PATHOLOGY - AIM4PG

Pelger-Huet anomaly • Inherited as autosomal dominant condition • Mutation in lamin B receptor (LBR), that is essential for maintaining the nuclear membrane structure Heterozygous- • Neutrophil function remains normal. • Resistance to infection is intact. • No gross features • PBS- reduced nuclear segmentation, bilobed neutrophils described as pince-nez. (Pinched-nose spectacles) Homozygous- • Very rare • Maybe associated with abnormal neutrophil functioning • Associated with skeletal anomalies like polydactyly, short metacarpals, and short stature • PBS- Single, eccentric nucleus with clumped chromatin, little or absent nuclear segmentation Pelger Huet anomaly vs Pseudo Pelger Huet cells in other conditions- • The proportion of abnormal neutrophils are usually > 50% in Pelger Huet anomaly • Pseudo- Pelger Huet cells- seen in - Myelodysplasias and myeloid leukemias- the proportion of abnormal neutrophils is around 5% or less. Plus there will be accompanying anemia and thrombocytopenias. Require a bone marrow biopsy - following chemotherapy - transient and self resolving - reported to be seen in COVID 19 patients - infections and sepsis - panhypopituitarism By: Dr Gudly For more notes join www.aim4pg.com/study-group

pelger huet cells

Factors involved in apoptosis . Regulators- BAD, BIM, BID, PUMA, NOXA . Pro apoptotic- BAX, BAK, P53, BCL XS . Anti apoptotic- BCL 2, BCL XL, MCL 1

Graft vs Host disease • Occurs in immunodeficient individuals • Usually seen after HSC transplant, can also follow solid organ transplant containing lymphoid tissue and unirradiated blood transfusion • Type IV hypersensitivity reaction • The transplanted cells/ graft attack host tissues, mediated by T lymphocytes in the transplanted donor cells • Prevented by HLA matching Manifestation- 1. Acute- Skin- • most commonly involved • Generalised rash, may lead to desquamation • Dermal infiltrates with lymphocytes and macrophages Liver- • Cholestatic jaundice with raised bilirubin, ast, alt and alp GIT- • Mucosal ulceration and bloody diarrhea Ocular- • Hemorrhagic conjunctivitis, pseudomembrane 2. Chronic- Skin- • Shows extensive fibrosis and sometimes atrophy, resembling systemic sclerosis • Can cause contractures limiting joint mobility GIT- • Chronic liver disease, cholestatic jaundice, esophageal strictures leading to dysphagia Ocular- • Keratoconjunctivitis Sicca Oral- • Atrophy of oral mucosa with lichenoid lesion

Still from The Good Doctor- teenage girl suffering from SCID

SCID/BUBBLE BOY DISEASE Defect in both cell mediated and humoral immunity Pathogenesis: 1. X-linked SCID • most common form • M>F • mutation in the common γ-chain subunit of cytokine receptors • Defective IL 7 signalling leads to defect in development of T cells which in turn hampers antibody production by B cells (CD40 L- CD 40 pathway) • Defective IL 15 signalling leads to deficiency of NK cells 2. Autosomal Recessive SCID • deficiency of the adenosine deaminase (ADA) • Leads to accumulation of toxic purine metabolites, that hampers the development of the rapidly dividing lymphocytes 3. DNA repair defect- NHEJ defect Features: • Recurrent and severe infections by a host of bacteria and viruses including- Candida, Pneumocystis, Cytomegalovirus, EBV, Varicella, Mycobacterium etc • Hypoplastic thymus and lymphoid tissues with marked depletion of t cell and b cell areas • Mucocutaneous candidiasis • Extensive diaper rash • URTI and LRTI • Delayed wound healing • GVHD can be seen in SCID patients receiving blood transfusion due to weak immune system • Failure to thrive

Hyperplastic arteriolosclerosis • Lesion affecting small arteries and arterioles • Develops in Malignant Hypertension (≥ 180/120 mm Hg) Histopath: • Arterioles exhibit laminated concentric rings due to hyperplastic proliferation of smooth muscle cells and intima giving an “onion skin” appearance on histology • Marked luminal narrowing causes downstream ischemia • Associated with fibrinoid necrosis (type 3 HS reaction) and local pin point hemorrhages • These pin point cortical hemorrhages in kidney lead to classical “flea bitten appearance” in Malignant Nephrosclerosis. By: Dr Gudly For more notes join www.aim4pg.com/study-group

