Final Study Guide Patho - Newest

Role of T-effector cell Thelper17 in exacerbating C. Diff infections in patients with IBD

- c. diff can have exaggerated immune response to Th17 (T Helper cell 17) in those with inflammatory bowel disease.....severity of illness more related to Th17 response rather than severity of toxins/spores/etc. - T helper cells releases IL6 to activate Th17 to secrete cytokines/IL's to result in macrophages/epithelial cells/etc. TEST: 1. A key immune process involved in the enhanced triggering of Inflammatory Bowel Disease includes: Answer: T Reg decreased response

Explain the role Telomere and Telomerase in cancer

- cancer has unlimited lifespan due to manipulation of *telomerase* - in cancer cells, telomerase is activated to restore telomere length when approaching critical stage/age - Telomerase expression requires increased oncogenes (RAS, MYC) and decreased TSG (P53, Rb) TEST: 1. Telomerase contributes to cancer cell immortality through: sustaining and elongating telomeres

Describe Diffuse Axonal injury

- damage to neuronal axon (typically shear, stretch and swelling) and associated bleeding - axon breakage=severe DAI and persistent coma: Shaken Baby is an example of DAI - Concussion is mild DAI

Describe Alzheimer's

- excess beta-amyloid in hippocampus, neurofibrillary tangles - cell body dysfunction, amyloid (senile) plagues = synaptic dysfunction

Describe the compensatory mechanisms that take place prior to hypoxia in shock

- flow charts

Know the Anti-inflammation cytokines leading to diminished immune response

-T reg has CD 25 arm - shows up during infection of sepsis to try to calm things down.... Decreases MHC 2 expression on macrophages to decrease response to antigen BUT we still have an infection going on.....so high T Reg levels are bad for prognosis of sepsis......but also low T helper cells are also not good T reg usually signals that we are good....so bad that we have too much T reg does 3 things: 1. Decrease MHC 2 antigen presentation expression (normal job) 2. Decreases T helper proliferation 3. Decreased cytokines

Explain the 4 stages of Proto-oncogene mutation into an Oncogene:

1) Growth Factors--EGF 2) Membrane Receptors—EGFR (HER2) 3) Cytoplasmic signaling--RAS 4) Transcription Factors—MYC, JUN, FOS TEST: 1. Which of the following processes can lead to the conversion of a protooncogene into an oncogene? ANSWER: All of the above A. inappropriate cytoplasmic signaling B. alterations in membrane receptors C. transformations in growth factor 2. Which normal gene is typically specified for normal cell growth and differentiation but if exposed to mutagenic substances may code for cancer? ANSWER: proto-oncogenes

State 4 scientific influences of the microbiome

1) more diverse microbiome, less severe IBD. 2) decrease in microbiomes increases depression 3) gut dysbiosis maybe be associated with autism. 4) gut-dysbiosis also leads to increased severity of heart failure TEST: 1. Which of the following is TRUE regarding normal intestinal microbiome? Answer: It produces a healthy environment that prevents colonization by pathogenic microorganisms.

Understand the role of BUN and creatinine

BUN - What is it? Blood Urea Nitrogen - Nitrogen is a product of protein catabolism which, in combination with other elements forms urea, which is waste; serves as stand in for all small molecule toxins.- What does it mean? Highly contextual. In renal disease elevation may represent low toxin clearance, but also rises with high protein intake, absorption of blood, catabolism, volume depletion, etc.- How much of it matters? Uremic symptoms generally more important than number, but > 100 more likely symptoms. Creatinine - What is it? Creatinine is produced from metabolism of creatine in muscle primarily, with some dietary intake as well. Useful because production is fairly constant.- What does it mean? Still pretty contextual. Important factors in variation include: muscle mass (amputation (le > ue), wasting, normal aging, hypertrophy); change in secretion (higher in sickle cell disease, nephrotic syndrome; lower with trimethoprim, cimetidine)- How much of it matters? Only important as marker of renal function, no indication to dialyze re: particular level. TEST: *1. An elevation in the blood urea nitrogen (BUN) in the presence of a normal serum creatinine is usually due to a problem with dehydration and___________.* *Answer: renal blood flow* *2. Which of the following are potential causes of elevated blood urea nitrogen (BUN) SELECT ALL THAT APPLY:* *Answer: B. Low renal toxin clearance AND C. High protein intake* 3. All of the following are definitions of acute kidney injury EXCEPT Answer: Rise in blood urea nitrogen (BUN) more than 30 percent from baseline *4. The grad patho student understands that a patient who is postoperative day 3 from a right nephrectomy may have a normal BUN/creatinine as a result of which of the following?* *Answer: nephron hypertrophy* 4. Serum creatinine is Answer: produced from metabolism of creatine in muscle cells *5. The grad patho student who is fluent in the role of creatine in the body, understands that a doubling of the serum creatinine level is most commonly associated with which of the following?* *Answer: decrease in nephron function*

Describe the Corticospinal tract of the Spinal cord Motor pathway

Corticospinal tract - Efferent - Impulse travels from motor cortex through brainstem and crosses to *opposite* side at brainstem-spinal cord junction - Lesions in spinal cord result in *ipsilateral* (same side) loss of motor function - Synapses in gray matter of anterior horn before leaving spinal cord -- Upper motor neuron lesion: occurs before this synapse - *Corticospinal pathway crosses over at brainstem....so if you have issue at right side of brain it effects left side of bottom BUT if you have issue in spine below brainstem, right side issue effects right side!!*

Describe the key elements of the Acute Lung injury diagnosis

EVALI: diffuse alveolar damage, high neutrophil count, macrophages, lymphocytes, granulomatous pneumonitis, resulting in inflammation, epithelial sloughing, airway edema, hypoxemia TEST: 1. Acute respiratory distress syndrome is diagnosed in a young man. The pathophysiologic process of ARDS is based upon Answer: *alveolocapillary injury* 2. All of the following are manifestations of ARDS, EXCEPT: Answer: inflammatory suppression

The role of Dendritic cells in surveillance of pathogens in the GI tract and the role of T Reg in IBD

diminished T-reg response with decreased secretion of IL-10 allows for enhanced inflammatory process. TEST: 1. A key immune process involved in the enhanced triggering of Inflammatory Bowel Disease includes: Answer: T Reg decreased response

Describe COPD-expiratory airflow obstruction

not significantly reversible. Inflammation and structural damage to airways. Inflammation leads to impaired angiogenesis, elastogenesis, and disruption of secondary septa that normally divide alveolar saccule into alveoli (larger, boggy alveoli). Neutrophil cells noted in pathology. TEST: 1. In COPD, inflammation leads to disruption of all of the following processes EXCEPT Answer: inspiratory airflow

Explain DKA

o Increased glucose demand d/t stressor o 30% of type I present with DKA o Hyperglycemia but cells are starving o Cells without glucose; proteolysis, lipolysis, gluconeogenesis, glyconeolysis, o Ketones=acids o Decreased pH TEST: *1. Which of the following would NOT be found in the patient with diabetic ketoacidosis (DKA)?* *Answer: increased pH* *2. A primary trigger of diabetic ketoacidsosis (DKA) includes:* *Answer: infection*

UNDERSTAND ALL FLOW CHARTS FOR SHOCK

slides!!!

Describe the cell effects of epilepsy and the process that contributes to cerebral hypoxia

• Increased O2 consumption (>60% more than normal)• Increased ATP use by 250%• Increased glucose use (anaerobic)• Lactate accumulates despite increased CBF d/t O2 usage-- Blood flow cannot keep up with demands• Refractory seizure (prolonged) activity leads to cerebral hypoxia• Damage 5-20 minutes (broad range; data not precise) of seizure activity can relate to hypoxia

Understand Kidney and Lungs as Acid Mgt Organs

(H+HCO3~H2CO3~H2O+CO2): Body does not like free H+. Lungs act quicker than kidneys to compensate for altered conditions. Metabolic alkalosis is not as common and acidosis. TEST: 1. Understanding the pH of the GI tract, the graduate patho student knows that a patient with a nasogastric tube and copious output of gastric secretions is at risk for: Answer: metabolic alkalosis 2. Which of the following would NOT be found in the patient with diabetic ketoacidosis (DKA)? Answer: Increased pH *3. The clinician understanding the anion gap calculation reports that an increased gap is associated with Answer: acidosis*

Describe characteristics of Tumor Suppressor Gene (2 alleles)) and Know common TSGs (Rb, TP53 & BRCA)

- *Cancer cell activation requires overstimulation of growth-promoting signals AND inactivation of elements of the proliferation-inhibition pathway* . - Tumor Suppressor Genes (TSG) inhibit proliferation - *Rb* codes for a protein that blocks cell division by binding transcription factors - *TP53* inhibits cell cycling by stalling cell division and allowing time for DNA repair. With excessive DNA damage, TP53 may initiate cellular apoptosis. - *BRCA1 & BRCA2* TEST: 1. Tumor suppressor genes such as RB and BRCA are considered to be: ANSWER: recessive 2. The p53 gene: A. refers to a tumor suppressor gene B. creates susceptibility to cancers if mutated C. normally participates in DNA repair, or in initiating apoptosis in mutated cells that cannot be repaired *E. a, b and c*

Discuss Autonomic Hyperreflexia (aka dysreflexia)

- *Dysreflexia = SBP > 150 mm Hg (>20% ↑ in SBP)*. Usual resting BP for tetra- in upright position is 90-110 mm Hg. - Flushing/sweating/piloerection (hair stands up) usually above level of lesion. Elevated BP with no or minimal symptoms = silent autonomic dysreflexia - Most common with chronic SCI *at or above T6*

Describe the process of iodine deficiency and it's influence on the thyroid; including goiter

- *Iodine deficiency*: Lack of iodine prevents production of T4 and T3, but does NOT stop thyroglobulin. Elevated TSH leads to thyroglobulin production into the follicles leading to goiter. TEST: *1. After stimulation by TSH, the thyroid follicle begins the process of hormone production. The final process prior to the secretion of T3/T4 into the circulating blood stream involves which of the following?* *Answer: cleaving of thyroglobulin from T3/T4* *2. In conditions of iodine deficiency, which of the following conditions leads to the development of a goiter, assuming that TSH effectively stimulates the thyroid gland?* *Answer: Thyroglobulin production*

Describe the impact of cervical SCI on respiration

- *Leading cause of morbidity and mortality* - Decreased FVC -- *Atelectasis (lung collapse at low volume)*, decreased cough strength -- Improves over weeks to months - Decreased airway clearance - *Sympathetic denervation = parasympathetic overstimulation = Increased bronchial tone* - Sleep-disordered breathing

