA reductase / increase LPL receptors in the liver - Gall bladder to the right scapula

- Biliary colic is dt contraction of GB on an obstructed duct

- Phototheraby doesn’t conjugate bilirubin, it just makes it soluble

- Viral hepatitis : UCB increase dt damage of hepatocytes / CB increases dt damage of bile ductules

- Acute hepatitis : hepatic lobules / chronic hepatitis ? portal tracts - Fibrosis in cirrhosis by TGF-beta from stellate cells

- Coagulopathy in cirrhosis ? decrease activity of epoxide reductase - Mallory bodies are damaged intermediate filaments in hepatocytes - Hemochromatosis : brown pigment in hepatocytes

DD : lipofuscin : wear and tear pigment / iron do Prussian blue

- Wilson’s : inability to incorporate copper in ceruloplasmin / can’t put it into bile  build in hepatocytes  free radicals

- Primary sclerosing cholangitis : peri-ductal fibrosis with onion-skin [ figure] - P-ANCA / UC association ##

- Hypoglycemic child , elevated LFTs , N, V : check history for Reye’s - Rupture adenoma – bcz it’s subcapsular

- Aspergilous  aflatoxins  mutations in P53 mutations ## - HCC  vein  increase risk of budd chiari

- Nodular free edge of liver ? metastasis

REPRODUCTIVE

- unilateral lesion in the side of the vulva adjascent to vaginal canal  bartholin cyst “ painful”

- HPV  vulva / vagina / cervix = lower tract - HPV : low risk = condyloma  6/11

HPV high risk = Dysplasia and carcinoma  16/18/31/33 - Risk is due to DNA sequence [ DNA virus ]

- Lichen sclerosis : parchement like vulva  postmenauposal women BENIGN – slightly increased risk of sq cell carcinoma

- Lichen simplex chronicus  opposite : hyperplasia of sq epithelium dt chronic irritation and scratching

BENIGN – NO increased risk

- Sq cell carcinoma in vulva  resembles leukoplakia  do biobsy - Maybe HPV related “ VIN  carcinoma ‘ 16/18 /3 1 / 33

- Non HPV  long standidn lichen sclerosis [ elderly women larger than 70 yrs ] - Extramammary paget’s diseases : malignant epithelial cells in the epidermis

- DD : carcinoma Vs. Melanoma  do stains - Pagets  Pas +ve / Keratin +ve / s100 –ve

Melanoma  PAS –ve / Keratin –ve / S100 +ve ONLY epithelial cells make mucus and PAS +ve ##

- Paget’s diseases in the nipple  usually there’s a cancer in the breast Vulva ? usually NO cancer in the lower genital tract

- Adenosis ; persistence of columnar epithelium in the lower part of the vagina ## DES use - These women are high risk for  celar cell adenocarcinoma

- Mass protruding from vagina / penis  child  think rhabdomyosarcoma [ picture] - Malignant cell is Rhabdomyoblast 1) cytoplasmic cross-straiation / +ve for Desmin or

Myoglobim ##

- VAIN ? vaginal intraepithelial neoplasia ( Vs VIN : vulvar )

- HPV infection – cleared by immunity  only PERSISTENT infection with HIGH risk may do CIN

- High risk ? produce E6 [ X p53] and produce E7 [ X Rb ] - Rb bing E2F  no Rb ? E2F free  progression of cell cycle - Cervical carcinoma : bleeding or pain after intercourse

- Immunodeficiency is highly associated with high risk HPV [ AIDS defining lesion ] - Cervix : squamous AND adeno are possible , however squamous is more common , but

BOTH can occur and BOTH are related to hPV

- Cerial cancer may invade through uretine wall into bladder / ureter and for hydronephrosis

- PAP smear is sensitive – colposcopy is specific THEN Biobsy

- PAP smear is at transformation zone ##

PAP doesn’t detect adenocarcinoma as well ## much more difficult to detect - The prevalence of cervical ADENOcarcinoma has not reduced , only squamous ## - Quadrivalent vaccine 6/11/16/18 – 5 yrs protection