Amniotic fluid embolism Obstetric emergency occurring during labor or in the immediate postpartum period (within 30 minutes of placental delivery), can result in sudden death Risk factors- • Multiparity • Increased maternal age • Rapid labor or Induction of labor • Instrumental delivery • placenta previa • Abruptio • polyhydramnios • amnioinfusion • Eclampsia • classical C-Section • D & C. Pathogenesis- Amniotic fluid containing fetal debris after a tear in the placental membranes or at placental implantation site or at the LUS or cervix, can travel through uterine veins and embolize to the lungs. Activation of coagulation factors, release of vasoactive substances, increased endothelin 1, cause bronchoconstriction, acute pulmonary hypertension leading to RHF, negative inotropism leading to LVF and pulmonary edema, and diffuse alveolar damage. Immune mechanisms like complement activation and mast cell degranulation have also been postulated to be a cause Histopath- laminated swirls of fetal debris (squamous cells, mucin, lanugo hair, vernix caseosa) and trophoblasts seen in maternal pulmonary circulation The diagnostic criteria for AFE proposed by Society of Maternal Fetal Medicine (SMFM) and the Amniotic Fluid Embolism Foundation: (1) sudden cardiac arrest or both respiratory and hemodynamic collapse, (2) biological disseminated intravascular coagulopathy (DIC), (3) absence of fever, (4) clinical onset during labor or within 30 min of delivery C/F- classic triad of AFE is hypoxia, hypotension and consumption coagulopathy. • Phase 1- cardiorespiratory collapse, • phase 2- consumption coagulopathy and fulminant DIC, dyspnea , shock, neurological complications • Fetal compromise due to decelerations in heart rate and fetal bradycardia Diagnosis- • ABG showing maternal acidosis • Chest Xray- may show features of pulm edema • PT prolonged • Decreased platelets due to platelet trapping • Decreased fibrinogen and increased fibrin degradation products • Decreased complement levels (C3 and C4) due to excess complement activation • Autopsy shows fetal squamous cells in maternal pulm circulation. By: Dr Gudly For more notes join www.aim4pg.com/study-group

laminated swirls of fetal tissue and fluid in amniotic fluid embolism

HAPPY NEW YEAR 2022 A SMALL GIFT FROM AIM4PG www.aim4pg.com/calendar WISHING YOU A PROSPEROUS YEAR WITH YOUR DREAMS COME TRUE From AIM4PG Team

Stains in pathology . Hemosiderin- prussian blue stain/ perls . Mast cell- Toluidine Blue . Copper- Rhodamine, Rubeanic Acid . Copper associated proteins like ceruloplasmin- Orcein . Calcium- Von kossa, Alizarin Red . Glycogen, Mucin, Fungi, Amyloid, basement membrane - PAS stain . Mucin- Mucicarmine, Alcian Blue . Amyloid- Congo Red . Fungi- Gomori silver methenamine . Lipid- Oil red O, Sudan Black . Melanin- Mason Fontana . Reticulin- Silver stain . Collagen- Mason Trichome, Van Geison, Azan trichome . Elastin- Ver Hoeff . Neuronal tissue/ Tau protein- Bielchowsky silver stain . Nissl body in neurons- Nissl stain . Myelin- luxol fast blue . PBS and BM- Romanowsky stains including Wrights, Giemsa, Jenners By Dr Gudly www.aim4pg.com

Histological events timeline in ischemic stroke 12-24hrs- red neurons with eosinophilic cytoplasm, small pyknotic nuclei and karryorrhexis, spongiosis (cytotoxic and vasogenic edema) 24-72hrs- necrosis with neutrophilic infiltration 3-5days- foamy macrophages (microglial cells) 1-2weeks- reactive gliosis (astrocytes) and neovascularization >2weeks- glial scar By Dr Gudly www.aim4pg.com

types of amyloid deposition -Primary amyloidosis- AL -Secondary amyloidosis- AA -Alzheimers- Aβ amyloid -Diabetes Mellitus- AIAPP(Amyloid Islet Associated Pancreatic Peptide) -Medullary Thyroid Cancer- Acal (calcitonin) -Prion diseases- Apr -Cerebral Amyloid Angiopathy- Cystatin C -Long term dialysis in chronic renal failure- A β2 microglobulin -Senile Amyloidosis- ATTR(transthyretin) -Familial Amyloidotic polyneuropathy- mutant ATTR -Familial Mediterranean Fever- AA By Dr Gudly www.aim4pg.com

