Robbins and Cotran 9th Edition Questions

Chapter 1: The Cell as a Unit of Health and Disease

Short Answer Questions

How much of the human genome is coding and what does it code?  Of the 3.2b basepairs, there are 20,000 genes that comprise about 1.5% of the genome that code for proteins (enzymes, structural components, and signaling molecules used to assemble and maintain all the cells in the body What do we think that the rest of the genome does?  80% of the genome binds proteins, implying that it is involved in regulating gene expression, related to the regulation of gene expression, often in a cell-type specific fashion. List the major classes of functional non-protein-coding sequences found in the human genome.  1. Promoter & enhancer 2. Chromatin binding site structures 3. non-coding regulatory RNAs 4. Mobile genetic elements (transposons) 5. telomeres 6. centromers. What are the two most common forms of DNA variation in the human genome?  1) Single nucleotide polymorphisms (SNPs) 2) copy number variations (CNVs) What are the possible implications of SNPs.  {{{2}}} Define epigenetics.  Heritable changes in gene expression which are not caused by alterations in DNA sequence. List the 6 types of epigenetic changes.  1) Histone & histone modifying factors (Histones organize chromatin into heterochromatin and euchromatin 2) histone methylation 3) histone acteylation 4)histone phosphorylation 5) DNA methylation 6) Chromatin organizing factors. What is the function of micro-RNA (mi-RNA)?  It does not encode protein, instead they function primarily to modulate the translation of target mRNAs into their corresponding proteins, and are responsible for post-transcriptional silencing of gene expression. What is knockdown technology?  The use of synthetic si-RNA (short RNA sequences) introduced into cells that serve as substrates for Dicer and interact with the RISC complex in a manner analogous to endogenous miRNAs, and are used to study gene function, and are being developed as therapeutic agents to silence pathogenic genes, e.g. oncogenic in neoplasms. What is long non coding RNA?  Lnc-RNA modulate gene expression by binding to regions of chromatin, restricting RNA polymerase access to coding genes within the region, and may exceed the number of mRNA's by 10-20 fold. What is XIST?  XIST is a lnc-RNA which is transcribed from the X-chromosome and plays an essential role in physiologic X chromosome inactivation, though not inactivated itself, it forms a repressive cloak on the X chromosome from which it is transcribed resulting in gene silencing. What are the cellular housekeeping functions?  1) protection from the environment, 2) nutrient acquisition, 3) communication, 4) movement, 5) renewal of senescent molecules, 6) molecular catabolism, 7) energy generation. List the cellular compartments and the role in the cell.  {{{2}}} Describe the basic structure and functions of the cell membrane.  The plasma membrane is composed of a lipid bilayer of phospholipids studded with a variety of proteins and glycoproteins involved in ion and metabolite transport, fluid phase and receptor-mediated uptake of macromolecules, cell-ligand/cell matrix/cell-cell interactions. How are the large complexes in the plasma membrane formed?  They aggregate under the control of chaperone molecules in the RER or by lateral diffusion in the plasma membrane followed by complex formation in situ. What are aquaporins?  Special integral membrane proteins which augment passive water transport in tissues where water is transported in large volumes. How are channel and carrier proteins different?  Channel proteins created hydrophilic pores, permit rapid movement of solutes, restricted by size and charge, where Carrier proteins bind to their specific solutes and undergo a series of conformational changes to transfer the ligand across the membrane, relatively slow transport. What is the "multidrug resistance (MDR) protein"?  A type of transporter ATPases which pumps polar compounds (e.g. chemo drugs) out of cells which may render cancer cells resistant to treatment. What are the two fundamental mechanisms of fluid or macromolecules by the cell (endocytosis)?  1)Caveolae -invaginations of the plasma membrane, 2) Pinocytosis/receptor mediated endocytosis - macromolecules bind to receptor and membranes invaginate around it. What is exocytosis?  It is the opposite process of pinocytosis, where the receptor bound macromolecule is move to the cell surface and released. Describe the difference between phagocytosis and transcytosis.  In phagocytosis microbes are ingested forming phagosomes, which fuse with lysosomes and become phagylosomes, releasing undigested residual material when fusing again with the external membrane, in contrast transcytosis the materials are carried across the cell membrane unaltered. List the three major classes of 3 cytoskeleton proteins.  