- PAP smears are still uses “ other strains ##

- Endometrium : functionalis layers sheds , Basalis persitis  regenerates Asherman syndrome  damage to basalis eg by excessive D&C

- DUB ? anovulatory cycle :

proliferative phase – no secretory phase – no shedding - another proliferative phase on top of the last one – cells grow beyond blood supply – necrosis and dysfunctional bleeding

- Endometritis – retained parts of the placenta - Chronic endometritis – have to see plasma cells

- Endometrial polyp : protrusion of endometirum : result of Tamoxifen bcz it’s agonist on the breast

- Endometriosis : (((GLANDS + STOMA )))

- Endometriosis increases the risk of carcinoma at the site of endometriosis – especially at the ovary ##

- Endomatrial hyperplasia – unopposed estrogen : GLANDS ONLY relative to the stroma ##

- Endometrioid ? the cancer endometrium looks pretty much like the normal endometrium  usually from the hyperplastic endometrium – usually in age of 50 - OTHER type is sporadic : from atrophic endometrium  papillary serous ## occur in

elderly ## p53 mutation

- Psammoma bodies may arise in sporadic type

- Leiomyoma is realted to Estrogen and shrinks after menopause - Multiple is MOSTLY benign NOT leiomyosarcoma

- White whorly masses and multiple and Pre-menopause : benign Vs he and necrosis and single nad post menopause

- Leiomyomas are asymptomatic ( may be bleeding / infertility / pelvic mass ) - Leiomyosarcoma :

 De-novo NOT from leiomyoma

 Post menopausal not like leiomyoma

 SINGLE lesion with he and necrosis

 mitotic activity and cellular atypia - maybe hge in CL  CL hgic cyst

- Ovarian tumors : epithelial / sex cord / germ cells

 Surface Epithelial : Present LATE , and vague symptoms CA-125

(35-40) benign (60-70) malignant

1) Cystadenoma : flast lining of the cells : single layer ( serous / mucinous ) 2) Cystadenocarcinoma : multiple complex cysts and shaggy lining not smoothe (

serous / mucinous ) cells invade into cT post menopausal women

BRCA 1 mutation  serous carcinoma of the ovary / fallopian tube also ## 3) Border line tumors : but metastatic potentials

4) Endometrioid histology : usually malignant , 50% have separate carcinoma in the endometrium as well : check there

5) Brenner tumor : Bladder like

 Germ cell

Reproductive age ( 15-30 ) 1) Fetal tissue : Cystic teratoma

Benign , except of 1) immature teratoma ( usually neuro ectoderm) 2) if the tissue contains cancer itself [ somatic malignancy]

struma ovarii : contains thyroid tissue : THrx with mass In the ovary 2) Fetal tissue : Embryonal carcinoma : primitive and aggressive with early

3) Germ cells : Dysgerminoma : oocytes : large cells with central nuclei Most common type , resembles seminoma

LDH tumor marker

4) Yolk sac : Endodermal sinus tumore  MC in kids produces AFP

schiller duval bodies : glomerular like 5) Placental : Choriocarcinoma

NO VILLI  just the trophoblast

EARLY HGIC spread : programmed to invade poor response to chemo ?? ##

 Sex-Cord

resemble granulose and theca cells ( vs : Leydig and sertoli )

1) Granulosa theca cell tumor : produces Estrogen : usually in child with precocious puberty / adult with heavy menses / elderly with postmenopausal tumor

2) Sertoli-Leydig cell tumor ? may develop in female dt common origin - contain Reinke crystals : pink cells with crystals

produce androgen

3) Fibroma : fibroblasts  meigs’ syndrome

 Metastasis

1) Kruckenberg tumor : Classically but not only : Gastric cancer diffuse type : signet ring cells ( maybe breast in lobular carcinoma – colon cancer )

mucinous tumor ? ask if it’s primary or metastatic

one ovary : more likely primary / both ovaries : metastatic 2) Pseudomyxoma peritonei : mucin within peritoneum : jelly belly

usually a tumor within the appendix  metastasize to the ovary [ appendix / ovary / peritoneum ]