Understand the differences between spina bifada occulta, meningocele, myelomeningocele

- *Spina Bifada Occulta*: No protrusion of meninges or neural elements -- Posterior vertebral laminae don't close → mesodermal and epidermal tissue fills space - *Meningocele*: sac (meninges) filled with CSF protrudes through opening (no neural elements) - *Myelomeningocele*: sac (meninges) *and neural elements* (spinal cord/nerves) protrude through opening

State the process through which T cytotoxic with CD8 arm releases perforins

- *T cytotoxic cell* binds to the antigen component, sticks out its *CD8* arm to the *MHC1*, costimulate, adhesion, BUT T cytotoxic cell releases *granules* to then kill the macrophage TEST: 1. T cytotoxic cells kill target cells using: Answer: Perforins

Describe the cause of Type IA DM

- *autoimmune attack, changes to MHC region on chromosome; 90% of those with Type 1* - Type 1A (subtype of T1DM) = Immune mediated, genetic change on *chromosome 6* in the same gene that codes for MHC (in 80 -90% of people with Type 1A). --Immune system now attacks beta cells. - Some issues in promoter region of *chromosome 11 (the other 10%)* TEST: 1. Which of the following is NOT true regarding Type 1 diabetes? Answer: It is highly associated with obesity

Describe ALS

- *progressive degeneration of upper and lower motor neurons* Proposed mechanisms: - Genetic predisposition with environmental triggers? → - Inflammation/degeneration: -- Anterior horn cells of spinal cord - →*denervation and atrophy of muscle fibers* - *Glutamate toxicity, mitochondrial dysfunction, autoimmunity may all play a role*

Describe the role of Excitotoxins:

- Glutamate: (Excitotoxin: Neurotransmitter) binds to NMDA = ion channel protein; when activated allows positively charged ions to enter cell) and controls calcium transport and post-synaptic excitation—in toxic amounts caused by brain injury results in neuronal dysfunction.- Inflammatory markers such as WBC, IL-1, IL-6, and C-reactive protein have been correlated with prognosis.

Understand the stages of TBI Patho; including mechanism of neuronal injury and secondary injury mechanisms

- 1. Direct damage with impaired CBF and metabolism; ischemia leads to lactic acid, increased membrane permeability and edema; ATP stores and depleted in anaerobic metabolism and Na/K pump fails- 2. Membrane depolarization with release of excitatory neurotransmitters, NMDA activation, and activation of Na+/Ca++ channels. Influx of ions leads to catabolic intracellular processes; activating peroxidases and proteases (damaging); increases free fatty acids and oxygen free radicals; also caspases (caspase 3 plays role in apoptosis) are activated- 3. Membrane degradation of vascular and cellular structures; necrosis or apoptosis• Primary Traumatic brain injury (TBI) is defined as an alteration in brain function manifested as confusion, altered level of consciousness, seizure, coma, or focal sensory or motor neurologic deficit resulting from blunt or penetrating force to the head.• Skull fx (fracture)• Hemorrhage• DAI - diffuse axon injury• ConcussionSecondary = Indirect consequence of primary injury: Hypotension, Hypoxia, Ischemia, Edema, Increased ICP, oxidative stress, excitotoxicity, vascular injury, inflammation and neuronal death (can alter BBB) TEST: 1. What are the 2 biomarker proteins released into the bloodstream after a TBI? Answer: UCH-L1 and GFAP

Describe the role of ADH, Angiotensin II, Aldosterone, ANP, Urodilantin and Uroguanylin/Guanylin in regulation of blood fluid volume and osmolality.

- ADH, Ald, AII = increased fluid reabsorption - ANP, Urodilantin, Uroguanylin/Guanylin = decreased fluid reabsorption - *Antidiuretic hormone (ADH)*: Secreted from pituitary gland in response to elevation in extracellular fluid osmolality; *leads to higher levels of fluid reabsorption -> decreased blood osmolality*. - Aldosterone and Angiotensin II (AII): result in *increased Na+ reabsorption*; H2O follows Na+ resulting in *increased H2O reabsorption*. - Atrial naturetic peptide (ANP): is released from the atrium in response to increased stretch, usually from hypervolemia. *ANP inhibits AII--> Na+/H2O loss decreasing ECF*. - Urodilantin: Similar action to ANP *(decreases Na+ and thus water reabsorption)*, but secreted by distal tubule/collecting tubule cells in response to hypervolemia. - Uroguanylin/Guanylin: Similar effect to ANP/urodilantin, but yet another mechanism. Secreted from intestine in response to NaCl load; bind to guanylyl cyclase receptors in proximal tubule and collecting duct -> cGMP -> decreased Na+, Cl-, H2O -> ECF. TEST: 1. ADH released from the posterior pituitary acts to: Answer: Quickly control water excretion from the kidney 2. Aldosterone acts on the distal tubules and collecting ducts to increase sodium reabsorption. Aldosterone works over Answer: weeks

Describe the process of Bell's Palsy development

- Acute facial paralysis caused by *cranial nerve VII inflammation* at/near stylomastoid foramen - symptoms, likely due to compression, ischemia, demyelination - Viral infection (HSV, HZV) may trigger

Describe the process of acute Guillain-Barre Syndrome/GBS

- Acute inflammatory demyelinating polyneuropathy (AIDP) impacting PNS that causes areflexic weakness - Preceded by viral illness in 60-70% of cases, usually URI (upper resp. infection) - *Autoimmune destruction of myelin sheath +/- axons - T cell autoimmune response, inflammation of peripheral nerves, macrophages cause demyelination and axon destruction*

Describe ITP

- Autoimmune production of IgG against platelet antigens - Platelet with receptor is bound to vWF and for some reason is being seen as foreign and we make antibodies for it - Macrophages destroy the platelets ; results in more platelets trying to be made (increased megakaryocytes but decreased platelets) TEST: 1. You are evaluating an 8 year old boy in the ED who presents with epistaxis (bloody nose) and small discolorations on his gums. You are concerned for ITP. You recall from Patho class that ITP involves: *Answer: An immune process with antibodies reacting to platelet membrane glycoproteins*

Discuss Autoregulation and factors that influence it, including BP and CO2

- Autoregulation is the inherent ability of blood vessels to maintain a constant CBF over a variety of blood pressures- Overall CBF is defined by factors, such as its radius and length, and both blood viscosity and pressure, as they influence ANY vessel in the brain.- In brain injury, autoregulation is lost and changes in blood pressure directly affect CBF- Cranial vessels constrict when BP elevated and dilate when BP decreases; also dilate with increased CO2 and constrict with decreased CO2 TEST: 1. A compensatory alteration in the diameter of cerebral blood vessels in response to increased intracranial pressure is called Answer: Autoregulation

Explain the role of activated B cells in creating plasma cell and memory cell

- B Cells are part of adaptive immunity - B cells with specific antibodies are specific to each antigen (adaptive!) - B cell tags onto antigen to activate it to create B memory cells and B effector cells (B plasma cell) - B plasma cells go on to make antibodies - - B cell needs bound pathogen, endocytosis, presentation on MHC II, AND T-helper stimulation (releases cytokines) in order to differentiate into memory or plasma/effector cell TEST: *1. The immune system cell responsible for antibody proliferation is:* *Answer: B Plasma*

Explain the uniqueness of T and B cells with antigen specific receptors (as compared to TLR)

- BOTH adaptive! - Every B cell is for a very specific antigen - antibodies -T cell also has specific targeting to specifics - not antibodies TEST: 1. Antigen presenting cells such as macrophages identify and phagocytose antigens using specialized receptors called: Answer: Toll-like receptors *2. The T helper effector cell releases a cytokine called interleukin-4 (IL-4) which stimulates which cell to activate and proliferate* *Answer: B lymphocyte* *3. Antigen presenting cells release the following cytokine to stimulate a T helper response:* *Answer: IL-1* *4. Which of the following immune responses requires T helper cell assistance?* *Answer: proliferation of T memory cells* *5. Which of the following is not considered a true phagocyte?* *Answer: B Cell* *6. The epitope portion on the pathogen binds to the following portion of the B cell:* *Answer: variable portion of the antibody* 7. The antigen presenting cells of the immune system include: A.Dendrites B. B cells C. T effector cells D. Macrophages E. all of the above Answer: *F. a, b, & d*

Understand Nerve injury and axon regeneration

- New terminal sprouts project from the proximal segment, Process limited to myelinated axons, Generally only in the PNS

Understand and compare the 2 types of IBD

- Both resulting from genetic, environmental, & immunologic factors - Transmural and can effect any portion of GI tract (mostly ileum!) - Blockage of lymphoid and results in inflammation of surrounding tissue leading to deep linear ulcers - 20% of those with Crohn's have IBD - Associated with *Granulomas = walled-off chunks of macrophages* - Recovery from IBD flares—changes in adaptive immunity - Immune response through *Th17 becomes "hyperactive"* - High amounts of *IL-6* noted - Cause unknown; associated with *Mutation on Chromosome 16* - Strictures - Fistulas - Severe Malnutrition - Skin Maceration (due to diarrhea) TEST: 1. The clinician caring for a patient with an exacerbation of Inflammatory Bowel Disease understands that the microbiome is probably not functioning optimally due to: Answer: decreased diversity *2. A key immune process involved in the enhanced triggering of Inflammatory Bowel Disease includes:* *Answer: T Reg decreased response*

Describe the process of C. Diff toxin damage.

- C. diff causes spores and toxins (specifically TcdA, TcdB, and Binary Toxin (CDT) = *inactivating actin*! - Activates intestinal neurons to enhance motility = diarrhea! - Toxins damage epithelial cells, disrupts tight junctions, causes fluid leak and diarrhea, activation of neutrophils (inflammation) = more diarrhea, pseudomembrane, intestinal perforation - Translocation of bacteria across lumen can cause sepsis - Toxins can also become mutated to evade immunization - Fecal Transplant = can help significantly with c. diff treatment TEST: 1. The graduate patho student knows that all of the following points about Clostridium Difficile are true EXCEPT: Answer: Not found in the microbiome of GI tracts of healthy individuals

Describe process of chronic Myasthenia Gravis

- Chronic autoimmune disease with acute exacerbation that causes fatiguable weakness - *relationship with thymus; Antibodies block Acetylcholine binding at receptor (diagnostic test)* - *T-cell dependent, antibody complement-mediated deterioration of NMJ* - ACh [1] is released into the synapse [2] but cannot bind to ACh receptors on the muscle fiber due to antibodies [3] on the receptors blocking entry of ACh. Without triggering of the muscle fiber [4], resulting in muscle weakness and ACh deficiencies.