1) Actin, 2)Intermediate filaments, 3)Microtubules Describe actin.  Actin - 5 to 9nm diam fibrils, G-actin polymerized into F-actin, the form double strands helices, which interact with myosin (filamentous protein). List the various intermediate filaments, which are 10nm in diameter.  1) Lamin A, B, and C (nuclear lamins of all cells, 2) Vimentin (mesenchymal), 3)Desmin (scaffold for actin/myosin), 4) Neurofilaments (axons of neurons), 5) Glial filament protein (glial cells), 6)Cytokeratins (acid and basic and vary based on cell type). Describe microtubules.  Microtubules are 25nm diam fibrils of dimers of a and b tubulin, with a negative end embedded in the centrosome near the nucleus, the + end grows or shrinks as needed. There are kinesins and dyneins motors that move stuff around the cell, also found in cilia and flagella. What is clatharin?  A molecule found in the cell membrane that when the cell membrane invaginates forming a basket like structure. List and describe the 3 main classifications of cell junctions.  1) Tight /occluding junctions - form a high resistance barrier to solute movement, and allows the cell to maintain polarity, 2) anchoring junctions / desmosomes - mechanically attach the cell and their cytoskeleton to other cells and the ECM (hemidesmosome), 3)communicating/gap junctions - mediate the passage of chemical or electrical signals from one cell to another. What is the "unfolded protein response"?  Excess accumulation of misfolded protiens, which exceed the capacity of the ER to edit and degrade them, leads to the the ER stress response (UPR) that triggers cell death through apoptosis. What cell organelle has a reactive hyperplasia with repeated exposure to phenobarbitol catabolism in the cytocrhome p450 system?  Smooth endoplasmic reticulum. List three main functions of mitochondria.  1) Energy generation, 2) intermediate metabolism (instead of ATP make intemediate that can be used to make lipids, nucleic acids, and proteins), 3) Cell death ( necrosis & apoptosis) List and describe the four extracellular cell-cell signaling pathways based on the distance the signal travels.  1)Paracrine (immediate vicinity), 2) Autocrine (cell affecting itself), 3) Synaptic (neurons sending neurotransmitters at synapse), 4) endocrine (signals released elsewhere into bloodstream). What are the two characterizing features of stem cells?  Self renewal and asymmetric division (one daughter cell stays a stem cell) What are the two types of stem cells?  {{{2}}} What is the Warburg effect?  Increased cellular uptake of glucose and glutamine, increased glycolysis, and decreased oxidative phosphorylation by the cell. Which CDKI's have selective effects on CDK4 and CDK6?  p15,p16,p17,and p19 List some examples of signal transduction pathways.  1) Receptor tyrosine kinases (RTKs), 2) Nonreceptor tyrosine kinase, 3) G-protein coupled receptors, 4) nuclear receptors, 5)Notch family receptors, 6) Wnt protein ligands (Frizzled family receptors). Why does nuclear beta catenin occur in some neoplasms?  When Wnt ligand bins to frizzled it recruits Disheveled, this leads to the disruption of the wnt-ubiquitin complex, this stabilized pool of b-catening is then translocated to the nucleus forming a transcriptional complex On Page 19 there is a table of growth factors involved in regeneration and repair, please review.  Describe the function of cadherin.  What are the functions of the extracellular matrix?  Mechanical support, control of cell proliferation, scaffolding for tissue renewal, establishment of tissue microenvironments What are the two basic forms of the ECM?  interstitial matrix (fibrillar and non fibrillar collagen, fibronectin, elastin, proteoglycans, hyloronate, and other stuff), basement membrane (type IV collagen and laminin) What are the three proteins groups in the ECM?  1) fibrous structural proteins (collagen, elastins), 2) water hydrated gels (proteoglycans and hyaluronan), 3) adhesive glycoproteins (connect ECM to each other and other cells) Describe the structure of a protein that is dependent on vitamin C.  Collagen is composed of 3 seprate polypeptide chains braided into a rope like triple helix, lateral cross linking of the triple helices by lysyl oxidase (requires vitamin C) give it it's tensile strength. List three non-fibrillar collagens.  Type IV -basement membrane, Type IX - Fibrillar associated collagen with interrupted triple helices (FACIT), Type VII (provides anchoring fibrils to basement membrane beneath skin) Which structural protein is associated with Marfan syndrom?  Fibrillin synthetic defects, which wrap the elastin core.