- MC site in ectopic pregnancy : fallobian tube dt scar 1) PID 2) endometriosis - lower quadrant Abd pain weeks after missed period

- vaginal bleeding / cramp pain / pass fetal tissues - placenta previa : preview of the placenta

- preeclapsia is realted mainly to placenta – fibrinoid necrosis in placental vessels - SIDS : 1 month to 1 year : usually during sleep

- Snow strom in hydatiform mole ? bcz grape masses full of fluid : black and white - Complete mole :

 Completely molar with no fetal

 Compeletely involves ALL the villi

 Complete risk for carcinoma

- Choricarcinoma 1) complication of gestation or mole or even normal preg 2) SPONTANEOUS germ cell tumor

- Gestational way responds well to chemo , BUT germ cell tumor NOT RESPONSIVE to chemo ## HY

Penis

- Hypospadius : failure of fusion of urethral folds - Epispadius : abnormality of genital tubercle - Orchitis : Chlamydia D-K / NG in child

E.coli and pseudomonas Mumps

Autoimmune ( DD TB : acid fast and necrotizing granuloma)

- Torsion : twist of the cord : artery patent vein collapsed : blood get in but no out --? Hgic infarct

Adolescent with sudden onset and absent cremastric reflex - Testicular tumors : only SC or Germinal

- Testicular tumors are NOT biobsied 1) it will seed to scrotum 2) mostly Germ cell tumors and are malignant

 Germ cell tumors : Seminoma and non seminoma

 Seminoma : large cells with clear cytoplasm and central nuclei = dysgerminoma Mass is homogenous with no hge or necrosis

May produce HCG  Embryonal carcinoma :

hge and necrosis

CTX may result in differentiation AFP or HCG

 Yolk sac tumor

AFP and shiller duval body “glomeruloid like “  Choricarcinoma

B-HCG : resemble TSH so can cause hyperthyroidism You don’t get villi : only trophoblasts

Tiny mass is primary and metastasis is large “ against logic”  Teratoma

AFP or B-HCG  Mixed

Prognosis upon the worst

 Leydig cell

produce androgen and precocious pubery Reinke crystals

 Sertoli cell

tubules – clinically silent

- Testicular tumors : 15-40 : germ cell 95% / >60% is lymphoma - Prostatitis = orchitis organisms

- BPH may cause blebing of the bladder

- PSA is elevated : produced by glands : extra glands ? slight elevation - 5-alpha reductase take months

- Prostatic adenocarcinoma clinically silent bcz it’s peripheral and post away from urethra so no obstruction

- Screen by DRE / PSA from 4-10 or higher

- Gleason grading : architecture alone not nucleus : the higher score the worse prognosis ENDOCRINE

- In prolactinoma : no galactorrhea in males bcz they have no sufficient glandular tissue and lobules

- Octeriotide : blocks response of Ant Pit to GHRH

- Sheehan : no lactation / loss of Pubic hair dt loss of Androgen bcz no LH - Empty sella : herniation of SAH into sella leading to death of Ant pituitary - SIADH : Hyponatremia and mental changes ( vs water deprivation ) - Thyroxin : hyperglycemia

- Grave’s : woman in child bearing age

- Grave’s diseases : scalloping of the colloid : space between colloid and the edge of the follicle

- Thyrotoxicosis : my use steroids to maintain the circulation

- Dyshormogentic goiter ? deficiency in Peroxidase enzyme ( mostly )  hypothyroidism - Myxodema  GAG deposition in the larynx “ deep voice” and tongue

- Hashimoto : destryoy thyroid follicles  some will leak into the blood giving hyperthyroidism , then goes back to normal and less than normal