Discuss the process of Multiple Sclerosis (MS) plaque development

- Chronic, immune-mediated, demyelinating disease of the CNS - T- and B-cells cross the blood-brain barrier, attack myelin, repair myelin, overtime sclerotic plaques - Possible Causes: - Infectious - Primarily viral (association with EBV) - Environmental - Geography (Vitamin D), smoking, obesity - Genetics - 1st degree relative = ↑ risk -*Immunologic - T- and B-cell mediated destruction of myelin sheath and formation of sclerotic plaques* - *HLA region of Chromosome 6. Changes in this area increase the probability of getting MS*. - T regulatory cells, a type of T cell, dampen or turn off inflammation. *In MS, T regulatory cells to not function correctly and do not effectively turn off inflammation*. - T cytotoxic cells directly attack and destroy myelin sheath - B cells become activated with the help of T cells. B cells produce antibodies and stimulate other proteins and in MS, these cause damage in the CNS.

Describe the difference between complete and incomplete SCI

- Complete: loss of all motor and sensory function below level of injury; no sacral sparing - Incomplete: some preserved motor or sensory function below injury; sacral sparing

Understand the x-linked recessive disorder of Duchenne Muscular Dystrophy

- Congenital myopathy that results in progressive muscle weakness and degeneration - *Genetic mutation of dystrophin gene → deficiency of dystrophin protein at the cellular level → weakness of cell membrane → extracellular fluid leaks into cell → protease activation and inflammation → muscle degradation and muscle cell fibrosis* - Primarily impacts skeletal and cardiac muscle - Starts at birth, symptoms by age 2-5, typically lose ability to ambulate by adolescence (12-14 yo) - Develop respiratory, cardiac, and orthopedic issues - Intellectual delays/learning difficulties - Life expectancy late 20s-early 30s

Explain the process through which a fever develops

- Controlled elevation of body temperature resulting from an upward shift in the hypothalamic temperature set-point - Immunocompromised = lower threshold (lower set-point) -- WBC release cytokines which activate prostaglandin E, which changes temperature set point in hypothalamus ........aspirin inhibits prostaglandin E and thus your hypothalamic temperature set point won't change TEST: 1. A fever develops as a result of immune system activation. The components in the pathway to fever development include: Answer: Release of cytokines and alteration in hypothalamic temperature set-point 2. A basic advantage of a fever includes Answer: inability of the microbe to survive 3. The older person is less likely to mount a substantial fever due to *Answer: alterations in pyretic cytokines (Il-1, IL-6 and TNF)*

Discuss key elements of spinal anatomy:

- Cord terminates at L2 allowing for lumbar punctures below the site - fractures can occur without damage to cord (spinous process, tranverse process) - tranverse foramen allows for passage of vertebral artery which connects to basilar artery and finally, circle of willis. - Vertebral arteries run through vertebral foramen of vertebrae

Describe process of production of fibrin degradation products ie. D-dimer

- D-dimer = Fibrin degradation/split product measured in the blood that allows us to measure degree of clot breakdown!!!! (level, not rate) TEST: 1. The conversion of plasminogen to plasmin results in clot retraction and eventual clot disintegration. The end-products of this process are fibrin degradation products. Fibrin degradation products are measured by Answer: D-dimer

Describe the development of spina bifada/neural tube defect

- Developmental anomaly (neural tube defect (NTD)) caused by incomplete closure of vertebral ring, with or without protrusion of meninges and neural elements - *Blastocyte - differentiation* of cells into germ layers - endoderm, ectoderm, mesoderm on Day 18. - *Ectoderm folds to form neural tube*. Abnormal fusion/failure to fuse = spina bifida.

Understand the EMG pattern in GBS

- EMG/NCS: consistent with demyelination (may not be present early in disease course)

Understand the roles of cytokines Leptin and Resistin

- Obesity = increased FFA; impairs insulin/glucose transport leading to decreased sensitivity to *leptin* therefore, satiety decreased which increases *resistin* hormone and increases LDL/dyslipidemia - Leptin: an adipocytokine, acts on hypothalamus to *block hunger* - Resistin: an adipocytokine, pro-inflammatory molecule, *blocks action of insulin*; directly causes endothelial dysfunction TEST: 1. Obesity utlimately leads to decreased sensitivity to which of the following adipocytokines and triggers decreased satiety Answer: Leptin

Describe the process of Antigen presentation and name the cells that present

- Epitope = point where antigen connects to the receptor - Macrophage AKA "antigen presenting cell" b/c presents that antigen to the rest of the immune system *this can all be happening extracellularly, in various tissue* 1. Macrophage presents antigen with MHC2 arm, at which point T Helper Cell (from adaptive immune system) arrives to reach out with a receptor to bind to the antigen as well 2. T Helper Cell reaches out CD4 receptor arm to attach to MHC2 --- MHC2 created by endoplasmic reticulum 3. T Helper Cell also attach to the antigen itself to determine what it is 4. Adhesion molecules are then released to keep these molecules attached to allow antigen recognition 5. Co-stimulatory molecules are also released which are the "conversation" taking place between each molecule (involving IL-1 and IL-12) (IL = interleukin = cytokine which allows cells to talk) 6. T Helper releases IL-2 which helps differentiate and proliferate which T cells are needed specifically to help this (tells other T cells what is needed to help further and adapt) 7a. T Helper cell makes T memory cells to react more quickly next time this happens 7b. T Helper cell also makes T effector cells which help fight the current pathogen Scenario 2: - Macrophage ingests pathogen, presents on MHC2 arm to present the antigen --- IF the antigen is a VIRUS, the macrophage is infected with a virus! 1. Macrophage now will also stick out MHC1 arm which notifies other cells that it is infected 2. T helper cells binds CD4, costimulate, adhere, IL1 and IL12, send IL2, make memory and effector cells just like usual but now MHC1 will bind to a T cytotoxic cell! 3. *T cytotoxic cell* binds to the antigen component, sticks out its *CD8* arm to the *MHC1*, costimulate, adhesion, BUT T cytotoxic cell releases *granules* to then kill the macrophage 4. Since T helper cell got there first, it is initiating an army of T cells to come attack the pathogen MHC1 cell is always presenting itself as identifying itself, it's just not always holding an antigen to show it has been infected TEST: 1. When an extracellular pathogen encounters a dendritic cell in the epithelium: Answer: A. the pathogen is engulfed by the antigen presenting cell and presented on MHC II B. the pathogen antigen is processed into antigen fragments and carried to lymph nodes by the dendritic cell C. the pathogen is presented to T and B lymphocytes in the lymph nodes, as appropriate *E. all of the above* 2. Antigen presenting cells such as macrophages identify and phagocytose antigens using specialized receptors called: *Answer: Toll-like receptors* 3. Antigen presenting cells release the following cytokine to stimulate a T helper response: *Answer: IL-1* 4. The antigen presenting cells of the immune system include: A. Dendrites B. B cells C. T effector cells D. Macrophages E. all of the above *F. a, b, & d*

Describe the Patho of Cerebral Infarct

- Every infarct has a central core of ischemia that is irreversible- White matter myelin unravels and Axons swell- rCBF levels <8 ml/100g/min; neurons die within minutes (2 million brain cells die a minute!)- Inflammatory response; macrophages phagocytose neurons and myelin- As core disintegrates, peripheral endothelial cells proliferate and capillaries grow into the dead tissue (Neovascularization)- Astrocytes proliferate and form a glial scar; neurons do not regenerate- Ischemic Penumbra - surrounds with core with a zone of borderline ischemic tissue- Hypoperfusion <20mL/100g/min- Area of dysfunction but without structural damage- Window of salvaging the zone is short; ischemia develops if untreated- Penumbra is what we attempt to treat! Depending on cause of stroke, ideally treat within 3 - 24 hours. Determined by imaging now, used to be just determined by time. TEST: 1. The cerebral zone that comprises an area of hypoperfusion with a CBF of approximately 20 yet contains potentially salvagelable neurons is referred to as Answer: ischemic penumbra

Explain the Renin-Angiotensinogen-Aldosterone System/RAAS

- Factors that cause renin release in the presence of low BP- 1. Kidney - Afferent arterioles goes into glomerulus, juxtaglomerular cells sense flow, convert pro-renin into renin (when low BP or low afferent)- 2. OR SNS senses vasoconstriction and activated J.G. cells to release renin- 3. OR Macula Densa in distal convoluted tubules can sense decrease in sodium, assuming decrease in water, and leads to release of renin from J.G. cells- 4 Effects of Ang2:- Angiotensin 2 is a potent vasoconstrictor and can constrict afferent vessels kidney vessels to decrease urine output (increases BP)- Angiotensin 2 in pituitary initiates release of ADH = water reabsorption (increases BP and TPR)- Angiotensin 2 can cause adrenal glands to release aldosterone = sodium reabsorption (increase BP)- Angiotensin 2 causes smooth muscles in arteries to vasoconstrict (increased TPR) *TEST:* 1. Overactivity of the renin-angiotensin-aldosterone system (RAAS) has long been recognized for contributing to primary hypertension. True statements about RAAS pathway include: (CHECK ALL THAT APPLY) Answer: increased sodium retention AND increased preload 2. The renin-angiotensin-aldosterone system is activated by all of the following EXCEPT: Answer: hypokalemia 3. The primary initiator of the renin-angiotensin-aldosterone system is the release of renin from: Answer: juxtaglomerular cells 4. As a mechanism to raise blood pressure, angiotensin II activates the following EXCEPT Answer: pituitary release of prostaglandins

Tetralogy of Fallot

- Features (MULTIPLE CHOICE QUESTION) - *VSD (large, unrestrictive, subaortic)* - *RV outflow obstruction* - *Aortic Override* - *RV hypertrophy* TEST: 1. The most common congenital heart disease lesions include: (CHECK ALL THAT APPLY) Answer: all of the above (A. Tetralogy of Fallot B. Pulmonary stenosis C. Ventricular septal defect D. Endocardial cushion defect E. Atrial septal defect)

Explain the determinants of Glomerular Filtration Rate

- GFR is determined by outward pressure generated by *blood flowing into the glomerulus* which is *offset* by counter pressure from *hydrostatic pressure* in the glomerular space and *osmotic pressure* from proteins in the capillary. - GFR is maintained by both intrinsic (renal autoregulation) and extrinsic (neural/hormonal control) factors. - GFR is more sensitive to changes than BUN/creatinine TEST: 1. What is the definition of glomerular filtration rate? Answer: The total of the filtration rates of the functioning nephrons in the kidney 2. GFR is more sensitive to renal changes than BUN/creatinine Answer: true 3. The segment of the nephron primarily responsible for glomerular filtration is referred to as Answer: renal corpuscle