Chapter 2: Cellular Responses to Stress and Toxic Insults: Adaptation, Injury and Death

Experimenting, please ignore

What are the four aspects of a disease?

1. Etiology Genetic - Inherited mutations and disease-associated gene variants, or polymorphisms. Acquired - Infectious, nutritional, chemical and physical. 2. Pathogenesis - The sequence of cellular, biochemical, and molecular events that follow the exposure of cells or tissues to an injurious agent. 3. Morphological changes - The structural alterations in cells or tissues that are either characteristic of a disease or diagnostic of an etiologic process. 4. Clinical Manifestations - Symptoms and signs of disease, as well as its clinical course and outcome.

Chapter 5

MC cause of spontaneous abortion is ?
A demonstrable chromosomal abnormality.

1% of all newborn infants possess a gross chromosomal abnormality and 5% of people <25y present with
a genetic disease.

Mutation
permanent change in the DNA, if affect germ cells are transmitted to the progeny

List and describe 4 broad categories of human genetic disorders:

[[Disorders related to mutation sin single genes with large effects i. Usually follow classic Mendelian pattern of inheritance ii. Often highly penetrant (large proportion of pop with gene has disease) b. Chromosomal disorders i. Structural or numerical alterations in autosomes and sex chromosomes ii. Uncommon, high penetrance c. Complex multigenic disorders i. Interactions between multiple variant forms of genes and environmental factors (polymorphisms), poly genic means disease when many polymorphism present d. Single gene disorders with nonclassic patterns of inheritance (not mendelian) i. Disorders resulting from triplet repeat mutations ii. Mutations in mitochondrial DNA iii. Those influenced by genomic imprinting iv. Those influenced by gonadal mosaicism]]

List and describe the possible outcomes of a point mutation in a coding region?
[[a. Missense mutation – pt mutation changes amino acid code, conservative when the amino acid is preserved, non conservative when replaced with another amino acid, b. Nonsense mutation – makes a stop codon ]]

List and describe the possible outcomes of point mutation or deletion in a non-coding region.
[[a. Promoters/enhancers – interfere with binding of transcription factors, marker reduction or total lack of transcription, b. Introns – defective splicing > failure to make mature RNA > no translation]]

List and describe the possible outcomes of deletions and insertions.
[[a.Small coding: not multiple of three = frameshift, if multiple of 3 than add or del amino acids accordingly, often premature stop codon i. Tay Sachs disease: 4 base pair insertion in Hexosaminidase A gene ]]

List and describe the possible outcomes of trinucleotide repeat mutations.
[[a. Usually G&C, dynamic and increase during gametogenesis, “RNA stutters”,b. Fragile X – CGG 250-4000, Huntinton’s Disease ]]

List and describe three examples of inheritance of single gene mutations

[[a. AD – manifested in the heterologous state, one parent of index case is usually affected, males and females affected and both can transmit conditioni. De novo cases may not have affected parentii. Penetrance = fraction of people with gene who have the traitiii. Variable expressivity = those with mutant gene have variety of phenotypesiv. Often age of onset is delayed so can reproduce before die from diseasev. Biochem mechanisms1. Reduced production of a protein or dysfunctional/inactive protein2. Involved in regulation of complex metabolic pathyway subject to feedback inhibition3. Key structural proteins (collagen and cytoskeleton of RBC)a. May be a dominant negative , e.g. osteogenesis imperfecta4. Gain of function are rare, 2 formsa. Increased in proteins normal function (excess enzyme activity)b. Huntinton’s diseas (abn protein accumulates, toxic to neurons)b. ARi. Largest category – both alleles at a locus are mutated1. Expression is uniform, complete penetrance common, early onset, unaffected carrier family members, mostly enzymesc. X Linkedi. All sex linked, and almost all are recessive , if Y Chromosome affected usually infertile males > no progenyii. Male expression b/c hemizygous, daughter carriers with variable phenotype because of lionization of 2nd X e.g G6DPiii. Dominant . vitamin D resistant rickets]]