- Hashimoto : antithyroglobulin and anti microsomal

- Germinal centers  form marginal zone  may develop lymphoma - Hurthle cells : large cells with eosinophilic cytoplasm

- Subacute granulomatous thyroiditis : tender and NO hypothyroidism - Reidel : maybe fibrosis of local structures

- Reidel ? young patients / Old age ? anaplastic carcinoma

- Radioactive I  increased in nodular goter or graves / decrease in carcinoma or adenoma

- Then DO FNA , not true cut biopsy bcz it’s very bloody

- FNA cannot distinguish  MUST see the capsule ## - Follicular carcinoma like blood metastasis

- Ret mutation ? prophylactic thyroidectomy -

- PTH activates osteoblasts which in turn activated osteoclasts ## - Hyperpara  MCC parathyroid adenoma

- Hyperpara  hypercalcemia  enzyme activator  pancreatitis ## - High PTH  osteitis fibrosa cystic

- Why ALP elevation when you bone resorbtion ? bcz it first activates osteoBlasts - Pseudohypopara : KKDD , proplem in Gs protein  hypocalcemia with increased PTH - DM : hyperkalemia but low total potassium bcz it’s escreted in urine

- So ttt : replace potassium

- Osmotic damage : schwan cells / pericytes of retinal bl vs “ he” / lens

- Cushing : gluconeogenesis : high glucose : excess insulin : increase fat storage on face / trunk / back

- Htn bcz upregulated alpha-1 reeptors

- Sac of blood adrenal : waterhouse fridrichson syndrome - Lung cancer lovers to go to the adrenal

BREAST

- Breast develop in the milk line ( from axilla to vulva) can develop anywhere - TDLU : Terminal duct lobule unit : Functional unit : lobule secrete , ducts deliver - Duct and lobules : inner luminal layer and outer myoepithelial layer

- Breast is hormone sensitive : develop after menarche / tenderness during menses / hyperplasia in pregnancy / atrophy after menopause

- Galactorrhea is not realted to breast cancer - Acute mastitis : staph dt fissures due to lactation

Continue drainage “ continue to feed the child” and use dicloxacillin

- Pericuctal mastitis : subarelolar duct inflammation / usually in smokers bcz loss of vit A and loss of speciality of epithelium / sq metaplasia and keratin plugs the duct /

inflamataion

fibrosis and nipple retraction [ vs breast cancer ]

- Mammary duct ectasia : inflammation of the wall of duct  dilatation [ ectasia ]  green brown nipple discharge and maybe a mass

multiparous post menopausal woman [ vs cancer ] Biopsy : chronic inflammation and plasma cells

- Fat necrosis : maybe minor trauma and biopsy show calcifications and giant cells - Fibrocystic change : pre-menopausal women

change : bcz it’s related to changing hormonal levels cysts are blue in color : blue domed appearance ##

BENIGN – NO RISK OF CANCER : fibrosis / cyst / apocrine metaplasia [ this is an exception of metaplasia : no cancer risk]

some carry risk of INVASIVE CARCINOMA IN BOTH BREASTS ? * ductal hyperplasia : excess number of cells [ X2 risk ]

* Sclerosing adenosis : too many glands + fibrosis and hardening  often calcified [ X2 risk ]

* Atypical hyperplasia : Atypical cells in ducts / or in lobules : ductal or lobular hyperplasia [ X5 risk ]

- Intra ductal papilloma : benign variant has BOTH layers : epithelial cells and myoepithelial cells  post menopausal woman with bloody nipple discharge papillary carcinoma ?? NO myoepithelial cells ##

- Fibroadenoma : most common tumor in premenopausal women wel demarcated and mobile

- Phyllodes : similar to fibroadenoma  but overgrowth of the fibers and leaf like projections [ post menopausal women  can get cancer ]

- Cancer : first degree relative : sister / mother / daughter

- DCIS  only in the duct  walks it’s way into the terminal duct and the nipple ? Paget’s disease