Describe the incretin effect as influence by GIP and GLP-1

- GIP and GLP-1 (insulinotropic hormones) - These hormones sense food intake (and size of meal) and alerts pancreas to start producing insulin accordingly = the *Incretin Effect* -- those on TPN (total parenteral nutrition) - can ingest same glucose but have less insulin response - *DPP4* inhibits the Incretin effect by deactivating GIP and GLP-1 - In Type 2 DM, GIP is incompetent but GLP-1 works fine = sub-optimal response - Pharmacological interventions: incretin mimetics; incretin enhancers: DPP4 inhibitors ---crohns disease + diabetic can cause hyperglycemia from inflammation but also have it from incretin effect TEST: 1. What is the term for the process by which insulinotropic hormones are secreted by the small intestine and account for 50% of the total insulin secreted after oral ingestion of food? Answer: Incretin Effect

Describe the process of glycosylation; including the rationale for elevated HgBA1C

- Glucose attaches to proteins in body; weakens tissues; endothelial cell gaps - Increases clotting risk because macrophage releases (IL & TNF-alpha) with inflammation - Glucose binds to globulin in the RBC in all people but in non-diabetics, lower percent of hemoglobulin has glucose attached - Initially a rapid but unstable bond forms with glucose and globin in response to high glucose levels, more stable over time - BG levels over the 120-day lifespan of the RBC -- Reflective of *60-90 day BG level* - *5.6% * or less of Hgb are covalently bonded to glucose in non-DMs TEST: 1. Hgb A1C is a measurement that reflects glycosylation : Answer: of hemoglobin over the past 2-3 months 2. HgbA1C 5.4 indicates normoglycemia and is a reflection of: Answer: the % of Hgb molecules irreversibly bound with glucose

Describe the angiogenesis process involving HIF 1-alpha and VEGF

- HIF-1a = results FROM inactivated tumor suppressor genes + increased oncogenes = increased angiogenesis by increasing *VEGF*, which also induces anti-apoptosis protein expression- elevated HIF-1a leads to chemo resistance, increased tumor glycolysis, increased metastasis, and poor prognosis ---- possibly b/c VEGF induces anti-apoptotic proteins and activates IC survival pathways - MMP-9! TEST: 1. Cancer cell characteristics that ultimately lead to growth : A. involve the increased expression of VEGF with angiogenesis to promote increased vascularization B. involve the EMT process with supression of adhesion molecules and reduced adherence to adjacent cells & extracellular matrix (ECM). C. involve cancer cell survival through Tumor Associated Macrophages (TAM) and Cancer Associated Fibroblasts (CAF) ANSWER: *D. all of the above* 2. What is the name of the enzyme that digests ExtraCellular Matrix (ECM) allowing for the release of latent angiogenic factors as well as the production of new angiogenic factors? Answer: Matrix Metalloproteinases (MMP-9)

Describe HITT

- Heparin inhibits thrombin by activating *antithrombin III*, preventing fibrinogens conversion to fibrin - Heparin is bound to platelet factor 4 which our body sees as foreign and makes antibodies for it - This increases platelet activation/clotting = reduced platelet count in blood = thrombocytopenia and thrombosis - This puts people with HITT at a 50% greater risk for PE/DVT (or arterial) - Should see elevated megakaryocytes b/c trying to increase platelet production TEST: *1. The coagulation disorder, HIT:* *Answer: is an antibody reaction to a platelet factor 4 and heparin complex*

List the 3 causes of spinal cord injury (SCI)

- Hyperflexion - Hyperextension - Vertical compression/axial loading

Name the factors which contribute to cardiac remodeling and heart failure progression

- Hypertrophy - Fibrosis - Myocyte loss - Abnormal energy production - Ventricular dilation TEST: 1. Myocardial injury often results in myocardial remodeling. Remodeling results from all of the following EXCEPT: Answer: increased receptors

Understand the roles of the following cytokines: Interferon, IL-1 & 12, IL-2, IL-4, TNF-alpha

- IL-1 and IL-12 = co-stimulatory molecules allowing cells to talk (T Helper and APC) - IL-2 = released by T Helper cell to help differentiate and proliferate which T cells are needed to help - IL-4 = stimulates B lymphocytes - TNF-a = secreted by macrophages to increase innate and adaptive immunity. Pro-inflammatory TEST: *1. The T helper effector cell releases a cytokine called interleukin-4 (IL-4) which stimulates which cell to activate and proliferate* *Answer: B lymphocyte* *2. Antigen presenting cells release the following cytokine to stimulate a T helper response:* *Answer: IL-1*

Explain elements of Peds Immunity

- IgM in utero - limited IgA (available in colostrum and breast milk) - IgG passed via placenta - Full adult immunity not available until 1-4 years of age TEST: 1. The following antibody is produced in sufficient quantities in the fetus in utero Answer: IgM 2. During what gestational time period are fetuses most vulnerable to the teratogenic effects of mutagens? Answer: 4 Weeks

Describe the Diagnostic testing associated with MS

- Imaging - MRI of brain and spinal cord - demyelination (plaques) - Neurophysiologic studies - Evoked potential/nerve conduction studies - Laboratory studies - *Elevated IgG in the CSF with presence of oligoclonal bands*

Explain the rationale for initial hyperinsulinemia in Type II DM

- Initial hyperinsulinemia: insulin made but can't enter cells. Beta cells eventually burn out and/or Beta cells desensitize to glucose over time TEST: 1. The clinician caring for a patient with relatively newly diagnosed type II diabetes mellitus might anticipate lab values that demonstrate hyperglycemia and: Answer: hyperinsulinemia

Describe the mechanism of intestinal ischemia.

- Initial tolerance followed by decreased vascularization. - Anaerobic metabolism and decreased ATP. - Reperfusion injury—distribution of inflammatory mediators and presence of ROS leads to cellular destruction. TEST: 1. Vasculopathic conditions such as intestinal ischemia can be problematic even during the recovery phase because re-perfusion can result in the circulation of which of the following? Answer: inflammatory mediators

Describe the Breakdown of Na/K pump due to insufficient ATP in shock

- Insufficient ATP leads to impairment in cell membrane strength; breakdown of Na-K pump 1. Na inside cells and K outside; nerves and myocardium with reduced action potentials—severe impairment 2.Water follows Na into cell--cellular edema, disrupts membranes & lysosomes. 3.Water pulled from vasculature decreases circulatory volume

Discuss Neurogenic Shock

- Interruption of sympathetic fibers causes vasodilation, venous pooling, unopposed vagal tone with bradycardia and decreased contractility - Injuries above T6 Management - Monitor; treat bradycardia - Avoid hypotension; restore volume, then use vasopressors - High index of suspicion for other injuries - Also monitor temp b/c of altered thermoregulation

Describe the APC, T helper T cytotoxic and TNF-mediated immune response to Hepatitis B infection

- Little pieces of HBV peptides that were once the core are now available to go to MHC1 arm to notify *T cytotoxic cells to attack the virus (via CD8)* - The surface antigens released when envelope is dismantled, are picked up by antigen presenting cells to stick out MHC2 arm where *T helper cells with CD4* arm recognize and recruit other cells - T helper calls T cytotoxic AND B cells (b plasma cells to make antibodies) AND T helper itself is targeting the APC TEST: *1. Characteristics of hepatitis C infection that lead to tolerance to the virus include each of the following EXCEPT:* *Answer:suppression of double-stranded DNA* *2. Hepatitis B virus affects the liver primarily by:* *Answer: Stimulating the immune system and its T-cytotoxic cells, which kill infected cells* *3. The TNF-mediated immune response to Hepatitis B infection of a hepatocyte ends with caspase activation but starts with which of the following?* *Answer: binding to TNF-R1 receptor*

List the areas of the nervous system commonly impacted by MS

- Optic nerves - Oculomotor nerves - Brain - - Brainstem - - Cerebellum - - Periventricular (edge of ventricles) - - Juxtacortical (where gray and white matter atteches) - Spinal Cord

Discuss the Secondary injuries and impact of secondary injuries in SCI

- Local vascular changes - Thrombosis or hemorrhage due to endothelial changes - Vasospasm - Compression from edema or clot - Systemic hypotension and hypoxia - most targeted therapy - Loss of ATP-dependent cellular processes - Free radical production and lipid peroxidation - - destroys cell walls - Increases in intracellular calcium and sodium - Accumulation of glutamate - Inflammatory/immune response - Cell death: loss of neurons and glial cells due to necrotic and apoptic cell death - Necrosis - - Severe insult overwhelms cell's homeostatic mechanisms - - Intracellular edema, membrane lysis, spillage of cell contents - - Significant inflammatory response - Apoptosis - - No significant inflammatory response - - Implicated in death of oligodendrocytes and demyelination - Axonal demyelination - Glial scar formation related to reactive astrocytosis

Explain the roles of the sympathetic nervous system in Heart Failure

- Low BP sensed by baroreceptors in carotid and aortic bodies. As a compensatory mechanism it, leads to vasoconstriction which increases heart rate and contractility.- It also increases SVR(systemic vascular resistance) leading to increased workload of ventricle which increases heart failure- SNS is an early and immediate compensatory response to low CO.- Juxta-glomerular cells receive SNS input when CO drops.- Cells release renin and initate RAAS. As a compensatory mechanism, RAAS increases blood volume through Na and water retention.- However, excessive and chronic SNS activation significantly increases Left Ventricle afterload. Increased afterload increases cardiac workload and may decrease stroke volume.- Long term SNS leads to HF Progression and Cardiac Remodeling with thickening of the ventricle resulting in the ventricular chamber becoming smaller and stiffer which exacerbates heart failure TEST: 1. A patient is diagnosed with left ventricular systolic heart failure (HFrEF). His pathophysiologic processes include all of the following EXCEPT : Answer: SNS denervation 2. Which of the following result from HF and contribute to the feedback loop which exacerbates the complications of HF? Answer: increased SNS tone and inflammation

Describe Sepsis

- MAP (>65 is goal) - Mixed Venous O2 (Reflection of oxygen-demand by tissues) In septic and distributive shock, mixed venous oxygen remains high because cells cannot use the oxygen because some organs have extreme vasoconstriction, as organs become dysfunctional they will start to pull oxygen and this will eventually decrease mixed venous oxygen --- in other shock conditions - decreased mixed venous oxygen constantly) - Oxygen Delivery: 1. hemoglobin 2. oxygen saturation 3. cardiac output 4. oxygen tension gradient/diffusion distance - Lactate (higher lactate = worse prognosis - alanine plays a role in the feedback loop)

