RUSM

Sequestration Crisis in Sickle Cell Anemia

"Acute Sequestration Crisis" - Sickled cells become trapped in the spleen --> obstructing blood flow with pooling and enlargement of the spleen * leads to shock and hypovolemia - circulatory collapse and death can occur in less than 30 minutes * leads to an enlarged spleen

Necrotizing lymphadenitis

"Catscratch disease" - mixed B and T cell hyperplasia - self-limited lymphadenitis seen in children - stellate, necrotizing granuloma in regional lymph nodes (ex. axillary, cervical) - due to bacterial infection (Bartonella Henselae)

Sympathetic system deals with

"Fight or flight or freeze"

Primary Hyperparathyroidism

"bones, stones, groans (brain fog) " Abnormall high calcium levels, leads to: - stealing calcium from bones, leading to weakening - excreting excess calcium can lead to kidney stones - calcium imbalance can cause changes in muscle, nervous functions, and several conditions in the digestive system including pain

Calcitonin is thought of as the

"emergency brake"- a hormone that prevents pathology rather than ensure normality Calcitonin works to - Decrease clacium ---- Calcitonin is - secreted from parafollicular C cells of the thyroid- stimualted by gastrin or elevated plasma calcium - inhibits osteoclast mediated bone resorption (decreasing serum calcium) * NOT essential for human survival - poential treatment for hypercalcemia (path) - stimulates cAMP production in bone and kidney

Mesenchymal stem cell gives rise to

"fixed" cells of connective tissue - fibroblasts - adipocyte - chondrocytes - osteocytes - chondroblasts - osteoblasts

Vitamin D itself can be considred a

"prodrug" - WONT be effective in regulation of Ca homeostasis during established renal failure

Sickle cell disease vs Sickle cell anemia

"sickle cell anemia"= disease found in homozygote "sickle cell disease": two usages: 1. Disease found in homozygote 2. Descriptor for everyone who has any sickled cells = homozygotes + heterozygotes ** heterozygotes most frequently described with "sickle cell trait" ** the two usages of sickle cell disease are in current use in different laboratores

Pluripotent

(blastocyst inner cell mass) can become all cell types of embryo, but CANNOT become extra-embryonic cells/tissues

What is the purpose of a differential WBC count

(this is the % of total counted WBC type- out of 100 of counted blood cells % that are neutrophils, eosinophils, etc.) the differential counts the percentage of each type and will determine if: - if the cells are present in normal proportion to one another - if one cell type is increased or decreased - if immature cells are present

Hassals or Thymic Corpuscles (corpuscle= a rounded globular mass of cells)

* Formed by the epithelial reticular cells - they are found ONLY in the thymic medulla ** diagnostic for the medulla** - the central area consists of degenerating or necrotic cells Function: secrete factors that aid in thymocyte development

What are the types of Hb that are present

* HbF= alpha2-gamma2 * HbA = alpha2-beta2 (normal adult Hb) * HbA2= alpha2-delta2 (minor adult Hb) - HbGower(1)= zeta2-epsilon2 - HbGower (2)= alpha2-epsilon2 - HbPortland= zeta2-gamma2

Which hormones are involved in Calcium and Phosphate balance (6)

* Parathyroid Hormone (PTH) - Parathyroid Hormone-Related peptide (PTHrP): only in pathology as marker for some cancers * Calcitrol (aka 1,25- (OH)2 cholecalciferol, or 1,25-(OH)2D3) - NONE are VitD but are called this by patients - Calcitonin: corrects significantly high Ca2+ levels * Fibroblast Growth Factor 23 (FGF-23) ***= the main 3

A patient comes to your office with extremely low blood pressure while dealing with Pneumonia.. What are you concerned of?

* When sepsis is accompanied by low blood pressure, it is called SEPTIC SHOCK and carries the highest risk of death and complications *** sepsis is a serious condition that occurs as a complication of a severe local infection when it spreads throughout the body - it develops when the chemicals of immune system released into the bloodstream to fight and infection cause inflammation throughout the ENTIRE BODY instead of just locally * cytokines released in a large scale inflammatory response result in - massive vasodilation - increased capillary permeability - decreased systemic vascular resistance ***** low blood pressure, reduces tissue perfusion pressure, causing the tissue hypoxia that is characteristic of shock

Modulation pathways for insulin secretion

* With the right modulation, a given increase in BG could result in as much as 3x more insulin being secreted than with no modulation at all * the main pathway MUST have occured for any modulation to occur What gets modulated? 1. The amount of additional calcium in the cytoplasm whose source are intracellular calcium depots (ex. endoplasmis reticulum) - 2 most common stimulators are parasympathetic neurotransmitters (ACh) acting through muscarinic receptors, and free fatty acids (FFAs) acting through GPR40 receptor --> both act through Gq --> PLC --> IP3 increases intracellular calcium --> more motor protein binding and more exocytosis 2. The responsiveness and/or activity of the motor proteins involved in actual exocytosis: adenyly cyclase second messenger pathway is uses - Stimulated by incretins binding to GLP-1 receptors --> Gs --> adenylyl cyclase --> cAMP --> PKA potentiates motor protein action - Inhibited by sympathetics via Gi acting on alpha-2 adrenergic receptors **** both of these work together to increase insulin secretion- via increased intracellular calcium and increased responsiveness/activity to that calicum (3x main path insulin secretion rate)**** ----- It is possible to provide parenteral nutrition (via IV) but oral food intake is always preferred because the incretins associated with oral nutrition yield a better insulin secretion and better blood glucose control

Characteristics of Innate Immune response

* born with it It is Group specific: - multiple, relatively specific antigen receptors per cell - recognize antigen based on common structural motifs - recognize antigen marked by complement Always present/immediate response Short-lived- NO MEMORY

Calcitrol (aka 1,25 (OH)2cholecalciferol- 1,25(OH)2D3)

* the two forms of VitD are precursors to calcitriol, the active steriod hormone in calcium and phosphate balance Calcitrol functions as a steroid hormone - req. transport proteins and intracellular hormone receptors - alters gene transcription for a number of proteins in target tissues - effects are slow to start but also slow to stop, has a long half life *** its 3 OH's come from 1. part of precursor steroid 2. Liver 3. Kidney ---- VitD comes from 3 sources: solar radition of Pre-VitD3 into Vit D3, or ingested Vitmains D2 or D3

alpha1-globulin (these are negative APRs)

* this is seen in an electrophereis - they are mostly transport proteins and protease inhibitors (limit inflammation and vascular damage) Main one= alpha1-antitrypsin: is synthesized by hepatocytes and inhibits trypsin and elastase ** especially in the lungs (neutrophils) and other proteases (so its main function is antiprotease activity in the lung: pulmonary emphysema- it inhibits elastase (a protective protein) in the lung.) ** alpha1- antitrypsin is measured by the trypsin inhibitory capacity

Monocytopoiesis

** Note that monocytes and neutrophils shar the same progenitor (CFU-GM) Monoblast --> Promonocyte --> Monocyte --> Macrophages Promonocyte: cytoplasm is bluish and houses numerous azurophilic (non-specific) granules (lysosome) Monocyte: Every day, the avg adult forms more than 10 billion monocytes, most of which then enter the circulation- within a day or two, the newly formed monocytes enter the CT spaces of the body and transform into macrophages