Stopped at P142

Chapter 11: Blood Vessels

• Describe the two principal mechanisms underlying vascular disease.
• Describe the four main disease mechanisms and the vessels for which they have a predicliction.
• Describe the three layers of artery/vein walls.
• Describe how the media of arteries changes as one gets further away from the heart.
• List 5 differences between arterial vessels and venous vessels.
• List and briefly describe three vascular anomalies.
• List 5 functions of endothelial cells.
• List 5 factors which activate endothelial cells.
• List 6 features of an activated endothelial cell.
• Define endothelial dysfunction.
• List 5 functions of vascular smooth muscle cells.
• Describe how intimal thickening occurs in a healing vessel.
• List 5 difference between neointimal and medial smooth muscle cells.
• In a non diabetic what are the thresholds for diastolic and systolic blood pressure associated with increased atherosclerotic disease.
• List 5 causes of secondary hypertension.
• List 5 diseases resulting from hypertension.
• About 50% of patients with hypertension die from what 3 diseases.
• Define malignant hypertension, and list 3 ocular findings.
• Describe how cardiac function affects blood pressure.
• Describe how blood volume affects blood pressure.
• Describe how peripheral resistance affects blood pressure
• Describe the pathophysiological mechanisms associated with renovascular hypertension.
• List some single gene disorders which cause secondary hypetension.
• List four factors are mechanisms of essential hypertension.
• List five vascular changes associated with hypertension.
• Describe the differences between hyaline and hyperplastic arteriosclerosis.
• List three types of arteriosclerosis.
• What is Monckeberg medial sclerosis and how is it different from atherosclerosis?
• What disease causes more morbidity and mortality than any other in the western world?
• What is an atheromatous plaque?
• List four constituitive risk factors for atherosclerosis.
• List 5 modifiable risk factors for atherosclerosis.
• List five non constituituve and non modifiable risk factors for atherosclerosis.
• Briefly describe the pathogenic steps in atherosclerosis.
• What are the two most important causes of endothelial dysfunction?
• Briefly describe the role of LDL in atherosclerosis.
• How does inflammation contribute to atherosclerosis?
• List three viruses for which there is limited evidence of contribution to atherosclerosis.
• How do smooth muscle cells contribute to atherosclerosis?
• What are the differences between a fatty streak and a atherosclerotic plaque?
• List five most common locations of atherosclerotic plaques.
• What are the three main components of an atherosclerotic plaque.
• What is neovascularization of an atherosclerotic plaque?
• What four clinically significant changes can occur in an atherosclerotic plaque?
• What are the four major consequences of atherosclerosis?
• Define critical stenosis and the possible sequelae there of?
• What is the catch 22 of a fibrous plaque?
• What is one possible explanation for the abrupt rise in MIs after 9-11.
• What four basic mechanisms cause vasoconstriction?
• What are the possible sequelae of thrombi in a coronary artery?
• Classify aneurysms.
• List three syndromes where the connective tissue quality results in aneurysms.
• Briefly describe how collagen degradation and synthesis maintained.
• What is cystic medial degeneration and how does it relate to aneurysm formation?
• How does syphilis cause aneurysms of the aorta, and how to most of the patients die?
• What are the two most important causes of aortic aneurysms?
• What is a mycotic aneuryms and what are the three possible origins?
• Who most classically gets a AAA and where is it?
• List three variants of AAA and briefly describe each.
• What are the four most common clinical manifestations of a AAA aside from a palpable pulsating abdominal mass.
• Describe how the risk of rupture of a AAA increases with size.
• What is the most common cause of thoracic aneurysm, and describe 5 features of this syndrome.
• List 5 signs or symptoms of thoracic aneurysm.
• What two groups of patients have aortic dissections?
• What is the most significant risk factor for aortic dissection?
• Describe the difference between an aneurysm and a dissection.
• Classify aortic dissections.
• Classify vasculitides.
• List 5 defining features of Giant cell arteritis.
• List 5 defining features of granulomatosis with polyangitis.
• List 5 defining features of Churg-Strauss syndrome.
• List 5 defining features of Polyarteritis nododum.
• List 5 defining features of Leukocytoclastic vasculitis.
• List 5 defining features of Beurger disease.
• List 5 defining features of Behcet disease.
• List 5 defining features of Takayasu arteritis.
• List 5 defining features of microscopic polyangitis.
• List 5 defining features of Kawasaki disease.
• List 5 immune complext mediated vasculitides.
• List 3 granulomatous vasculitides.
• What is a pauci immune vasculitis and give three examples.
• List some causes of infectious vasculitis.
• List 5 features of Raynaud's phenomenon.
• What is the difference between primary and secondary Raynaud's?
• What is Takotsubo cardiomyopathy?
• List 5 causes of myocardial vessel vasospasm.
• What are varicose veins? List three risk factors. List 5 clinical feautures.
• What three sites are venous varicosities most commonly found?
• What are the 5 most common sites of venous thrombosis?