Explain Cerebral Oxygen Extraction Fraction

- MAP increases, increasing ICP, causing hypoxia, hypercapnia, and thus ischemia = decreased CBF, increased oxygen EF, decreased CMRO2 TEST: 1. Increased oxygen extraction fraction is an indication of stressed/injured neurons. *Answer: true* 2. When describing cerebral oxygenation status, the grad patho student references oxygen extraction fraction understanding that: Answer: *All of the above* (A. oxygen extraction fraction will increase as blood flow diminishes B. increased oxygen extraction fraction signifies increased O2 demand by the cells C. the fraction of oxygen removed from the blood by the cerebral tissue)

Describe the process by which T helper with CD4 arm differentiates into effector and memory cells

- MHC1 = "self" = all nucleated cells ! (keeps immune sells from attacking these cells) - MHC2 = arm of antigen presenting cell to notify that it found a pathogen - MHC1 with antigen = T cytotoxic cell with CD8 T cell - MHC2 = T helper cell with CD4 2. T helper cells binds CD4, costimulate, adhere, IL1 and IL12, send IL2, make memory and effector cells just like usual but now MHC1 will bind to a T cytotoxic cell! TEST: *1. The outcome of the binding of the T helper cell CD 4 arm with the antigen presenting cell is dependent on* *Answer: the cytokines released*

Describe differences between single gene and sex linked disorders; including influence on offspring; recurrence risk

- Most sex-linked traits are located on the X chromosome and are said to be X-linked!!! - Sex-linked (X-linked) disorders are usually expressed by males because females have another X chromosome to counteract the abnormal gene ! - *X-linked recessive* - Most X-linked disorders are *recessive* - Affected males cannot transmit the genes to sons, but they can to all daughters - Sons of female carriers have a 50% risk of being affected Example) *Hemophilia*; deficiency of Factor VIII - Males cannot pass because they pass the Y chromosome to the son BUT if he has a daughter, theres a 50% chance the daughter has it but it'll be recessive unless the mother has it too TEST: 1. Individuals affected with which genetic disorder are almost never females? - Answer: X-linked disorders 2. The graduate patho student is assisting the team in counseling a mother who is a Hemophilia carrier. The father does not carry the mutation. Understanding the the condition is X-linked, the following statement about Hemophilia is TRUE Answer: A son is more likely to express Hemophilia than a daughter

Identify the benefits of the following immune entities within the GI tract: IgA, Paneth, Peyer patches

- Mucosal secretions produce antibodies (IgA) - *Paneth cells*- near crypts; produce *defensins* and other antibiotic peptides and *lysozymes* important to mucosal immunity - *Peyer patches* (collections of lymphocytes, plasma cells, and macrophages) produce *IgA* as a component of the gut-associated lymph tissue in the small intestine TEST: *1. Peyers patches are collections of immune cells within the GI tract lymphatic tissue that produce IgA* *Answer: true*

Describe the roles of nitric oxide and prostacyclin after released by endothelial cells

- NO and PGI2 maintain platelet inactivity and vasodilation TEST: 1. Nitric oxide and prostacyclin are produced by endothelial cells. Their primary function includes which of the following? Answer: Vasodilation while platelets are inactive

Explain the process of both Vitamin B12 and Iron absorption

- Na-dependent active transport with Vit B12 bound to intrinsic factor and absorbed in ileum - Iron is absorbed in duodenum. Transported by transferrin. Transferrin = major transporter (25-35% saturated with iron). Unbound iron triggers free radical activity -- Transferrin moves iron around and Ferritin stores iron TEST: 1. Conditions such as starvation, decreases in Vitamin B12 and intake of cytotoxic medications can lead to suppression of small intestinal villi cell division, resulting in shortened villi and diarrhea Answer: true 2. Disruption of which of the following transporters interferes with the movement of iron from the duodenum to the target cell? Answer: transferrin

Describe Saltatory conduction

- Nerve impulses travel down axon, skipping myelin sheaths

Explain fibrinolysis: plasminogen to plasmin via t-Pa or U-pa (plasminogen activators)

- Plasminogen converted by t-PA to plasmin 2 types of plasminogen 1. Tissue plasminogen activator (t-PA) -- intravascular 2. Urokinase plasminogen activator (u-PA) -- extravascular or tissue compartment - t-PA converts plasminogen to plasmin which breaks down fibrin! - u-PA can also do this if coming from endothelium (these occur independently but can work together) TEST: 1. The plasminogen activators that promote the conversion of plasminogen to plasmin resulting in Fibrin Degradation Products are Answer: Tissue plasmin activator and urokinase-like plasminogen activation

Describe Procalcitonin

- Produced by thyroid and secreted by neuroendocrine cells of lung/intestine Procalcitonin - increases in 2-4 hours, peaks with in 24-48 hours -*More procalcitonin generally means higher degree of sepsis* -Located on calc 1 gene (chromosome 1) - bacterial infections increase expression of the calc 1 gene

Describe MODS

- Progressive dysfunction of two or more organ systems resulting from an uncontrolled inflammatory and stress response to severe illness or injury - Causes: ◦Most common: sepsis, septic shock ◦Other: any severe injury (trauma, burns, major surgery) - Manifestations: ◦Respiratory ◦Hepatic ◦Renal ◦GI ◦Myocardial failure

Describe the components of the neuron cell

- Receive stimuli - Conduct impulses to other neurons, muscle fibers, and glands - Excitatory or inhibitory - Found in brain, spinal cord, and ganglia - Vary in structure, size, and function Cell body (soma) Dendrites - Short, multiple projections - Conducts impulse to cell body Axon - Longest projection of neuron - Conducts impulses away from cell body

Explain the 3 components that describe AKI

- Serum Cr rise ≧ 0.3 mg/dL in 48 hrs - Rise in Cr ≧ 1.5 times baseline in 7 days - Urine volume <0.5 mL/kg/h for 6 hours TEST: 1. All of the following are definitions of acute kidney injury EXCEPT Answer: Rise in blood urea nitrogen (BUN) more than 30 percent from baseline

Understand the normal process of glucose transport into cells

- Skeletal muscles 1. store glycogen and 2. oxidize glucose - Insulin binds to receptor, sends message to cell to activate GLUT 4 which moves from inside of cell to plasma membrane to become a GLUT 4 transporter - Blood glucose enters cell through GLUT 4 transporter via diffusion (no ATP needed b/c down gradient) - If blood glucose drops, no gradient, GLUT4 detaches from plasma membrane - Insulin and muscle contraction are primary drivers of activation of GLUT4 transport TEST: *1. Which GLUT transporter has an active role in the diffusion of glucose across the plasma membrane of the Pancreatic B cells?* *Answer: GLUT 3* *2. Cells require the presence of insulin on the insulin receptor with signaling of an intracellular cascade pathway in order glucose to be transported intracellularly.* *Answer: True*

Describe Spinal Shock

- Spinal shock = Loss of reflexes below level of injury - Return of bulbocavernous reflex: within days - Return of deep tendon reflex's: within weeks - 4 phases

What is thrombin's role in negative and positive feedback loops?

- Thrombin (factor 2a) = leads the negative feedback loop to stop clotting b/c we have enough fibrin BUT ALSO leads the positive feedback loop to call for additional fibrin 1. Thrombin converts Fibrinogen (Factor 1) to Fibrin (loose) (fibrin is factor 1a), fibrin (loose) is converted to fibrin (stable) 2. Thrombin ALSO activates Factor XIII (13) into 13a, activated factor 13 stabilizes fibrin further TEST: *1. The Protein Factor which manages both the positive and negative feedback loop of the clotting cascade is:* *Answer: Factor IIa / Thrombin*

What is the role of Factor XIIIa?

- Thrombin ALSO activates Factor XIII (13) into 13a, activated factor 13 stabilizes fibrin further TEST: *1. The Protein Factor necessary for the activation of crosslinks which connects fibrin strands and stablizes the blood clot is:* *Answer: factor XIIIa*

What is the role of calcium in the clotting cascade?

- Tissue Factor and Inactive Factor VII are activated by Calcium that is released from activated platelets TEST: *1. Which of the following is a potent catalyst in the clotting cascade?* *Answer: calcium*

Discuss the difference between upper and lower motor neurons

- Upper motor neurons - Contained in CNS, send impulses to LMN - If injured, pt has hyperreflexia, spasticity, positive Babinski (upgoing toes) - Lower motor neurons - Carry impulse from UMN to effector organ (muscles) - If injured, pt has flaccid paralysis, loss of tone, areflexia, atrophy, negative Babinski (downgoing toes)

Understand Newer Strategies in Septic Management as they apply to Patho:

- Vit C, Thiamine, Hydrocortisone

Understand the process of progressive intracranial HTN

- Volume overload = Change in volume of 100-120 ml.-- Hemodynamic failure, autoregulatory capacity exceeded-- Pressure from volume compromises neuronal oxygen.- MAP increases, increasing ICP, causing hypoxia, hypercapnia, and thus ischemia = decreased CBF, increased oxygen EF, decreased CMRO2- Decreased CPP = Autoregulatory vasodilation to maintain CBF. TEST: 1. The acute brain injury patient is experiencing an increase in intracranial pressure. If unmanaged, this increase is likely to result in: Answer: brain tissue hypoxia

Describe Pediatric Sepsis

- Young myocardium; higher baseline contractile state With sepsis, depend on HR to increase CO (can't contract much more) ◦Tachycardia needed. Peds already has high HR; unlikely that CO can be maintained to meet needs ◦Low CO increases mortality risk ◦Vasoconstriction occurs with decreased SV and contractility ◦COLD SHOCK immediately, no warm shock first like in adults

Describe DIC

- abnormal activation of the proteins involved in blood coagulation, causing small blood clots to form in vessels and cutting off the supply of oxygen to distal tissues - Usage of platelets is greater than the bodies ability to make platelets Characteristics of DIC: (TEST QUESTION!) - Surge of Clotting Cascade - Overwhelming Platelet Consumption/Usage - Consumption exceeds Production - Thrombocytopenia yields Bleeding TEST: 1. The following conditions may be used to describe elements of DIC with the EXCEPTION of: Answer: Results from an inherited condition

Describe the Penumbra

- area of hypoperfusion/moderate ischemia - CBF approx20 - neurons are salvageable. Increased amount of 'healthy' collaterals leads to increased likelihood of recovery of neurons. TEST: 1. The cerebral zone that comprises an area of hypoperfusion with a CBF of approximately 20 yet contains potentially salvagelable neurons is referred to as Answer: ischemic penumbra