Action of Glucagon on Fats (lipids)

** less effect in adipose tissue than in the liver- only a few glucagon receptors in adipose tissue, so it only exerts a minor effect there 1. Stimulates lipolysis (as does epinephrine) 2. Inhibits TAG synthesis, especially in liver 3. Promotes conversion of the TAG glycerol component into glucose, in the liver 4. Promotes conversion of free FAs into ketoacids as an alternate fuel source for muscle, particularly when glucose is more chronically low, in liver also *** epinephrine is a MUCH more important hormone in adipose tissue than is glucagon - EPIs effects in adipose and in muscle, where there are NO glucagon receptors, dominate the energy-mobilizing aspects of these two tissues, to help provide the resources that glucagon-stimulated hepatocytes can use to convert to glucose or create ketone bodies for cellular metabolism ** since one of the singals for Epi secretion is low blood glucose, glucagon and epi act together

Cinacalet

*Parathyroid Related* - Ca-sensing receptor (CaSR) activator - allosteric modulation of the Ca receptor enhances response to calcium - reduces PTH release USES: 1. secondary hyperparathyroidism in renal disease 2. primary hyperparathyroidism 3. sometimes parathyroid carcinoma ** in all these situations this drug "sensitizes" the CaSR to serum calcium, changing the set point between level of calcium and the rate of secretion of PTH such that PTH secretion is suppressed by lower amounts of calcium than normal Adverse effects: - primary problem to watch for is hypocalcemia - concerns about cardiac and renal effects and other potential problems in systems that are sensitive to calcium, but not yet well described

Describe the Stroma "LAND" of the Red Bone Marrow

- 3- dimensional meshwork of reticular cells (Type III collagen) AKA adventitial cells, but are basically fibroblasts & a delicate web of reticular fibers containing hematopoietic cells, macrophages, and a few adipocytes Reticular cells: - secrete reticular fibers composed of Type III collagen - send cytoplasmic projections outward (away from basal lamina of endothelial cells)- these touch projections of other reticular cells; forms a 3-D network surrounding discrete hemapoietic cords (islands) ** remember that reticular fibers are agyrophilic (silver loving) ** remember that this reticular cell and fiber network is THE supporting mesh in soft tissues such as the: liver, bone marrow, and the tissues and organs of the lymphatic system (such as spleen, and lymph nodes) The stroma also contains fibers and ground substance like other CT: - collagen types I and III - fibronectin - laminin - proteoglycans Laminin and fibronectin and others interact with cell receptors (integrins) to bind developing cells to the reticular fibers in the stroma - when the developing cells are mature and ready to enter bloodstream, they inactivate their integrins and release from meshwork

Contents of a mature RBC

- 35% Hb - 60% water * has 2 alpha and 2 beta chains with an iron (Fe2+) and a heme attached to both (so in Hb there is extensive interactions between unlike subunits ) ** oxygenation to Hb causes a considerable structural conformational change

Type AB blood

- A and B antigens - No antibodies in serum ----------- Receives RBCs from Type AB, A, B, O and Plasma from AB

Type A blood

- A antigen on RBC - Anti-B in serum ----- Receives RBCS from Type A and Type O and Plasma from A and AB

Thyroid Gland

- A deep structure of the neck - Consists of left and right lobes connected by the isthmus, which normally lies at the level of the 2nd-4th tracheal rings - A pyramidal lobe may also be present in some individuals; being a remnant of the thyroglossal duct and found extending superiorly from the isthmus --- Thyroid gland is supplied by the R and L superior and inferior thyroid arteries and sometimes the thyroid ima (from the brachiocephalic trunk but this is NOT present in all individuals Drains via the superior, inferior, and middle thyroid veins to the internal jugular vein and via inferior thyroid to brachiocephalic vein

Hemolytic Disease of the New Born (ABO) *****not same as Rh

- A mild version occurs with ABO incompatibility: O mother and A, B, or AB father - most often the anti-A and anti-B antibodies are IgM, that CANNOT cross the placenta - when they happen to be of the IgG type that CAN cross, then problems may occur - relatively common cause of mild neonatal jaundice, rarely more severe - can happen with the first child (Rh incompatibility almost always cause problems in later parties) *** in rare cases this can lead to hemolytic disease just as severe as the one caused by Rhesus

Hematopoetic Growth Facotrs

- ALL are secreted proteins that bind to receptors on their target cells - they control rates of hematopoeisis of stem cell (can have other functions as well) ex: Erytropoietin (EPO): synthethezied and secreted by cells in the KIDNEY in response to decreased blood oxygen concentration * acts on recepetors on surface of CFU-E

Para-cortical hyperplasia (where T cells are)

- Activated lymphoyctes in T-cell regions of the cortex (inter-follicular regions (paracortex) show activated T cells) - Found in viral infection ex. Infectious mononucleosis

Mechanism of action of ADH

- Acts at the distal tubules and collecting ducts of nephrons in the kidneys - it increases the formation of cAMP via Gs proteins, adenyly cyclase - increased cAMP in turn increases the aquaporin protein channels in the collecting duct of the nephron - reabsoprtion of water through aquaporin channels (aquaporins needed due to the low permeability of water in the membranes) decreases urine volume and increase blood volume (ADH brinds water into the ECF but not sodium or chloride) ** on the side facing the waste products (the lumen), the number of aquaporin water channels that are located in the membrane is dependent on how much ADH is present in the blood, to bind to receptors in those cells. The more ADH there is, the more water is reabsorbed and the more blood volume goes up and urine volume goes down ** this is controlled by V2 receptors on basolateral membranes of these epithelial cells

What are other reasons for iron overload, other than Hemochromatosis

- Alchoholism: alcohol increases iron absorption, frequent iron excess in liver of patients with alcoholic liver disease - Anemia: even if not caused by iron deficiency, it increases iron absorption - Blood transfusions: iron introduced by blood transfusions ends up as storage iron

Alpha thalaseemia alleles

- Alpha thalassemia carriers: malaria areas of africa and asia (especially south-east asia), rare in Mediterranean * Allele alpha-thalassemia 1: usually found in ppl of Asian descent only (both genes deleted) * Allele alpha-thalaseemia 2: Africa and Asia (still one gene left) - a normal chromosome would have two copies producing alpha-Hb, so in a person with two copies of the chromosome (expected) missone one copy lowers production by 25% ex. 1/3 of ppl from Thailand are carriers of one of these two alleles

Clinical Features of Beta-Thalassemia Major

- Anemia > 6-9 months - growth retardation - delayed sexual maturation - splenomegaly/hepatomegaly - skeletal changes: osteopenic, expanded marrow cavity, thin cortex - systemic iron overload (due to blood transfusions): cirrhosis, cardiomyopathy/arrhythmia- congestive heart failure (CHF), death (2nd- 3rd decade) IN LABORATORY you will see: - Low Hb (3-6gm%) - PBS: Microcytic Hypochromic & target cells - Reticulocyte count: increased - BM exam: iron stores increased and erythroid hyperplasia