Invade  invasive ductal carcinoma

- LCIS  invade = invasive lobular carcinoma - DCIS :

no mass – detected as calcification on top of dead cells [ vs fat necrosis / sclerosing adenosis ]

Paget’s disease of the breast  THERE WILL be a cancer somewhere in the breast - INVASIVE DUCTAL :

 tubular : tubule like structures with ONE layer and Desmoplastic stroma 9 CT supporting the tumor)  good prognosis bcz tumor cells a re bound by stroma

 mucinous : good prognosis bcz malignant cells bound by mucus

 inflammatory : looks like infection and acute mastitis but not responsive by antibiotics [[ see after 10 days ]]

cancer in dermal lymphatics ( must see clinical and EM ) poor prognosis bcz it’s already seeding

 Medullary carcinoma : high grade [ in BRCA1 mutations] - LCIS

by chance : no mass or calcification

lacks E-cadherin : so cells are separated or not attached to each other due to mutation of cadherin gene

usually multifocal and bilateral

use Tamoxifen  low risk for development of invasive - INVASIVE LOBULAR

structures ##

- Metastasis is most important, but most patients don’t appear with metastasis , so most useful is Nodal affection

- Sentinel : inject dye and see the 1st LN affected  not to remove NORMAL LNs - HER 2 neu is a cll SURFACE – Estrogen is cytoplasmic that goes to the nucleus - Tripple negative ( ER / PR / HER 2neu )  poor prognosis

- BRCA 2 – breast cancer in males

- Male : usually ductal carcinoma bcz no lobules aslan BRCA2 and kleinfilter

-

CNS

- NTD : low folate PRIOR to conception

- Syrngomyelia : P/T on both sides – may be LMNL if expands – maybe lateral horn and horner’s syndrome

- Familial ALS ? Zinc copper superoxide dismutase mutation

- Meningitis is inflammation of leptomeninges : ie pia and arachnoid - Bacterial meningitis : PUS  may press on the brain causing herniation - Cerebral Vascular diseases :

 Global cerebral ischemia :

 mild ( conusion like in insulinoma )  severe ( vegetables )

 moderate ( infarcts and watershed area)  laminar necrosis : present in lines [ cerebellum or hippocampus ]

 Ischemic stroke :

 Thrombotic  PALE infarction at the periphery [ bcz you cannot lyse the thrombus it will reform ]

 Embolic : when embolus gets lysed  hgic infarction

 Lacunar : hyaline arteriolosclerosis in small Bl.vs  deep areas

 Intracerebral hge :

 rupture charcot bouchard aneurism

 SAH : berry anurism lack media layer in branching point ## - MLD  cannot degrade mylin – acumilate in lysozomes

- Adrenoleukodystrohpy : demylinating diseases : failure of adding coA to long chain fatty acids  fatty acids accumulate and damage adrenal gland and white matter

- JC virus  immunodeficiency activates it  PMLE - Apo E4  increase risk of beta amyloid [ 4 >2 ]

- DS ? APP is present on chromosome 21 , they have extra chr 21 and extra APP - Familial : presinillin 1 mainly mutation ( also presinillin 2 )

- Brain atrophy ? ventricles dilate to fill the space  Ex Vaco

- A-Beta amyloid may deposit on blood vessels of the brain  Amyloid angiopathy - TAU protein : hyperphosphorylated  cannot organize microtubules  neurofibrillary

tangles

- Vascular dementia : damage of brain areas ( 3,5,6 pyramidal neurons and hippocampus )  2nd

MCC of dementia - MPTP can result in Parkinson’s

- Parkinson’s dementia ?  LATER not EARLY

Early ? Lewy bodies in cortex  lewy body dementia not parkinson’s - Striatum ? it got a striate running in between ( internal capsule ) - Anticipation ? further expansion of tnr in SPERMATOGENESIS - LP improves normal pressure hydrocephalus

increased CSF bcz decreased absorbtion of CSF in arachnoid villi [ unknown reason] – stretch corona radiate