Explain secondary hemostasis:

- goal=fibrin mesh; tissue factor (factor 3), fibrinogen, thrombin, fibrin, serotonin, calcium - Endothelium releases Tissue Factor to work with activated platelets to start clotting cascade (make a permanent plug) - Fibrinolysis = helps with retraction of pieces we don't need; also helps to remove clot completely as wound heals TEST: *1. The cell adhesion molecules (CAM), P-selectin and PSGL-1,have a pivotal role in facilitating the accumulation of what protein factor at the site of endothelial cell injury?* *Answer: Tissue Factor III* *2. Which of the following is a potent catalyst in the clotting cascade?* *Answer: calcium* *3. The Protein Factor which manages both the positive and negative feedback loop of the clotting cascade is:* *Answer: Factor IIa / Thrombin* 3. Plasminogen converts the fibrinogen in the blood stream into fibrin which is a clot and all bleeding ceases. Answer: false

Describe the process of spinal cord injury

- loss of normal sensory, motor and/or autonomic function due to compression, tearing, laceration or ischemia; as well as edema and hemorrhage

Explain Cerebral Metabolic Rate of Oxygen

- no test questions

Describe anti-NMDAR as a cause of seizures

- presents as bizarre behavior and progresses to seizure; associated with ovarian tetratoma - Excessive excitation via glutamate attaching to (NMDA) receptors: Ca++ influx: increased activation - Reduced inhibition of GABA (too little); not attaching to GABA receptors: Cl- release: unable to inhibit activation (GABA stops the glutamate to NMDA connection) - Uncontrolled, rapid neuronal discharge - Increased cerebral metabolic demand - Increase in cerebral blood flow, but metabolic demand still exceeds supply

Explain epigenetic modifications:

- the processes of DNA methylation (could also be methylation or phosphorylation) and histone tail modification; Hypermethylation (CH3) in the CpG island blocks gene expression. (*understand hypomethylation: allows for gene expression—might be bad if it is an oncogene*). Histone modification tightens or loosens histone; manipulating gene expression: HAT (open/unwinds) and HDAC (closes/tightens). "Close the door with the AC on". HAT example : Acetyl negates the positive lysine making the bond neutral and opening the gene for expression. HDAC example: remove acetyl TEST: 1. Which is true about epigenetic modifications? ANSWER: Can be influenced by lifestyle and environment *2. Epigenetic changes that promote cell division in cancer:* *ANSWER: include hypermethylation of tumor suppression genes and hypomethylation of protooncogenes* 3. Which of the following best describe epigenetic mechanisms? ANSWER: DNA methylation, histone modifications 4. TRUE statements about the genetics of breast cancer include each of the following EXCEPT: ANSWER: The majority of cancers are inherited and the role of epigenetics is minimal 5. Histone tail modifications contribute to epigenetic changes. The modifications are known to include all of the following EXCEPT: ANSWER: carbonization

Explain the PD-L1 and PD-1 effect on cancer cells

- tumor produces ligand protein called *PDL-1 which binds to PD1 receptor on T-cells* , which *tells the cell not to kill the cancer*!! (1 of the 3 ways cancer cells can evade distruction) TEST: 1. Cancerous tumors have several strategies to evade immune destruction. One strategy involves the production of a protein/ligand that binds to T cells and signals the T cell not to attack. What is the protein/ligand called? Answer: PD-L1

Can the cascade produce fibrin with a mutation in one of the protein factors in the cascade?

- yes TEST: 1. The clotting cascade involves a sequenced series of protein factor activations that amplifies with each successive reaction resulting in fibrin mesh. The precise series of activation involving each factor without error is essential to the end product of fibrin mesh Answer: False

Understand the role of Ach as neurotransmitter at the neuromuscular junction.

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Describe chemical synapses (with Ca voltage gate) and electrical synapses (gap junction)

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Genetics, Epigenetics, Cancer

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Renal, Fluid, Electrolytes

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Endocrine

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Neuromuscular

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Pulmonary

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Shock / MODS

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Cardiac

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Neuro

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Hematology/Platelets

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GI and Hepatic

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Immunology

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Understand the basics of the 4 Antibody functions

-1. Neutralize toxins 2. Neutralize viruses - Individuals with antibody deficiencies are susceptible to viral infections 3. Opsonize encapsulated bacteria 4. Indirectly enhance inflammation - Antibodies form the "bridge" between antigens and inflammatory cells and complement so we "Focus" attack by creating antigen-antibody complexes that can be detected and destroyed TEST: 1. Antibody functions include each of the following EXCEPT: Answer: formation of granulomas

Discuss the role of Immunoglobulins in Septic Shock

-??

Differences between PT/PTT?

-PTINR = Measure of time for Extrinsic Pathway (activation of factor 7 to fibrin production) - PTT = time for Intrinsic Pathway (activation of factor 12 to fibrin) TEST: *1. The pathway within the clotting cascade which rapidly instigates the clotting process and is often measured by a PT value is:* *extrinsic pathway*

Describe atherosclerosis

1. *Damage to Tunica Intima* (endothelium) via smoking, DM, HTN etc; leads to release of Von Willebrand Factor 2. Coagulation leads to *Inflammation* with macrophage consolidation. - LDL in blood stream sneaks below basement membrane of damaged tunica intima and contributes to additional inflammation - Macrophages phagocytose LDL making Foam Cells 3. *Fibrin deposits* in damaged area to wall off injury (fibrin plaque with inflammation underneath). fibrin growth continues over time. A. Stable fibrin plaque: vessel narrows (ischemia with activity in extremity: claudication; chest pain with activity: stable angina; brain ischemia: TIA) ; will grow collateral vessels over time B. Unstable/vulnerable plaque: With much inflammation underneath, plaque opens and fibrin cap breaks off. Major inflammatory mediators are released; activates blood coagulation proteins; clot formation and release results TEST: 1. During the process of Atherosclerotic plaque development, macrophages phagocytose the LDL which maneuvered below the basement membrane, resulting in the formation of: Answer: Foam cells 2. The inflammation and atherosclerosis associated with DM diminishes the effect of the ERK-5 enzyme resulting in: Answer: diminished vasodilation

6 manifestations of ARDS and shock

1. Acute injury to A/C membrane 2. Massive pulmonary inflammation; neutrophil activation 3. Increased capillary permeability 4. Severe pulmonary edema 5. V/Q mismatch - alveolar damage = decreased V = decreased V/Q 6. Hypoxemia

Describe the processes of Impaired oxygen use in shock

1. Cell not receiving enough O2 2. Cell not able to use O2 3. Anaerobic metabolism- low pH and metabolic acidosis= shift in Hgb- O2 Dissociation Curve

List the 3 adverse manifestations of smoking on the lung parenchyma/tissue

1. Fibrosis 2. Alveolar wall destruction (emphysema) 3. Mucus hypersecretion *that is literally the test question*

Name the 4 most common Glut Transporters and the cell predominantly associated with each.

1. GLUT 1 - pancreatic beta cells (blood brain barrier) 2. GLUT 2 - pancreatic beta cells (liver) 3. GLUT 3 - pancreatic beta cells 4. GLUT 4 (muscle and fat; insulin dependent) TEST: 1. 1. Which GLUT transporter has an active role in the diffusion of glucose across the plasma membrane of the Pancreatic B cells? Answer: GLUT 3

Know the difference between genotype and phenotype; penetrance and expressivity

1. Genotype (what they have) - The composition of *genes at a given locus* 2. Phenotype (what they demonstrate) - Determined by genes and the environment. The outward *appearance, developmental processes or behavior* of an organism Penetrance - The percentage of individuals with a specific genotype who also express the expected phenotype --- (within a specific genotype, you see a specific phenotype) --- degree to which you can see the gene expressed = penetrance -- ex) Rb has incomplete penetrance Expressivity - Extent of variation in phenotype associated with a particular genotype-- (you have a gene but where any deficit occurs will alter expressivity) - ex) Hemophilia A TEST: 1. A phenotype has the following relationship to genotype: Answer: Phenotype is predominantly determined by genotype, as well as the enivornment 2. Within genetics, the same genotype will always result in the same phenotype: False 3. What is the scientific term used to describe the percentage of individuals who carry a specific genotype for a condition and also express the anticipated phenotype of the condition? Penetrance

Understand that impaired glucose use leads to what in shock?

1. Glycogenolysis 2. Lipolysis 3. Gluconeogenesis 4. Protein breakdown/loss -- 1. Protein breakdown leads to lactic acid production -- 2. Protein breakdown leads to ammonia and urea circulation -- 3. Protein loss contributes to decrease osmotic pressure; decreases circulatory volume (feedback loop) -- 4. Protein loss results in muscle wasting -heart and lungs

List common causes of Hyperkalemia and hypokalemia

1. Hyperkalemia (cell injury, rhabdomyolysis, kidney disease, and medications): deadly condition due to cardiac implications 2. Hypokalemia (Vomiting/Diarrhea, Steroids, Diuretics & low Magnesium—Magnesium facilitates K+ ion transfer in/out of cells). Caution with "Iso-Kalemia" because can "look" normal but have intracellular potassium depletion. TEST: *1. Which of the following conditions would alert the advanced practice nurse to monitor for hyperkalemia?* *Answer: renal dysfunction* *2. All of the following are likely causes of hypokalemia, EXCEPT:* *Answer: Decreasing glomerular filtration*

List common causes of Hypernatremia and hyponatremia

1. Hypernatremia (restricted water access, DKA, Diabetes insipidus & excess IVF; most common in elderly with mental/physical impairments) 2. Hyponatremia (CHF, diuretic induced TEST: 1. You receive a consult for hyponatremia in a patient who is post-op day 3 after a left total hip arthroplasty.The patient's nurse reports the patient is eating and drinking well and has not had any vomiting or diarrhea. They are not receiving maintenance intravenous fluids. She notes they have had a 3 KG weight gain since admission.The patient reports some new edema without any shortness of breath, cough, or orthopnea.Exam shows normal heart rate and normal blood pressure, less than 1+ lower extremity edema, clear lungs, no jugular venous distention, and moist mucus membranes.Labs are as follows:NA 129, lowK 3.6, normalCL 90, lowHCO3 25, normalBUN 8, normalCr 0.8, normalWhat is the most likely diagnosis? Answer:Syndrome of inappropriate antidiuretic hormone secretion (SIADH) causing water retention

Explain 3 states of Dehydration

1. Hypertonic: Lose more water than Na+ (too much sodium). 2. Isotonic: Balance of Na+ and water loss—Most Common, 3. Hypotonic: lose more Na+ than water (too little sodium). - Measure of hydration status is Body Weight. - Diarrhea is the most common cause of excess fluid loss in infants and children.