Hemolytic Disease of the newborn

- Anti-Rh+ antibodies (IgG) will cross the placenta and attack RBC of next Rh+ baby (mainly late in pregnancy) (anti-Rh sometimes called Anti-D) - Anemia, immature RBC in circulation; in severe cases: edema in utero (hyrops fetalis or erythroblastosis fetalis) and fetal death affects 0.125% of births - After birth, continued breakdown of RBC, lead to hyperbilirubinemia, and jaundice - Untreated, bilirubin build-up in brain leads to cerebral damage (kernicterus) and sometimes/usually death (blood-bran barrier not fully developed) *** treat with exchange transfusions (use blood of type O, Rh-) Occurs when a Rh- mother have previously been immunized with Rh+ antigen (so it is in her 2nd or later pregnancy) 4 reasons this can occur: - at birth of a Rh+ baby - at abortion of Rh+ fetus - by transfusion - by aminocentesis/chorion villi sampling

What are some physiological inhibitors of Coagulation

- Antithrombin III (activated by heparin) ** blocks mainly clotting factors in the Intrinsic Pathway - Activated Thrombomodulin (activates Protein C which inturn inhibits Factors Va and VIIIa) ** NOTE thrombin promtoes coagulation but it is also an anti-coagulant because it has mechanisms to prevent over coagulation

Iron uptake in the dudenum is facilitated by

- Ascorbate - Amino acids - Citrate - Iron deficiency It is inhibited by: - Phytates - Tannins - Soil - Iron overload - Antacids Competed by: - Lead - Cobalt - Strontium - Manganese - Zinc

Effect of fuel flow in the body

- Associated with postabsorptive state - Results in increased glucose and ketoacid release (use of free fatty acids in ketoacid production) * both glucose and ketoacids are fuels, the latter is especially important in prolonged fast (starvation)

Type B blood

- B antigen on RBC - Anti-A in serum ----- Receives RBCs from Type B and Type O and Plasma from B and AB

Absorption of Vitamin B12 (aka Cobalamin) in the intestine and transport in the blood requires specific factors such as:

- B12 is initially bound to transcobalamin I (TC I)- secreted by salivary glands to protect it against stomach acid - B12 then binds tightly to intrinsic factor, a protein secreted by the parietal cells of the stomach * the B12/IF complex is absorbed in the ileum - which then goes to the blood - in the blood, B12 is transported in complex with transcobalamin II (TC II) another protein, to be carried to the liver through the portal circulation ** B12 lost to excretion in the bile is recovered through re-absorption in the intestine (therefore: re-absorption in the intestine preserves B12)

What makes up the B cell receptor complex

- BCR (antibody molecule) that is surface bound It complexes with: - Igalpha and IgBeta which mediate intracellular signaling - CD19: is the signaling chain of the complex (along with Igalpha and Igbeta) - CD20 - CD21 (AKA CR2- Complement Receptor 2) which recognizes C3d fragments deposited on pathogens- this recognition augments B cell activation - CD81: forms signaling complex with CD19, as well as with other surface molecules --- NOTE: - CD21 was an important binding site for the Epstein Barr virus - CR1 was found on RBCs and other cells- necessary for immune complex clearance from circulation

Describe Episodic Release of hormones

- Baseline stays low until some condition occurs that stimulates hormone release - Acute release of hormone often starts with exocytosis of stored material (ex. preformed insulin) - Further release (second stage) of newly synthesized hormone occurs indefinitely - release ends only when the condition for stimulus ends *** this can be seen in water-soluble hormones (like insulin) and in lipid-soluble hormones as well

What are some abormal RBC inclusion bodies that could be found in the cytoplasm

- Basophilic stippling: from Pb (lead) poisioning- acutally caused by Fe granules - Howell-Jolly bodies: seen in Asplenia (no spleen), Hyposplenia, and in sickle cell - Cabots ring bodies: which are MT spindle remnants seen in megaloblastic anemias - Heinzs bodies: due to denatured Hb

How do RBCs enter blood stream from the marrow

- Because erythrocytes (unlike leukocytes) do NOT have sufficient motility to cross the wall of the sinusoid, they are believed to enter the sinusoid by a pressure gradient that exists across its wall * in red bone marrow, veins leaving are smaller than arteries entering, creates pressure "suction" that "sucks" mature RBCs from stroma into capillary *** ON THE CONTRARY: - WBCS (Leukocytes), after the action of releasing substances, cross the wall of the sinusoid by their own activity (diapedesis in reverse)

What is the genetics behind Beta-Thalassemia

- Beta-Hb production from the thalassemia allele can be none (Beta^0) or reduced (Beta+, sometimes milder versions are stated as beta++) - Homozygous Beta0Beta0 or compound heterozygote Beta0Beta+ usually have Beta-Thalassemia Major (this is most significant clinically) - Homozygous Beta+Beta+ usually have Beta-Thalassemia Intermida - the different type of heterozygotes with one normal allele all have beta-thalassemia minor (carrier usually no symptoms) ** genotype-phenotype correlation is incomplete: notice the use of the word usually indicating variation among patients

Pegvisomant (GH antagonist)

- Binds to GH receptors, but DOES NOT activate JAK-STAT signaling or stimulate IGF-1 secretion - Approved for the treatment of acromegaly when Octreotide and other Somatostatin analogs are not able to fully control the disease*** - Do NOT use if unexplained elevation hepatic transaminases - Side effects similar to somatostatin analogs and lipohypertrophy - Concern for GH secreting adenomas- monitor pituitary MRI

Anemias could be classified based on

- Blood loss - Increased destruction (hemolytic anemia) - Intrisic (intracorpuscular) abnormalities: can be Hereditary like membrane abnormalitites, enzyme deficiencies, and disorders of Hb synthesis or Acquired like membrane defects - Impaired RBC production - Extrinsic (extracorpuscular) abnormalities: which can be antibody-mediated, from mechanical trauma to red cells, or from infections like malaria

Which drug acts on Prolactin

- Bromocriptine (D2 dopamin agonist)

Aspartate Transaminase (AST) can be found in high concentrations in the cells of

- CARDIAC and skeletal muscle - LIVER - kidney - erythrocytes High levels may indicate: - Artefactual (hemolysis) - Physiological in neonatal VERY high levels seen in: - viral hepatitis - myocardial infarction - circulatory failure *** the two main condition with HIGH [AST]= Viral hepatitis and MI

what are the 3 isoenzymes of creatine kinase

- CK-MM (increased in damaged skeletal muscle) - CK-MB (cardiac muscle- increased in MI ) - CK-BB (increased in brain tumor) *** Creatine phosphate is an energy store in skeletal muscle that provides a phsophate to make ATP and creatine with aid of creatine kinase (CK)

Water-soluble hormones with half-lives measured in minutes not hours

- Calcitonin - Fibroblast growth factor-23 - Parathyroid hormone - Paraythroid hormone-related peptide

Delayed Hemolytic Reaction

- Caused by mismatch in blood types: NO preformed antibodies against RBC - Mechanism: slow destruction of blood cells as the antibodies are formed and light inflammation - slight fever, malaise, weakness, light anemia, sometimes hyperbilirubinemia - timeframe is one to two weeks (dont get symptoms right away) - normally not severe - this reaction is seen with other blood groups - CANNOT be caused by ABO mismatch

