PATHOLOGY

*Ubiquinated Neurofilament that presents as cytoplasmic inclusion consisting of aggregated α-synucleinAssociated with Parkinson's disease(Accumulates in substantia nigra reflects decreased proteosomal activity)

*Hemophagocytic Lymphohistocytosis.(AR condition associated with defects in perforin coding genes or it can be secondary to EBV -HSV 4-/DS,linear,Enveloped virus/infection)

Macropahge presents Antigen on MHC2 to CD4+T cell, then Macrophage secretes IL12 helping these T helper cells to differentiate into Th1 cells.*Th1 cells secrete IFNY to return favor to macrophages and activate them.(IFNY is what turns macrophage into epithelioid histiocyte and giant cells), Activate macrophahges secrete TNFalpha responsible for formation and Maintenance of granuloma(Hence reactivation of Tb with TNFa blockers)*while we are still at it think of IL12 R deficiency.*Autosomal Recessive Defect in Cellular immunity*Defect is on Th1 cells NOT macrophages(Macrophages are affected though)*Defect: Absence of IL12 receptor on Th cells>Less Th1 response >Less IfnY>Less macrophage activation*Patient has high risk of salmonella(LIVE att. vacine+IM polys. vaccine) and Mycobacteria TB(Live att. vaccine)infections.*CURE:Bone marrow transplant

Schistosoma Haematobium(Trematode=fluke) which is a helminth, whose eggs are most common cause of Squamous cell carcinoma of bladder WORLDWIDE, which happens to be the most common cancer of bladder WORLDWIDE.*Schistosoma Does form granulomas in liver and spleen and can cause hepatosplenomegaly (S.japonicum and S.mansonii are more linked to this type of inflammation in liver and spleen),note that even though granuloma formarion involves macrophages/Th1cells, EOSINOPHILS WILL STILL PREDOMINATE at the site of infection as shcistosoma is helminth.You can get shcistosoma from snail-infested water.*It can cause Dystrophic calcifications(Localized to damaged tissue, with normal calcium levels in blood).Hey Note: most common bladder cancer in U.S is Trasitional cell bladder carcinoma(Mostly associated with smoking)

EBV virus is a DNA, enveloped virus which is also known as HSV4, it can bind CD21 on B cells(and can remain latent in them) and has been associated with Nasopharyngeal Carcinoma(Which our patient most likely has)-ebv can infect epithelial cells and transform them.*EBV is also associated with Burkitt's lymphoma(Most common childhood tumor in Central africa which often affects jaw,often involves 8-14 translocation) *EBV is also associated with Hodgkin's lymphoma(Characterized by Binucleate Reed-sternberg cells, CD15+ and CD30+ Cells of B lymphocyte origin without other B cell markers)

*Hemochromatosis-Autosomal recessive(Chr.6p)*Mechanism-iron overload due to Increased absorbtion of iron.*Even though females loose iron every month(By loosing blood), they still can get it.*Increased ferritin, Transferrin saturation on labs.*Associated with HLA-3 subtype.*Can be secondary due to blood transfusions(Think of someone with thalassemia major)*Iron can form Free radicals by Fenton reaction(Reacts with H2O2)>Get deadliest OH:>Tissue damage.*Patient is at increased risk of cirrhosis and Restrictive cardiomyopathy.

*Patient has likely got HPV(DS,Non-enveloped,DNA virus)*Genital wart(Condylomata acuminata) is mostly associated with 6,11.(Don't let them confuse you as Plantar warts are mostly associated with 1,2)**Remember type 16,18 are associated with penile/cervical carcinoma and promote Dysplasia(Disordered cell growth) of Metaplastic squamous epithelium Oncogenesis Mechanism: E6 of HPV connects to E6AP(Which upon contact with E6, becomes a bad guy and Polyubiqutinates P53 which is a major tumor supressor in our body , so less tumor supression>Dysregulation of G1>S progression>oncogenesis) Note:Normally P21 is what halts G1>S progression(P53 Turns on P21) so when you block P53 by polyubiquitination you also decrease P21 activity and thus increase G1>S progression.