Discuss the complications of prolonged seizures

1. Hypoxic brain injury - Neurons receive inadequate oxygen for prolonged period - Prevention: airway management/oxygenation 2. Rhabdomyolysis - Release of creatine kinase into circulation due to prolonged muscle activity can cause renal failure - Prevention strategy: adequate hydration

Know the 5 components of pulmonary compromise in shock

1. Lower alveolar surface area 2. Greater energy expenditure to maintain respiratory drive 3. More compliant chest wall 4. Lower functional residual capacity 5. Increased SVR due to vasoconstriction limits oxygen delivery

Describe the Oxygen-Hemoglobin Dissociation curve

1. O2 bound to Hgb in relation to what is dissolved in plasma and available to tissues at various O2 pressures. Curve demonstrates how easily O2 binds to Hgb or is released into the plasma. As oxygen concentration increases (such as at the lungs), oxygen moves from plasma to Hgb. As oxygen concentration decreases (such as other body tissues), oxygen moves off Hgb into plasma. Cooperativity accounts for the steep slope of the Curve when O2 is moving readily from location to location. Curve works to reduce hypoxia/hypoxemia. "The Curve is NOT a pickle jar" Curve shifts to Right, loosens affinity for O2, when tissues need greater O2: increased CO2, fever, acidosis, exercise, increased 2, 3 DPG—(pregnancy-moves O2 to fetus, altitude, chronic hypoxemia: CHF, COPD, anemia-address tissue deliver impairment) 2,3 BPG made within RBCS and assists with regulation of O2 movement. Curve shifts to Left, tightens affinity for O2, when tissue needs are less; decreased CO2, hypothermia, alkalosis, decreased 2, 3 BPG. Fetal Hgb is the "most left" curve—fetuses hold tightly onto O2. TEST: 1. In a patient with septic fevers, the nurse would expect the oxyhemoglobin dissociation curve to shift: Answer: to the right, releasing O2 to the cells 2. The oxygen-hemoglobin dissociation curve represents the relationship between hemoglobin bound oxygen and dissolved oxygen which is released to tissues through pressure gradients Answer: true 3. The most 'left' Oxygen-Hemoglobin Dissociation curve represents Fetal Hgb, and signifies Answer: Tightly held O2 by fetal blood 4. Which of the following statements about the Oxygen-Hemoglobin Dissociation curve is TRUE? Answer: the curve shifts to the left with decreased 2,3BPG

Discuss the nuances of the 4 types of shock

1. Obstructive: Blockage leading to decreased CO 2. Cardiogenic: Pump failure leading to decreased CO 3. Hypovolemia: Mass loss of intravascular volume leads to decreased CO 4. Distributive: Massive vasodilation leads to decreased CO a. Anaphylactic—IgE, Mast Cell, Histamine b. Neurogenic-Impaired sympathetic innvervation c. Septic -peds different from adults

Discuss the difference between Stable and Unstable Spinal Cord injury

1. Stable injury to spinal column - Integrity of spinal canal maintained, even with patient movement - No risk to spinal cord 2. Unstable injury to spinal column - Integrity of spinal canal is compromised - Spinal cord at risk

3 Manifestations of Shock

1. hypotension 2. tachycardia 3. increased respiratory rate

Understand the process of gastric acid secretion

1. with stimulation from stomach distention or presence of food, G-cells release gastrin and vagus nerve releases acetylcholine, leading to histamine secretion. Histamine binds to receptors and acts on parietal cells to release HCL. Gastrin also independently initiates HCL release from parietal cells, absent histamine. TEST: 1. The duodenal ulcer results from the increase in stomach acid secretion and increased gastric emptying time. Answer: true

Understand ASD, VSD, AV canal

ASD - Failure of completion of atrial septal development - Since RA pressure is lower than LA pressure, creates L to R shunt and recirculation of oxygenated blood to the lungs (acyanotic! = lungs see more blood than they should = pulmonary vascular remodeling over a long time) VSD - Failure of closure of ventricular septum- L to R shunting at ventricular level (acyanotic also!)- End-diastole pressure gradient doesn't change much BUT during systole, pressure in RV stays low but LV squeezes to higher pressures = high pressure gradient between LV and RV = systole squeezes blood even more to pulmonary circuit (but RV doesn't change much) = systemic pressure extended to pulmonary artery AV Canal - Failure of development of endocardial cushions (which become valves)- "a hole in the middle of the heart"- ASD, VSD, common AV valve- Left to right shunt at atrial & ventricular level- If infant has failure of endocardial cushions form = where blood goes is still dependent on pressure but could be LV to RV, LA to RA, could go anywhere really TEST: Which of the following statements is commonly related to atrial septal defect (ASD) and ventricular septal defect (VSD)? Answer: left to right shunting

Discuss Complications of ATN in shock

Acute Tubular Necrosis (ATN) Mechanisms of action: 1. Intrarenal microcirculatory vasoconstriction occurs 2. Tubular obstruction by casts (slough from basement membrane) 3. Interstitial inflammation 4. Tubular injury/leakage - Hypotension and hypovolemia common but can occur without hypoperfusion - Decreased GFR

Describe Asthma

Airflow obstruction (reversible). Chronic inflammation of bronchial mucosa and hyperresponsive airways; increased reactivity to a variety of stimuli. Allergens are culprits, IgE and mast cells TEST: 1. Airway hyperresponsiveness in asthma (a condition of genetic and environmental factors) is related to: Answer: *exposure to allergen causing mast cell degranulation* 2. Steps in the immunologic process of asthma include each of the following EXCEPT: Answer: *T helper cell deactivation* 3. Manifestations of asthma with the pulmonary system include each of the following EXCEPT: Answer: small airway bronchodilation 4. The grad patho student who has been studying asthma and its relationship to the microbiome understands that which of the following are TRUE: Answer: bacterial diversity enhances asthma control

DIC and Shock

Disseminated Intravascular Coagulation (DIC) - Infection (gram negative usually) and Tissue Damage leads to coagulation = Tissue Factor III; leads to bleeding, therefore platelet use/consumption and more bleeding

Compare the difference between ductal dependent pulmonary blood flow and ductal dependent systemic blood flow

Ductal dependent pulmonary blood flow - cant get out right side of heart --Ductus Arteriosus can be life saving in CHD -- If there is obstruction to pulmonary blood flow - can allow left to right shunting -- If obstruction to left sided blood flow - can allow shunting right to left - Pulmonary atresia Ductal dependent systemic blood flow - If obstruction to left side (can't get from LV to body), you may need to maintain ductus flow! - Aortic atresia = blood cannot pump out LV and thus LV does not form completely - Blood returns to RA as normal, blood to RV, out to pulmonary valve and lungs....blood in lungs returns to LA , but since cannot get out of LV, goes to RV, out pulmonary trunk and thus out of the ductus to the body = ductal dependent systemic blood flow (if didn't go out ductus, couldn't get to body) - That blood is not completely oxygenated and is thus purple b/c mixed arterial and venous TEST: 1. The ductus arteriosus is important in congenital heart disease because: Answer: In children with right sided obstruction (e.g. Pulmonary atresia) blood can flow from the aorta to the pulmonary artery. AND in children with severe left sided obstruction (e.g. Aortic atresia), blood flows from the pulmonary artery to the aorta and prevents shock.

List the Innate defenses included in the battle against pneumonia:

IgA, dendritic cells, alveolar macrophages (Tumor necrosis factor and IL-1) , neutrophils ( Slide 83) Neutrophils: 3 actions: phagocytose, degranulate, NET. Destruction within phagosome is reliant on granules/proteases (neutrophil elastase, proteinase 3, cathepsin G) and reactive oxygen species, which degrade extracellular matrix of pathogen. External release of granules leads to extracellular damage. Diminished neutrophil apoptosis or prolonged neutrophil presence leads to chronic inflammation. Impairment of neutrophils enhances susceptibility to infection. TEST: 1. *Which of the following statements regarding innate defenses against pneumonia is CORRECT?* Answer: All of the above A. Dendritic cells are a type of innate pulmonary defenses. B. Macrophages release TNF and IL-1. C. DNAase can cleave a neutrophil extracellular trap (NET). *2. In pneumonia, the 3 primary roles of neutrophils include which of the following:* *Answer: phagocytosis, NET, degranulation* *3. Which of following conditions contributes to chronic inflammation in pneumonia?* *Answer: prolonged neutrophil presence*

Describe the difference between Innate vs Adaptive immunity: characteristics and cells

Innate: - *Fast (minutes to hours), non-specific, no memory* - Basic resistance mechanisms that are present in healthy individuals at birth and remain unchanged during their lifetime - Capable of broad recognition of pathogens (but not all pathogens) by conserved structures - Always responds to pathogens in the same manner, even after re-exposure - Includes: -- Neutrophils -- Macrophages -- Dendritic Cells -- Mast Cells -- Natural Killer (NK) cells -- Also, eosinophils, basophils, PMNs - Mac = macrophage = PRR (pattern recognition receptor) which says "something about cell wall doesn't belong here" ---- TLR (toll-like receptors) specific PRR on macrophages and dendrites- Pathogen grabbed by TLR, ingested into cell via phagocytosis forming a phagosome, lysozyme (full of digesting enzymes) surrounds pathogen forming a phago-lysosome, pathogen broke up into peptide strands (proteins), macrophage uses MHC2 arm (major histocompatibility complex 2) to reach out an arm holding the pathogen's (extracellular) remnants to alert the rest of the immune function to defend against thisMHC = HLA ! Adaptive: - *Slower (days to weeks), specific, memory* - Responds to pathogens with high specificity (antigen recognition) - Can establish memory - Improves response with second exposure (i.e. vaccine) - Includes -- T cells: Cell mediated response (helper, cytotoxic, regulatory) -- B cells: Humoral response -- (also Natural Killer T (NKT) cells) TEST: 1. A young man received a knife wound. Which of the following types of immunity was immediately enacted? Answer: innate immunity *2. Which innate immune cell is unique in its approach to pathogen removal because it does not require MHC I expression and does not phagocytose?* *Answer: NK cells* *3. The most abundant and mobile innate immune cell is:* *Answer: neutrophil* 4. Which of the following describes the adaptive immune system? Answer: able to establish memory

Describe the role of Natriuretic Peptides as contributors blood volume control , the role in suppressing RAAS and role of BNP levels in evaluation of HF progression