Second generation H1 blockers include

- Cetirizine - Fexofenadine - Loratadine

Integrated response to an acute stressor include

- Changes in cortisol, catecholamines, and insulin/glucagon - enhanced cortisol= extra nutrient availability with which to deal with the acute stressor - increased catecholamines help with overall sympathetic nervous system activation- which includes nutrient mobilization - insulin/glucagon ration drops (means increased glucagon present to further ensure that adequate glucose is available in the blood to deal with any acute threat)

Describe Pulsatile Release of Hormones

- Characterized by relatively stable time periods between releases (producing "peaks" of high concentrations of hormone) - Baselines are typical of time periods of very little secretion (allows target receptors and cells time to "reset", to better respond to the presence of the next "peak" - both the timing between peaks and quantity of hormone secreted can be modulated (Ex. 1 GnRH peak/hr promoted LH secretion but 1 GnRH peak/3 hrs promotes more FSH secretion instead

Febrile Nonhemolytic Transfusion Reaction

- Chills and rigors with fever of greater than 1 degree celsius - fewer is caused by destruction of the transfusion leucocytes, which causes release of cytokines - generally mild; this is the most frequent problem associated with transfusions* - timeline: during or up to 2 hrs after transfusion - often caused by preformed antibodies against antigens on leukocytes (HLA/MHC)

What laboratory test or studies would be most appropriate to order on a patient with a suspected hematological disorder?

- Complete blood count (CBC) - Peripheral Blood Smear (PBS) - Differential WBC count - Corrected Reticulocyte Count (Corrected Retic #) *** other lab tests that depend upon the results of the above tests: - Hemoglobin Electropheresis - Fe Panel, Serum B12, and folate levels etc -- You can also do a Bone Marrow examination if indicated

Pineal Gland

- Cone-shaped (5-8mm length; 3-5mm width), midline projection form the roof of the diencephalon (it is attached to the diencephalon (part of the brain between cerebrum and brainstem) via a stalk - Covered by pia mater - CT septa (containing blood vessels) originate in the pia mater and penetrate the pineal gland --- Arterial supply is profuse. The posterior choroidal arteries are the main supply; they are a set of 10 branches that arise from the posterior cerebral artery Venous drainage: via the internal cerebral veins

What are the functions/ hormones released from the Preoptic area of the hypothalamus

- Contains sexual dimorphic nucleus - regulates release of gonadotropic hormones ** controls ovulation (LH and FSH) and sexual behavious (SDN) and some parental behavior in some organisms Hormones: - GnRH - ADH - OXY (minor)

Glucocorticoids

- Corticosterone in ZG - Cortisol in ZF

What proteins are needed by CD8 T cells to preform their functions

- Cytokines (ex. IFN-gamma) - Cytotoxins (ex. perforin, granulysin, granzyme etc.) - Surface molecules (ex. CD95L or FasL)

What proteins are needed by CD4 T cells to preform their functions

- Cytokines (ex. IFN-gamma, IL-4, IL-17, IL-21 etc.) and surface molecules like: - CD40 ligan and CD40L and Fas ligand or FasL

Factors inhibiting insulin secretion

- Decreased BG - Fasting - Somatostatin (aka GHIH) - Alpha-adrenergic activity - Leptin (secreted by high fat) ------ Somatostatin and NE (by activating alpha-adrenergic receptors) inhibit exocytosis of insulin * somatostatin used to modulate beta cells in pancreatic islet is almost always paracrine, from delta cells in the same islet- here it is not endocrine hormone as it would be said if it were secreted from the hypothalamus and affecting the anterior pituitary somatotrophs

Factors stimulating glucagon secretion

- Decreased BG - Increased AA's - Exercise - Circulating Catecholamines (beta2)

An increase in Plasma D-Dimers could indicate

- Deep Vein Thrombosis - Pulmonary Embolism - Disseminated Intravascular Coagulation (DIC) *** Plasma D-Dimers are cross-linked fragments containing D-Dimer epitopes Q) If you have a patient with elevated plasma D-Dimer- this patient needs an anticoagulant. Which would you give? - you should use Heparin! which has immediate effects. Warfarin takes apprx. 17hrs so takes too long

Reasons for Hyperalbuminemia (increased albumin)

- Dehydration: loss of water and concentration of substances in within the vascular system - same albumin in the blood, but since less H2O it is more concentrated - Excessive stasis (slowing or stopping of normal flow) during venepuncture: increased hydrostatic pressure and lose H2O

List some Antigen Presenting cells ( Capture of antigens for display to lymphocytes)

- Dendritic cells: initiation of T cell responses - Macrophages: effector phase of cell mediated immunity - Follicular Dendritic Cells: display of antigens to B lymphocytes in humoral immune responses

Innocent Bystander effect

- Deposition and fixing of terminal components of complement (C5bC6C7C8, which can also create pores in lipid membranes..) on normal host cells can lead to the destruction of these cells-- can lead to systemic lupus erythematous, atypical hemolytic uremic syndrome, complocentric membranoglomerulopathies * this innocent bystander effect is limited by the action of CD59, and another host complement regulator, the S protein

Function of the Immune Sytem

- Detect potentially hazardous materials then - eliminate or inactivate them To preform that function, it must: - be able to recognize these material, and distinguish them from "self"

3 modes of physiologic regulation of ACTH secretion in HPA axis

- Diurnal rhythm (peak in morning, decline at end of day) - Negative feedback by corticosteroids - Increase steroidogenesis in response to stress ----------- Usually ACTH itself is not uses therapeuticlly bc it is limited due to its side effects, inconvenience, and unpredicatable) it also has: - rapid absorption (parenteral) - 15 min half life; rapid hydrolysis - adverse effects due to corticosteroid secretion * Cosyntropin (synthetic)- diagnostic testing HPA axis

Hematopoietic Growth Factors (Erythropoiesis Stimulating Agents)

- Epoetin alfa - Darbepoetin alfa

What is looked at when doing a Peripheral Blood Smear (PBS)

- Erythrocytes: size (related to MCV), abnormal shape, Hb concentration (gives RBCs its color- reflected by central pallor: related to MCH and MCHC) , RBC inclusion bodies? - Leukocytes: Differential count, abnormal cellular morphology? - Platelets: Presence/absence/size? Also look for abnormal cells/structures: - Immature cells (normoblast, myeloblast, lymphoblast) - Atypical lymphocyte - Medathrombocytes (very large platelets) - Parasites (malaria; filaria)

What are Neutrophil Extracellular Traps (NETs)

- Extracellular strands of decondensed DNA in complex with histones and granule proteins, which were expelled from dying neutrophils to ensnare and kill microbes ** NETs provide for a high local concentration of antimicrobial components and bind, disarm, and kill microbes extracellularly independent of phagocytic uptake ** NETs may also serve as physical barrier that prevents further spread of the pathogens ** Neutrophils can shoot NETs as traps to catch pathogens- just like spider man! **** This NET formation (NETosis) is one of the 3 ways that Neutrophils kills things- the other 2 ways are phagocytosis and degranulation (for "prey" too big to phagocytose)