*Asbestos-BUT never forget that asbestos exposure puts you at a higher risk of Bronchogenic carcinoma than mesothelioma.Asbestos exposure is associated with roofing and plumbing.*Berylium also increases risk of bronchogenic carcinoma but it is more associated with Space industry(Missile fuel and space vechiles,metal alloys in aerospace appliances and nuclear reactors.)*but know that mesothelioma due to asbestos exposure can present with abdominal symptoms as it can involve Peritoneum.*GOLJ question action:*Benign pleural plaques composed of fibrous tissue are the most common disorder related to asbestos inhalation. They frequently calcify and are present on the visceral pleura and dome of the diaphragm rendering them easy to identify with standard chest x-rays.They are not a precursor lesion for a pleural mesothelioma.The source of asbestos exposure can also be trough insulation material around pipes in old naval ships.

*Batteries and metal coatings contain-Cadmium.*He should be screened for lung cancer as cadmium also increases risk of Lung cancer.*Cadmium exposure -Industrial industries where Ore is Being smelted.*Nickel exposure is another possibility with Batteries so check for Bronchogenic carcinoma/Nasal cavity cancer, too.

*Silica-which would manifest as slowly progressive process causing Fine nodularity in UPPER lung lobes.*Ceramics, glasses, electronics-Exposure risk*Nickel exposure is another possibility with Ceramics ,so check for Bronchogenic carcinoma/Nasal cavity cancer, too.

*because it impairs Phagolysosomal Fusion in Maacropahges.*Can befound in miners.*Silica promotes macrophages to turn on inflammation by secreting TNF+IL1+LKTB4 and stimulation of fibroblasts takes place>Fibrosis around silica particle >Nodular lesions.*Function tests can show MIXED obstructive and restrictive defects(Still is Considered Restrictive lung disease-FEV/FVC>or=80%)+reducton in diffusing capacity.*In the heart, silicosis can cause Cor pulmonale(Right heart has to work harder) it undergoes hypertrophy and eventually fails.*Affects Upper lobes like coal contrast this with Asbestos(Diffuse fibrosis) which affects lower lobes.

*This process is Apoptosis(Programmed cell death) characterized by Pyknosis(Nuclear shrinkage)+Karryorrhexis(Fragmentation on nucleus by ENDonucleases which cleave at internucleosomal regions) >Thus Sensitive marker for apoptosis is DNA laddering(Fragmented DNA in multiples of 180Bp)*Cytoplasm becomes eosinophilic(Due to concentration of cytoplasm after cell shrinks)*Nucleus becomes basophilic(Condensation of chromatin)*Membrane Blebbing is characteristic, but it typically stays intact.*No significant inflammation follows this process,contrast this with necrosis.*First players, initiators of apoptosis are PROTEASES more specifically CASPASES.(Both in Extrinsic and INtrinsic pathways)

*Patient most likely has Follicular Lymphoma which involves 14-18 translocation(Basically IgH from chromosome 14 jumps next to BCL2 gene on chromosome 18>>OVERexpression of BCL2)*Now you should know that BCL 2 is Antiapoptotic molecule(In contrast to BAX and BAK which are PRO's).why BCL2 is antiapoptotic? *well it keeps mitochondrial membrane integrity(Prevents swelling) thus prevents release of Cytochrome C .+activation of caspase 9 is inhibited as BCL2 inhibits APAF1 which is needed by Cytochrome C to activate caspase 9 and Jump start INTRINSIC(Mitochondrial) apoptotic pathway.*So yea in this case due to overactive BCL2 we got Underactive APAF1 and thus Underactive Intrinsic Apoptotic pathway>Cell doesn't die when it is supposed to>TUMOR.

*Some examples of MI(Mitochondrial-Intrinsic) pathway of apoptosis are :*Apoptosis of Proliferating effector immune cells after IL2(Regulating factor-that induces T helper,cytotoxic,regulatory cell +NKcell proliferation) is withdrawn.*You can get Apoptosis due to TRH-not hormone but acronym for Toxins,Radiation,Hypoxia)*The reason you have fingers is INTRINSIC pathway of apoptosis, which remodeled your tissues and by selective removal of cells created spaces between your fingers.(So MI pathway is involved in Embryologic tissue remodeling)

**FasL-FasReceptor(CD95) interaction-involved in Negative selection of Tlymphcoytes in thymus medulla(if Tlymphocyte binds MHC molecule and antigen too tight, they die,)*TNFreceptor-TNF alpha is another example, rememberthat TNFalpha is associated with Cachexia in malignancy and it mediates septic shock, recruits WBC and promotes expression of E-selectin on endotelium.(needed for Adhesion and rolling of leukocytes)*Note: This processes include activation of Caspase 8 trough extrinsic pathway of apoptosis.