- Prion ? beta pleated sheets

- How can you get beta pleated ptn ? sporadic / inherited / Transmitted [ CJD : ( maybe corneal transplant ) RAPID dementia and patient die within a year + startle

myoclonus [ involuntary ms contraction wit minimal stimuli ] and ataxia / spike wave complexes on EEg ]

- Variant CJD ? mad cow

Familial fatal insomnia ? inherited with exaggerated startle response -

- 50% Glial cells : atrocytes – oligodendrocyes – ependymal cells - 50% neurons + meningothelial cells

- Meningeoma : female > male bcz it’s related to Estrogen - Compresses but doesn’t invade

- Medulloblastoma  Drop metastasis : to spinal cord

MSK

- Activating mutation in FGF3  inhibit cartilage - OI : blue sclera : exposure of choroidal veins

- Acidic environment is necessary to remova Ca from bone ##

CA is required to produce acid  CA deficience ? in osteopetrosis : failure of resorbtion - Tie in with RTA ##

- Alkaline environment is required to add Ca to bone ( Alk phosphatase ) - Paget’s disease starts by osteoclasts

- Lytic bone surrounded by sclerosis  osteomylitis - Osteoma : fascial bone / Gardner Syndrome

- Osteoid osteoma : osteoblasts tumor surrounded by active bone Diaphysis of long bone

cortex of long bone

bone pain resolves with Aspirin - Osteoblastoma :

vertebra

pain doesn’r respond to ASA

- Chondroma : small bones of hands and feet - Chondrosarcoma : pelvis or femur

- Pannus is inflamed granulation tissue in RA [ bl vs / fibriblast / myofibroblast] Myofibroblasts contract causing deformities

Systemic manifestaions

- Dermatomyoscitis : may get malar rash

- Dermatomyoscitis : Perimysium inflammation with perifascicular atrophy of the muscle Polymyoscitis : no skin  Endomysial inflammation

- Dystrophin links cytoskeleton to extracellular matrix - CK is elevated in Duchene dt damage of ms fibers - Lambert-Eaton :

 Improves with ms use

 Eyes are spared

 Anticholinergics are of no use

 Resolves with resection of cancer

- Rhabdomyosarcoma : desmin positive and rhabdomyoblast - Stratum spinosum : DESMOSOMES

- Acne : hormone related increase in sebum – excess keratin block the follicle ( comedones)

- Probionibacterium acnes : infection of acne : use benzoyl peroxides antimicrobial - Psoriasis : associated with HLA-C

- acanthosis : increase spinosum and epidermal hyperplasia

- Parakeratosis / neutrophils in coneum : munro abscess / elongated paplillae with thinning above them , exposure of bl. Vs [ asupitz]

- Ttt : steroids + PUVA : psoralin + UVA

- Lichen planus : Pruritic papules, purple , polygonal , planar

- Inflammation of dermal epidermal junction  sawtoothe appearance wicham stria

associated with hep c

- Pemphigus : basal cells is intact

- Wall of blister rupture easily bcz not all layers over blisters

- Separation bcz IgG gainst desmoglein  component of desmosome  separation : Acantholysis of strarum spinosum

- Bullous pemph : not rupture easily “ wall is entire epidermis” oral mucosa is spared

- Dermatitis herpetiformis : resembles little blisters of herpes  IgA deposits ( against gluten )

- Erythema multiforme : mycoplasma / HSV / malignancy Target lesion : necrosis of center

- EM + oral mucosa + fever = SJS

- Severe SJS = TEN ‘ drug’ with sloughing of skin

- Pseudocysts in seborrhic keratosis : contains pink keratin ## coin like stuck on lesions - Vitiligo  autoimmune destruction of melanocytes

- In lighter individual ? failure to tan

- Albinism : Melanocytes are normal  problem with tyrosinase

- Freckles  darker in sun lightdt increase number of Melanosomes NOT melanocytes [ organelle in melanocytes ]