IgM

- FIRST antibody secreted in immune response - Found on surface on naive B cells (IgM is also part of BCR or cell bound) - Secreted as a pentamer (5 identical units, bound by joining "J" chain, 10 antigen binding sites) - readily activates classical complement (more powerful in activating complement than IgG) ** if you only see IgM present= a new and current infection

Persistent HbF

- Fetal Hb is <1% in most adults - some ppl synthesize high amounts of HbF - no significant clinical problem (the high amts of HbF in ppl with inherited persistent HbF will happen even if they have no hemoglobinopathy alleles) * genetic variation at position- 158 of the G gamma globin gene - In ppl with HbSS, HbF constitute 2-20% - Hydroxyuria is used experimentally to increase HbF production in Beta-Thalassemia (it is hypothesized that this occurs as a selective destruction of the fastest dividing RBC precursers- it so happens that HbF producing cells (F-cells) are dividing at a slower pace

HbC

- Glu6Lys (glutamic acid to lysine: negative charge to positive charge- notice the codon number if 6, same location as in HbS) Glu and Lys are opposing charges so there is repulsion in HbC so sickling less severe than HbS * Mutation happened only once in western sub-saharan Africa (HbC crystals seen in blood analysis) * HbAC and HbCC BOTH significantly lower risk of Malaria death (heterozygote advantage)- significantly less pathology than HbAS and HbSS, respectively ** HbSC gives a somewhat milder sickle cell disease compared to HbSS but WORSE than HbAS --- HbSC is example of compound heterozygote--

Regulation of glycogenolysis by phosphorylation

- Glucagon in the liver and epinephrine in the muscle and liver activate glycogenolysis by phosphorylating and activating phosphorylase through cAMP-dependent signaling pathway - this strongly activates glycogeneolyiss and the production of Glucose-1-P ** in fed state, insulin activates protein phosphatase 1, which dephosphorylates and inactivates there enzymes -- - Ca2+ can also bind to calmodulin subunitof phosphorylase kinase, activating it without phosphorylation- can then activate glycogen phosphorylase, causing glycogen degradation - Under extreme conditions of anoxia and depletion of ATP, AMP activates glycogen phosphorylase B without it being phosphorylated

Insulin drives metabolism by driving changes in enzyme activity towards higher acitivty in those enzymes involved in storing and processing in coming energy such as

- Glucokinase - 6-Phosphofructo-1-kinase - Pyruvate kinase * decrease plasma glucose via glycolysis to pyruvate and further glucose oxidation past pyruvate, and decreases gluconeogenesis

Glucagon drive acitivty of those enzymes that are involved with the breakdown of molecules that will aid in increasing plasma glucose, these enzymes are

- Glucose-6-phosphatase - Fructose- 1,6- bisphosphatase - Phophoenolpyruvate carboxykinase ** in contrast to insulin, glucagon inhibits glycolysis and promotes gluconeogenesis and eventual glucose export in the plasma

Standard metabolic pathway for energy production in the fed state

- Glycolysis: transformation of glucose --> pyruvate; generates small amoutn of energy quickly (includes galactose and fructoes catabolism) - TCA cycle: breakdown of acetyl to CO2 with production of reducing equivalents (NADH and CoQH2 - Oxidative phosphorylation: electron transport. Converts high energy electrons (reducing power) to ATP and makes water from oxygen ** Also in the Fed states Carbohydrate can be used in: 1. Glycogenesis (major stores: liver and muscle. Many other cells store glycogen to a small extent) 2. Fat synthesis (in the liver, principally). A bit is stored locally, but most is sent to VLDL, which is secreted to circulation and delivers fat to peripheral tissues. In fed state, this is delivered mostly to adipose tissue

What are the half-lives for predominantly lipid-soluble endocrine hormones. Transported in circulation bound to binding proteins

- Growth Hormone (18-24 min) - Aldosterone (~30 min) - Cortisol (~60-90 min) - Porgesterone (12-16 hrs) - Triiodothyronine (T3) (16-24 hrs) - Thyroxine (T4) (~7days)

The Thre MHC-II genes (one for the alpha-chain and one for the beta-chain)

- HLA-DP (has an alpha and beta chain) - HLA- DQ (has alpha and beta chain) - HLA- DR (has alpha and beta chain)- this one encodes an extra beta chain ** these are usually restricted to pAPCs Nomenclature examples: - HLA-DQ*0025 stands for allele number 25 for the alpha-chain of HLA-DQ - Similarly, HLA-DQB*0003 stands for allele number 3 for the beta-chain of HLA-DQ

How to diagnose sickle cell anemia

- Hb will be low (anemia by 6 months (Hb 6.0-10.0g/dL) - High reticulocyte count Peripheral Blood Smear will show Sickle cells (drepanocytes) and Howell Jolly (HJ) Bodies( which reflect functional asplenia) * Infants are asymptomatic for the first 8-10 weeks of life, as they have high levels of HbF - A moderate- severe normocytic normochromic anemia shows by 6 months of age and persists through life - In adults with HbSS, the mean MCV is 90 - Blood smears show a variable number of sickled forms, target cells, cigar-shaped cells, and ovalocytes - Featurs of accelerate erythropoiesis may include polychromatophilia, basophilic stippling and normoblastosis - WBC count is consistently elevated due to an increase in # of mature granulocytes - Platelets are generally increased reflecting reduced or absent splenic sequestration

What traits modify severity of HbSS

- HbF (persistence of fetal Hb) - alpha-thalassaemia trait or silent carrier (lower Hb concentration) - HbC ** these are all expected to improve the clinical picture

What are the components of a Complete Blood Count (CBC)

- Hemoglobin (Hb) - Hematocrit (Hct) or packed cell volume (PCV) - Red blood cell count - RBC indices (MCV, MCH, MCHC): Mean Corpuscular Volume, Mean Corpuscular Hb, Mean Corpuscular Hb Concentration-- these are simply average quantities and may NOT detect abnormalities in blood with mixed cellular populations - Red cell distribution width (RDW) - White blood cell (WBC) count - Platelet count - Evaluation of peripheral blood smear (PBS)

Rate-limiting step for glucose entry in muscle

- Hexokinase is lower Km, below the circulating concentration, so it could be limiting if it was saturated constantly - However, the rate of glucose entry is limited by the Glut1 transporters and can be increased by recruitment of the Glut4 transporters - these essentially determine the rate of uptake into muscle. Most glucose entering becomes immediately trapped by hexokinase mediated phosphorylation ------------- Whereas in the liver, both glucokinase and Glut2 transporters are high Km to reflect increased activity in high glucose concentrations. In addition, glucokinase itself is regulated by glucose, F6P, F1P, and AMP. This is the key regulated step for glucose entry into cellular metabolism

Carbohydrate metabolism- Fed State

- High circulating glucose, signals high insulin - Insulin promotes general glucose utilization, glycogen synthesis, and general anabolism - Excess energy can aslo be stored as fat in adipose tissue -- Increased glucose from digestion is delivered from the intestinces through the portal circulation to the liver (the liver buffers the amount of glucose going into the circulation - excess glucose in liver: stored as glycogen or converted to fat an exported as VLDL to adipose tissue --- High circulating glucose enters pancreatic beta-cells and signals insulin secretion (insulin is secreted in response to high glucose) * insulin signals liver, skeletal m., adipose tissue and other organs to - use glucose as the principal energy source (increase uptake of glucose, turn on glycolysis) - store fat in adipose tissue - store glucose as glycogen in muscle - general anabolic signaling * circulating glucose in the blood is stored as glycogen in muscle and converted to fatty acids and stored as TAG in adipose and liver