Fat embolism syndrome presence of microscopic fat globules along with hematopoietic bone marrow in the microvasculature resulting in multiorgan damage Causes- • Trauma, • long bone fractures, • orthopedic procedures, • acute pancreatitis, • burns, • lipid infusions Pathogenesis- • presents within 1 to 3 days of insult • mechanical insult to long bones leads to fat embolus that occludes the microvasculature • Release of free fatty acids exacerbates injury to endothelium • platelet trapping within fat globules and splenic sequestration leads to thrombocytopenia C/F- Gurd’s Criteria - 1 major + 4 minor • Major - respiratory insufficiency (PaO2 < 60mmHg) causing dyspnea and tachypnea, - cerebral sequelae (agitation, delirium, seizures or coma), - petechial rash particularly in axilla (or subconjunctival or oral) • Minor- Tachycardia, hyperthermia, retinal changes on fundoscopy (haemorrhage with intra-arterial fat globules), renal dysfunction, jaundice, anaemia, thrombocytopenia, elevated ESR, Fat globules in sputum and urine • demonstration of fat microglobules by frozen sections and stains for fat like Oil red O- show orange red fat globules • X ray shows diffuse B/L pulmonary infiltrates like ARDS pattern • Helical Chest CT show nodular or ground glass opacity • NCCT of brain may show diffuse petechial hemorrhages in white matter. By: Dr Gudly For more notes join www.aim4pg.com/study-group

H & E stain – round clear fat globules seen in microvasculature in Fat Embolism

Kaposi Sarcoma • caused by HHV 8 • AIDS defining lesion Forms- Classic KS • Indolent course • Multiple red-purple skin patches, plaques or nodules, involving distal lower extremities later spread proximally. • typically, asymptomatic • localized to the skin and subcutaneous tissue Endemic African • HIV-seronegative • individuals <40 years • lymph node involvement common • not wearing shoes increases incidence in rural areas with volcanic clay soil possibly due to chronic lymphatic obstruction in feet from soil particles Transplant-associated KS • receiving T-cell immunosuppression • 100 fold increase in incidence • aggressive course involving lymph nodes, mucosa, and viscera • cutaneous lesions may be absent. AIDS-associated (epidemic) KS • Most aggressive Pathogenesis • HHV 8 • diminished T-cell immunity • characterized by the proliferation of spindle-shaped cells of pluripotent mesenchymal progenitor(polyclonal/oligoclonal) • increased endothelial factor VIIIa antigen, spindle cell markers like smooth muscle actin and macrophage markers like PAM 1 , CD 68, and CD 14 • slitlike vascular spaces with chronic inflammatory cell infiltrates that is recruited by proinflammatory and angiogenic factors produced by these spindle cells (that contain a virally encoded G protein) Histopath- • sheets of proliferating spindle cells and slitlike spaces with extravasated RBCs containing hemosiderin C/F- • Involves skin, oral mucosa, and visceral organs • Stages of lesion- patches- raised plaques- nodules • Cutaneous lesions typically involve lower extremities and head and neck region • Palpable and non pruritic • GI lesions- dysphagia, vomiting, abdominal pain, hematemesis, melena and obstruction • Pulmonary lesions- cough, dyspnea, hemoptysis . By: Dr Gudly For more notes join www.aim4pg.com/study-group

proliferating spindle cells with slit like vascular spaces and hemosiderin deposits in Kaposi Sarcoma

Approach To Nephritic Syndrome By: Dr Richa Aggarwal , MD Internal Medicine Watch Lecture Is Live https://youtu.be/pPqGsJJQd1w Listen To Lecture Podcast https://anchor.fm/aim4pg/episodes/Approach-To-Nephritic-Syndrome-e1bu5rp Download Lecture Pdf www.aim4pg.com/pdf More Lectures Of Faculty Coming Soon Stay Tuned

Examples of necroptosis . Physiological- chondrocyte death in mammalian growth plates . Neurological- Alzheimers, Parkinsons, Huntingtons , stroke . Reperfusion injury . Pancreatitis . HIV affecting T cells . Infarction of myocardium . IBD . Therapeutic- Counteracting apoptosis resistance in cancer cells during chemotherapy