- Melasma : mask like pigmentation of cheeks : pregnancy

- Nevus have hair mostly, but melanoma destroys skin and hair follicles - Acquired nevus 

starts in a child as Junctional

then progresses to dermis [ compound]

then junctional disappears and remains the intradermal [ most common in adults ] - Lentigo maligna : lentiginous means remain in d-epidermal junction  excellent

prognosis

- Superficial spreading : good prognosis

- Nodular melanoma : Early vertical phase  push epidermis up  nodules - Acral lentiginous  palms and soles  not related to sun  black people - Scalded skin syndrome : separation is at stratum granulosum : very superficial

Vs TEN : dermal epidermal junction  very deep -

NUTRITION

- Kwash : liver ptn decrease , muscle ptn is relatively unchanged - Anorecia / bullemia : MCC of death is Vfib dt hypokalemia

- In hyervitaminosis A : skin is yellow but sclera is normal unlike jaundice

- Alkalinephosphatase dephosphorylates pyrophosphate which normally inhibits bone mineralization

- Epoxide reductase activates vitamin K - Bitot’s spots in Vit A deficiency

- High fiber diet : decrease Estrogen deconjugation / binds lipocholic acid which colon cancer / increase fecal bacteria in fermentable type / increase stool freq

Renal :

- Unilateral renal agenesis : later on life there’s hyper filtration syndrome and Renal failure

- Dysplastic kidney ? cysts with wall containing cartilage : NON INHERITED !! don’t confuse with ADPKD

- Medullary cystic : shrinken kidnys + cysts in MEDULLA

- Most important in interstitial nephritis is eosinophilic cell casts

- Very important : in MCD there is effacement of foot processes because of cytokines, in Hodgkin’s Lymphoma there’s a huge amount of cytokines which is responsible for the B symptoms such as fever, night sweats, ……

- in type II MPGN : there’s antibody to C3 convertase which decrease serum C3 and increase c3a and c3b

- DM nephropathy ? NEG of efferent, so ACEi decrease it and good prognosis - Bladder cancer : 2 pathways :

 Papillary pathway: start LG  HG  invade

 Flat pathway : start HG  invade + EARLY p53 mutation - Bladder adenocarcinoma ?

 urachal remnants at the dome of the bladder

 Cystitis glandularis : cystitis followed by metaplasia

 Bladder esxtophy Respiratory :

- Nasal polyps : allergic rhinitis / Cystic fibrosis / Aspirin intolerance - Angiofibroma : in adolescent males : epistaxis

- African children and Chinese young adult : EBV NP carcinoma : epithelial cells [keratin] on a background of lymphocytes

- Laryngotracheobronchitis : parainfluenza virus

- Vocal cord nodules : degenerate myxoid tissue : singers

- Laryngeal papilloma is single in adult , multiple in children [ hpv] LOW risk of carcinoma - TB meningitis ? BASE of meninges

- Smokers : cenrtiacinar emphysema in upper lobes

- Alpha-1 antitrypsin deficiency : accumulation of unfolded protein in liver ER ## [picture] - PiM is normal allele , PiZ is the mutant

- Heterozygotes ? normal except if smoking - Homozygote : panacinar + cirrhosis - They will NOT have mucus cough - Very thin patients

- IL-5 calls in eosinophils - Bronchiactasis : Amyloidosis - TGF-B induce ILF

- Beryllium : In miners / aerospace NASA : non-caseating granuloma in the lungs and hilar LNs, various organ : NOT SARCOIDOSIS :Berryliosis

- Sarcoidosis ? lacrimal and salivary glands : mimic sjogren’s - Insulin inhibit surfactant “ in GDM”

- Free radicals : ROP + damage to the lung with bronchopulmonary dysplasia - Sq cell carcinoma : keratin pearls / Intercellular bridges

- Broncioloalveolar cell carcinoma : clara cell tumour , consolidation like on imaging , LM [ pic] excellent prognosis