Drugs that act as glucocorticoids

- Hydrocortisone (cortisol) - Prednisone (intermediate acting)- a corticosteroid agonist - Dexamethasone (long acting)

Glucocorticoid Drugs

- Hydrocortisone (equal anti-inflammatory and Na+-retaining potency) - Prednisone (more anti-inflammatory) - Dexamethasone (purely anti-inflammatory) Mineralcorticoid: - Fludrocortisone (mostly Na+ retaining) - a very potent mineralcotioid with high glucocorticoid activity ----------- These are given: oral, IV, IM, local site (synovial space, occular, skin, respiratory tract) -- ALL can do and achieve the same effects * Most are highly protein bound, if they are unbound they are active Metabolism: - All but two (Hydrocortisone and Prednisone) need enzymatic activation - Their mineralcorticoid effects of glucocorticoids are insufficient to replace aldosterone

Control of Cortisol Secretion (feedback loops)

- Hypothalamo-pituitary-adrenal-axis exerts primary control (long loop feedback from cortisol levels in the blood) - Many modulators: circadian signals, stress signals affect CRH secretion - ACTH is required to grow and differentiate cells of the adrenal cortex (ZG cells are the most immature and ZR cells next to the medulla undergo apoptosis) * ACTH is a basophil - ACTH signals the zona fasciculata to secrete cortisol - As cortisol works in the body, many of the stressors are relieved ---- Cortisols negative feedback- is the most important feedback chemical

Cytokines that are involved in inflammation

- IL-1Beta - IL-6 - TNF-alpha ** IL-1, IL-6, TNF-alpha, CXCL8- all induce local inflammaiton

Clinical Manifestations of Sickle Cell Anemia

- Icteric Sclera: jaundiced sclera - Frontal blossing: marrow expansion, hemolysis compensation-- expanded medullary cavity: diploic space is markedly widened due to marrow hyperplasia. Trabeculae are oriented perpendicular to the inner table, giving a "CREW CUT APPEARANCE**"

Describe the Antibody Isotype tissue distribution

- IgM is only in blood - IgG is in blood, tissues, and can cross placenta - IgA is found in the lumen of the guy, in secretions (saliva, tears, milk), on mucous membranes (respiratory and GI/GU) - IgE is found bound in FCepsilon receptors on mast cells in tissues

If there is a requirement for increased activity of any WBC type in the PERIPHERAL TISSUES, the number and proportion of that cell type rises markedly IN THE BLOOD. Can you give two examples of this?

- In a bacterial infection: neutrophil count will go up - In a parasitic infection: eosinophil count will go up

Factors inhibiting glucagon secretion

- Increased BG - Somatostatin (SST, from delta cells)

Pathogenesis of leukocytosis

- Increased production in BM (like in myeloproliferative disorders- ex. chornic myeloid leukemia, chronic inflammation (growth factor dependent) - Increased release from BM stroes (infection, endotoxemia, hypoxia) - Decreased margination (excercise, catecholamines) - Decreased extravasation into tissues (glucocorticoids)

Therapeutic uses of Oxytocin

- Induction of labor - Augmentation of labor - Prevent postpartum hemorrhage ------- it is IV administered or IM administered - half life is 1-15 minutes (needs continuous infusion) - urine excretion Adverse effects: - uterine hyperstimulation, hypotension, reflex tachycardia, uterine rupture, compormised fetal oxygenation, trauma to mother or fetus (passage through incomplete dilated cervix)

Causes of neutrophilia/neutrophilic leukocytosis

- Infections (acute bacterial infections ex. Acute Appendicitis, abscess) - Sterile inflammation (myocardial infarction, burns) - Drugs (decrease neutrophil adhesion and release from marrow stores- corticosteroids) ------- ** this is an incres in neutrophila (absolute count >7000cel/microliter ** shift to the left (immature neutrophil precursors in PB (>10% band neutrophil or any neutrophil younger than a band))

Permissive effects of cortisol

- Inhibit expression of genes for several pituitary hormones (ex. prolactin, POMC (preACTH), and ADH)

Permissive effects of cortisol

- Inhibits expression of genes for several pituitary hromones (ex. prolactin, POMC (pre-ACTH) and ADH) *** ex. Increased cortisol, decreased GnRH production (may cause a women to miss a cycle) - permissive effects on glucagon and epinephrine - regulates levels of insulin-sensitive GLUT-4 proteins, which then alters abilitiy to respond to insulin in skeletal muscle and adipose tissue

Actions of Glucagon on proteins

- Inhibits protein synthesis in the liver - Stimulates protein breakdown in the liver - DOES NOT normally affect protein in skeletal muscle (bc there arent supposed to be glucagon receptors there- it doesnt have the enzyme that dephosphorylates glucose-6-phosphate into glucose) - stimulates pathways that raise blood levels of glucose and fatty acids, a characteristic of the post-absorptive state * increased glucagon release during times of fasting (the post-absorptive state)

Reasons for a Microcytic Blood cell

- Iron deficiency - Thalassaemia (microcytic: MCV <76fL)

Pars Nervosa (posterior lobe)

- Irregularly organized - Contains PITUICYTES- which are neuralgia in nature: these may provide a supporting function for the unmyelinated axons within the pars nervosa - these axons whose cell bodies are located in the supraoptic and paraventricular nuclei of the hypothalamus enter the pars nervosa via the hypothalamo-hypophyseal tract * Axons have expanded axon terminals called HERRING BODIES within the pars nervosa - These Herring Bodies contain oxytocin and antidiuretic hormone (ADH/Vasopressin)- they STORE these hormones which are MANUFACTURED IN THE HYPOTHALAMUS

Sources of cholesterol include

- LDL and HDL from blood (low density and high density lipoproteins) - Endogenous synthesis - Stored cholesterol esters

Examples of other blood groups other than ABO and Rh

- Lewis (Le): most common reason for lack of compatibility between materials matched for ABO and Rh. The antigen in this system are also carbohydrate structures, just like ABO and contra most other blood groups - People with anti-U are problematic: so rare that is difficult to find donor - Autoanti-P (Donath Landsteiner) antibodies in hemolysis - the genes encoding blood groups C and E is physically close to the gene encoding the Rhesus blood group (which is sometimes called D), but is really acting independent of this - Kell antigen: large protein with antigenic regions. If abesnt, patient present with acanthocytosis, shortened RBC survival, and muscular dystrophy including the heart muscle - Duffy: has two alleles (Fya, Fyb) that are both binding sites for P.vivax. More than 70% of people in malaria regions lack these antigens - A delayed hemolytic transfusion reaction that occurs with blood tested compatible are often caused by delayed appearance of anti-Jka (one of the antigens in the Kidd blood group)