Natriuretic Peptides - Secreted by stretched atria when increased Na levels lead to increased water retention and increased blood volume - reduces RAAS function by decreasing aldosterone secretion from adrenal cortex TEST: *1. Deficiencies in natriuretic peptide (ANP, BNP, CNP) release lead to increased preload and afterload, due to:* *Answer: impaired Na+ excretion and impaired vasodilation* *2. Atrial natriuretic peptide (ANP)* *Answer: increases excretion of water and sodium by the kidney* *3. Atrial and B-type natriuretic peptides (ANP, BNP) play a role in BP management. Which of the following statements about these important hormones are true?* *Answer: ANP and BNP contribute to sodium and H2O excretion*

Describe value of CAM (cell adhesion molecules)

P-selectin and PSGL-1; recruit tissue factor to site of injury—help to trigger clotting cascade - P-selectin is a Cell Adhesion Molecule (CAM) which lines endothelial cells; expressed by activated endothelium and inflammatory processes; recruits WBC to injury site and promotes platelet/fibrin and platelet/platelet binding; PSGL-1 is also CAM - Alpha granule from platelet releases CAM's such as PSGL-1 and P-Selectin , helps start clotting cascade by bringing Tissue Factor to location of damage - Tissue Factor has role in initiate of clotting cascade - P-selectin and PSGL-1 have a role in clotting AND inflammation- Explains why certain inflammatory diseases result in more blood clots TEST: 1. The cell adhesion molecules (CAM), P-selectin and PSGL-1,have a pivotal role in facilitating the accumulation of what protein factor at the site of endothelial cell injury? Answer: Tissue Factor III *2. The Protein Factor which is released during injury or trauma from the subendothelial cells and arrives with white blood cells to initiate the clotting cascade is:* *Answer: tissue factor*

Describe Mutations: Point (Missense & Nonsense) vs. Frame Shift

Point Mutations: - Missense--- ex.) C is now a G via a mutation (a single point) can result in a different amino acid and either a different protein or even some sort of useless molecule- Nonsense--- molecule can be formed if the stop codon is read prematurely!--- Results in a non-functioning protein (aka Nonsense) Frame Shift - basically 1 is missing (not different) and it just shifts everything down and thus can create entire new cell TEST: Frameshift mutations that include the deletion of two base pairs will result in the production of an unintended codon and may lead to the development of an unintended amino acid. = TRUE

Discuss the role of the RBC as it carries O2; including Hgb, iron and cooperativity

RBC is produced based upon needs for O2. The kidney notes decreased O2 content with erythropoietin. If O2 low, hemocytoblast in bone marrow is activated and through a series of cellular processes, reticulocytes are produced. Reticulocytes mature into RBCs. RBC carries Hgb. Hgb carries O2 molecules; when fully saturated. As each O2 binds onto the Hgb. Hgb changes shape as the first O2 binds and makes each additional O2 easier to connect=Cooperativity. The same holds true for diffusion of O2 from the Hgb to the plasma; the first oxygen leaves with complexity and it is easier for each subsequent O2 to depart=cooperativity TEST: 1. Diffusion across the alveolar-capillary membrane is dependent on: CHECK ALL THAT APPLY Answer: All of the above (surface area, Hgb concentration, gas pressure, rate of blood flow, health of A-C membrane) 2. What is the process by which reconfiguration of the Hgb with the first O2 binding leads to increased ease of subsequent O2 binding? Answer: positive cooperativity *3. The most 'left' Oxygen-Hemoglobin Dissociation curve represents Fetal Hgb, and signifies* *Answer: Tightly held O2 by fetal blood* *4. Which of the following statements about the Oxygen-Hemoglobin Dissociation curve is TRUE?* *Answer: The curve shifts left with decreased 2,3 BPG*

Understand strategies to analyze hepatitis serologies

SLIDE 71- Infection with surface antigen, antibodies go to surface antigen, since it's acute and new, these are IgM- If we eradicate the virus (gray), no antigen (HBsAG-), ALT is normal, antigens negative and IgM not activate either, however, we do have adapted immunity so we still have antibodies to the surface and core....these are IgG (memory) antibody HBs and HBc- Yellow - did not eradicate, chronic active (orange) - still have hep antigen floating around and elevated ALT because of active hepatocyte damage, no IgM antigen and antibody because this is NOT ACUTE anymore, but we do have antibody HBc (core) present but it's weak- Green - carrier state but not eradicated - surface antigen present because we do have it but ALT is normal b/c liver is fine since it isn't active (just carried), no IgM because not new (no active replication), however, similar to chronic state, we have core IgG present but is weak- Hepatitis has surface antigens, virus has a core and thick envelope around it. -- HbsAg (hep B surface antigen) - negative if never encountered virus, positive if the antigen is present aka virus is present-- HbsAb (Hep B surface antibody) - negative is no immunity developed, positive means we have created some immunity-- HbcAb (Hep B core antibody) - positive if immune system has been exposed to proteins in the DNA that make the core, means the envelope has been dissolved = hepatocyte infected ! (unknown whether current or past infection b/c antibody encompasses IgM and IgG (IgM is made first = current, IgG = past infection and possibly chronic infection)-- HbeAg (hep b e antigen) = virus is replicating - tells us how much virus they have/how sickHc..... Same stuff but hep C TEST: A 36 year old male returns to the clinic after having been diagnosed with acute hepatitis B six months ago. His hepatitis serology is repeated and reveals that his HBs-Ag and Hbc-Ab are positive. *ANSWER: A.He is immune to Hepatitis B* *B. He remains infectious to others*

Discuss the differences between a membrane potential, graded potential and an action potential

Sodium-Potassium Pump in Relation to the Action Potential Na is predominantly extracellular Na+ 135-145 K is predominantly intracellular K+ 3.5-4.5 The Na/K pump actively (using ATP) contributes to the resting state by pumping Na out of the cell and brining K into the cell. For every 3 sodium that leaves, two potassium enter. There are more positive ions outside of the cell than inside. The inside of the cell is "more" negative. The voltage or electric potential inside of the cell compared to the outside is approximately -70mV. With a nerve cell (neuron), when a dendrite and soma receive a stimulus that transmits with enough strength to the axon hillock, the Na channels (which are abundant at the hillock) open and the positive Na molecules move into the cell. [ The sodium and potassium channels are typically closed at the resting potential] .If the stimulus is large/significant enough to open a plentitude of Na channels, the interior electric potential of the cell could rise from -70mV to -55mV (a more positive state). If the 'threshold' of -55mV is reached the action potential is "launched" with the opening of additional Na channels and rapidly raising the electric potential. This occurs in milliseconds. Shortly after the full action potential is reached and all available Na channels are open, the K channels then open, and the sodium channels begin to close. This leads to the free diffusion of positive K out of the cell and the return of the internal cellular electric potential to a more negative state. This process occurs down the length of the Axon within each of the Nodes of Ranvier. Graded potential Occurs in dendrite/soma, may trigger action potential at axon hillock if temporal or spatial summation is adequate, only needs resting potential change of approx. 10mV to trigger action potential

Compare and contrast the sympathetic and parasympathetic systems

Sympathetic - (thoracolumbar) - Nerve cell bodies located in thoracic/lumbar regions of spinal cord (T2-T6) - Adrenergic: release of epi and norepi - Increased HR and BP, peripheral vasoconstriction - Pupils dilate, decreased GI activity, diaphoresis Parasympathetic - Nerve cell bodies located in cranium/sacrum (craniosacral - head to bum) - Cholinergic: release of acetylcholine - Decreased HR - Increased GI activity

Describe the pathophysiology of pancreatitis

TEST: 1. Pancreatitis is caused by *Answer: obstruction of pancreatic ducts and activation of pancreatic enzymes* 2. Which of the following lab values is specific to the diagnosis of pancreatitis? Answer: *lipase*

State the elements involved in the apoptosis pathways

TP 53, Fas/CD95 receptor, Caspase 9, Caspase 8 and Caspase 3 Intrinsic vs Extrinsic Apoptotic Pathways - INTRINSIC = mitochondria release Capase 9 capase 3 which "karate chops" the DNA to cause cell death which only occurs if P53 is inactivate (phosphorylated) - EXTRINSIC - Capase 8 connects with FAS/CD95 can also directly activate Capase 3 to stop DNA and cause cell death ---these are both normal pathways! - But in cancer - P53 is inhibited so this process is inhibited, ultimately allowing cell proliferation (we don't have enough apoptosis) - over-expression of anti-apoptotic molecules (BCL-2 (B-Cell Lymphoma)) leads to lack of cancer cell apoptosis TEST: 1. The p53 gene: A. refers to a tumor suppressor gene B. creates susceptibility to cancers if mutated C. normally participates in DNA repair, or in initiating apoptosis in mutated cells that cannot be repaired Answer: *E. a, b and c* 2. In the final phase of the apoptosis pathway, which of the following molecules cleaves DNA? Answer: Capase 3

Discuss V/Q mismatch—be able to determine high vs low conditions; role of Pores of Kohn

be able to determine high vs low conditions •*Ventilation with poor perfusion: High V/Q; high O2* Ex. Zone 1; area of respiratory reserve that can be enhanced with increased blood flow •*Perfusion with poor ventilation: Low V/Q; low O2* Ex. Airway with partial obstruction; typically responsive to O2 treatment -*Pneumonia = blocked ventilation = decreased V/Q!* -*Bronchitis = inflamed airways = decreased V/Q!* -*Pulmonary HTN = blocked capillaries = increased V/Q!* - Pores of Kohn - openings between alveoli to allow for interchange of gasses TEST: 1. The grad patho student prepares a list of ventilation-perfusion facts for the study group. The list includes the following: CHECK ALL THAT APPLY Answer: *pneumonia and bronchitis are associated with low V/Q AND pulmonary emboli are associated with high V/Q*

Understand the process of primary hemostasis

goal=plug; Vasospasm, Vasoconstrict — endothelin and thromboxane A2, collagen exposure, von Willebrand aggregation vasoconstriction (primarily from endothelium releasing ET), platelet aggregation and adherence to activate platelet plug (thromboxane predominantly)--- aspirin reduced thromboxane A2 and reduces aggregation TEST: 1. Platelets are essential in what physiological process... ANSWER: hemostasis 2. Two molecules within the process of thrombogenesis that contribute to vasoconstriction and platelet aggregation at the site of injury are: ANSWER: Endothelin and Thromboxane A2 3. Platelet adhesion occurs as the direct result of: ANSWER: Von Willebrand, collagen, 1b platelet receptor complex creation