Secondary adrenal insufficiency

- Little production of ACTH - Without ACTH, adrenal gland produces little aldosterone and cortisol - ACTH levels will be low but it measureable in the lab, CRH levels would be high

Alanine Transaminase (ALT) is present in high concentrations in cells of the

- Liver - Skeletal and cardiac muscle (lesser extent) - Kidney (lesser extent) Marked increases are seen in: - circulatory failure - ACUTE VIRAL HEPATITIS Moderate increases are in: - LIVER CIRRHOSIS - CHOLESTATIC JAUNDICE - post cardiac surgery - skeletal muscle disease

Sinus hyperplasia

- Lymphatic sinusoids (distended and prominent, contain many histiocytes) found in - lymph nodes draining a cancer (breast carcinoma) - sinus histiocytosis with massive lymphadenopathy - langerhan cell hisiocytosis

Physiological functions of calcium

- Maintenance of skeletal structure - Intracellular messenger activity - Stabilizes DNA and RNA molecules

How do you prevent Hemolytic Disease of the New born (Rh)

- Make sure the mother NEVER develops antibodies - Rh- mothers: injection of anti-RH+ antibodies (RhoGam) max. 72h after birth prevents production of anti-Rh+ antibodies by the mother (current recommendation is to also inject at week 28 (or weeks 28+34) - this is safe because RhoGam contains IgG - should not be necesary if mother and 1st child are ABO incompatible, as anti-A or anti-B antibodies destroys the fetal RBC before damage is done * treat in current pregnancy to avoid problems in later pregnancies

HbE/Beta-Thalassemia compound heterozygotes

- Mild (15%): 9-12g/dL Hb- rarely need treatment except when infections hit - Intermediate (most): 6-7g/dL Hb- similar to beta-thal intermedia - Severe (rest- up to 1/2 in some reports): 4-5g/dL Hb (treat as Beta-thal major) What causes the variation? - Beta0 vs Beta+ - persistence of HbF to varying degrees: in many E/Beta0 with no HbA, 40-60% of Hb is HbE, the rest HbF (and a little HbA2) ** the genotype does not directly predict severity of phenotype

Main signs of Hypercortisolism (Cushing Syndrome)

- Moon-like face (lower voice, large amt of hair, acne) - Buffalo humps on back - Abdominal striae ------- Common Causes of Cushing Syndrome: - exogenous glucocorticoids (most common) - ACTH-producing pituitary adenoma, carcinoma, hyperplasia--> high ACTH --> bilateral adrenal hyperplasia ( CUSHING DISEASE) - Adenoma or carcinoma of the adrenal cortex (ACTH-independent, with low serum ACTH) - Paraneoplastic syndromes (common in lung cancers): disorders associated with production of biologically active substances (ex. hormones) by cancer cells (ACTH will stimulate the adrenal gland it doesnt mattere where it is produced)

Endocrine Pancreas

- Most islets of langerhands that comprise endocrine pancreas are too small to be seen by gross examination - they vary greatly in size ~70% are in size range of 50-250 micrometers in diameter. Smaller islets are dispersed throughout the acinar lobules and most larger islets lie along the main and interlobular ducts of the pancreas - Most islets are spherical or ellipsoid, but they can be irregular in shape - In adult humans the number of islets is calculated to be 500,000-1 million. Islets comprise 1-2% of the pancreas **** is a Serial section of one of these islets the following can be stained: - Alpha cells: glucagon - Beta cells: insulin (these are most present) - Delta cells: somatostatin (these are fewest)

IgA

- Mucosal Immunity- - secreted as a monomer and as a dimer - dimeric form contains J chain and secretory component: secretory component facilitates transport across epithelium into secretions of the mucosal system - Most predomiant isotype produced in the GUT Main function: - neutralization

Type O blood

- NO A or B antigens on the RBCs - both Anti- A and Anti- B in serum -------- Could receive RBCs from Type O blood only (note that compatability for RBCs is determine by the antigens on the cells in the donor- you DO NOT give blood to a recipient that has antibodies that would react with those antigens) Could receive plasma from: Type O, A, B, and AB (for this note that the same antibodies are present in the plasma as in the serum and you CANNOT give antibodies that would attack the cells of the recipient)

What Cells are part of the innate immune response

- Natural Barriers - Pagocytes: dendritic cells, neutrophils, macrophages - Mast cells, Eosinophils, Basophils - Complement (**this one also has an adaptive component)

What are 2 special cases of antigen presentation

- Natural Killer Cells - Intraepithelial T lymphocytes (IEL)

Increased levels of plasma cholinesterase (BuChE) could be indicative of

- Nephrotic Syndrome (excretion in urine) - Rapidly growing cells: liver recovery

Adjustments to chronic fasting

- No cortisol component at first - As body transitions to chronic starvation, ketone body production increases (cortisol secretion promotes skeletal muscle protein wasting as a source of emergency energy) - Muscle begins to use fatty acids and ketone bodies as a major fuel source and stops using glucose * after 3 days, glucose is reserved mostly for brain and erythrocytes * prolonged chronic starvation results in muscle breakdown, autophagy and eventual organ failure

Etiology and Pathogenesis of Beta Thalassemia

- Normal HbA Globin Chain Production - Beta Thalassemia Absent (beta0) or Decreased (beta+): beta chain production of Hb --> Reduced Hb and Excess unpaired alpha- chains leads to insoluble RBC inslusions that lead to membrane damage and cause hemolysis of RBCs (premature destruction <120days) ** the excess unpaired alpha chains aggregate to cause hemolysis - unstable tetramers of alpha chains formed that percipitate in the cytoplasm of developing erythroid precursors

What are the types of classifications for the concentration of Hb in RBCS (reflected by central pallor (paleness) (related to MCH and MCHC)

- Normochromic: normal Hb concentration - Hypochromic: decreased Hb concentration and increased central pallor - Hyperchromic: increased Hb concentration and loss of/decreased central pallor (seen in hereditary spherocytosis and some sickle cells) - Polychromasia: RBCs with more than one color and loss of central pallor

Which drugs have antagonist activity on growth hormone

- Octreotide - Pegvisomant

Which drugs act on the posterior pitutary

- Oxytocin Vasopressin (AKA ADH): - Desmopressin (agonist) - Conivaptan (antagonist)

Which hormones are produced by the pars nervosa (neurohypophysis, or posterior pituitary)- smaller part of pituitary gland

- Oxytocin and Vasopression (AVP or VP, aka ADH)

Stimuli and signaling events that result in IL-12 secretion by macrophages, as well as cytokines and signaling pathways that activate macrophages to become M1 macrophages include

- PAMPs and DAMPs activating the canonical pathway leading to IL-12 secretion - TNF-alpha signaling leads to increase in IL-12 secretion - IFN-gamma signaling leads to an increase in the killing response of macrophages

Proteolytic enzyme products tell us about the structure of the antibody molecule

- Papain: IgG --> 2 Fab + Fc - Pepsin: IgG --> (Fab')2 + Fc' *** Significance of enzymatic cleavage of IgG: - ability to cross the placenta - Fabgamma CANNOT cross - Fcgamma CAN cross - because the Fcgamma receptor on placental cell- allow for active crossing of IgG - Fabm cannot cross - Fcm cannot cross

Name the Hypothalamic nuclei involved in endocrine function (produce hormones)

- Paraventricular and supraoptic nuclei - Preoptic area - Arcuate nucleus - Ventromedial nucleus

If calcitonin is only evoked in extreme hypercalcemia, how does the body lower a mild (nonpathological) hypercalcemia?

- Passively just stop secreting PTH - if it was extreme then you need to hit the calcitonin break

Disorders (neoplasma) of the adrenal medulla

- Pheochromocytoma: secrete epinephrine and norepinephrine in adults with severe hypertension, wont metastasize - Neuroblastoma: affects children (mainly malignant)

Long term complications of Sickle Cell Anemia

- Pigmented gall stones: from increased bilirubin turnover - Susceptibility to infections: Pneumonia due to streptococcus pneumoniae or Hemophilus influenzae, Miningitis, Osteomyelitis due to staphylococcus aureus or salmonella ** recurrent infection with encapsulated bacteria - Splenomegaly in children (increased spleen) - Autosplenectomy in adults (due to repeated infarctions as a result of micro-vascular occlusions--scarring and atrophy)

Name some signaling biomolecules that are hydrophilic

- Polypeptides - Proteins - Glycoproteins - Catecholamines (ex. epinephrine) *** these usually have NO transport proteins, their plasma half-life is short (minutes), their receptor is usually in the plasma membrane ** certain exceptions (ex. growth hromone and Insulin-like growth factor I (IGF-1)) also bind to transport proteins - so these take longer to disappear from the blood unlike most water-soluble hormones) MOA: second messengers (cAMP, cGMP, Ca2+, DAG, phosphokinases, etc.)

Clinical presentation of Diabetes Mellitus (DM)

- Polyuria (peeing a lot), polydipsia (drinking a lot), and polyphagia ( eating a lot) - Fasting blood sugar (FBS) > 126mg/dL - Random blood sugar (RBS) > 200mg/dL - HbA1c >6.5% (this is long-term glycosylation- helps you to check if a pt has been noncompliant with their Diabetes medication) * if they are symptomatic: 1 abnormal value * asymptomatic: 2 abnormal values [symptom is something reported by a patient, a sign must be observerd or measured- it is possible for a patient to have signs of DM but not have noticed them] ------- DM Type 1 (5-10%) - Autoimmune: injury and/or inflammation (insulinitis) of islets of Langerhans - Morphology: lymphocyte infiltration and beta-cell destrcution ---- DM Type 2 (90-95%) - Peripheral insulin resistance or impaired insulin secretion (could be do to consuming so much sugar the the receptors became downregulated) Morphology: - Amyloid accumulation - Beta-cell atrophy (transition from Type 2 into Type 1)

What are some causes of Iron deficiency Anemia

- Poor nutrition - rapid growth - menorrhagia (heavy periods) - pregnancy - acute blood loss - blood-sucking parasites - occult bleeding: colon cancer?

RBC count is increased in

- Primary polycythemia (aka primary polycythemia vera) - Secondary polycythemia - Hemoconcentration (due to dehydration in an individual)

Progestins

- Prognenlone - Progesterone * in ZG

Mecasermin

- Recombinant human IGF-1 - 2nd product available in combination with its binding protein IGFBP-3 (prolongs half life) Therapeutic uses: - Used in Laron syndrome in which there is a lack of responsiveness to GH due to either a mutated GH receptor or development of antibodies to the GH receptor - short stature is caused by IGF-1 deficiency despite high GH - other- severe insulin resistance, muscular dystrophy, HIV releated adipose redistribution syndrome Pharmacokinetics: - subcutaneous injection - nearly 100% bioavailable - metabolized in kidney and liver - bound to circulating proteins - half life ~ 6 hours Contraindications: - close epiphysis - active or suspected neoplasia (similar to GH) Adverse effects: - hypoglycemia (give with a snack) - Lipohypertrophy - others similar to GH ** pt's with severe hyperglycemia this can be a treatment for them

What are the functions/ hormones produced from the Paraventricular and Supraoptic Nuceli of the Hypothalamus

- Regulate water balance - produce ADH and oxytocin - destruction causes diabetes insipidus - paraventricular nucleus projects to autonomic nuclei of brain stem and spinal cord ** Paraventricular: fluid balance (ADH), milk let-down (OXY), parturition, integration of autonomic and control of anterior pituitary *** Supraoptic: fluid balance, milk let-down, parturition- mostly gives ADH and OXY. Hormones produced: - CRH - TRH - ADH - OXY (major)

Two examples of how EPO is used in real life

- Renal failure patients on dialysis were universally anemic before the advent of commercial EPO and required transfusions - EPO is also (illegaly) sometimes used as a blood doping agent in endurance sports such as bicycle racing, triathlons and marathon running

Treatment for Growth hormone deficiency

- Replacement therapy - Historically, GH for therapeutic use was purified from human cadaver pituitaries (the drawbacks were limited quantities and it was linked to Creutzfeldt-Jakob disease) - currently GH is produced by recombinant DNA technology * Somatropin - referes to multiple brand name GH preparations that match native GH - net effect of somatropin is to increase linear growth (if epiphyses are open) and lean body mass - therapu is continued until adequate height is attained, epiphyses close, or response stops

Describe the aberrant response that occurs in Leishmaniasis

- Response with Th2 rather than Th1 leads to a disseminated infection * an abberant immune response by some individuals contributes to a severe form of the infection or disease, in the disseminated form of this diseases (multiple lesions over while body) as opposed to control of the infection (cutaneous leishmaniasis or oriental sore; a few localized legions) ---- ** same thing occurs in Leprosy (Th2 is produced instead of Th1 - leading to the lepromatous form of hte diseases - as opposed to the controlled form (tuberculoid form) the pt would have gotten if they expressed the controlled form of the infection mediated by Th1) ** leprosy is better controlled by the TH1 response ---- Some in HIV pts with a Th1 response have a slower progression to AIDS in the absence of therapy- whereas those with an aberrant TH2 response have a faster progresssion to AIDS

Molecular Testing for HbS

- Restriction enzyme difference (MstII) and allele specific oligonucleotide (ASO) hydridization ** this was presented by Dr. Lawson- review this**

Complications of Sickle Cell Anemia

- Retinopathy - Crapiomegaly --> congestive heart failure - Pulmonary infarcts --> Pneumonia - Splenomegaly --> Splenic atrophy (autosplenectomy) - Infarcts of extremities - Aseptic bone necrosis--> osteomyelitis - Ulcers - Cerebral infarts (stroke)--> mental retardation - Vaso-occlusion - Bone Marrow hyperplasia - Renal infarcts --> Hematuria

Pancreas

- Retroperitoneal organ - Found within the epigastric, and left hypochondria regions (possibly umbilical) - It traverses diagonally from the descending (second) duodenum all the way over to the spleen Has 4 anatomical parts: Head: lies against the second and third parts of the duodenum. Lower portion extending inferiorly from the head is the uncinate process Neck: directly anterior to superior mesenteric artery and veins, and the portal vein Body: Tail: the tail of the pancreas extends into the splenorenal ligament which is associated with the spleen

Suprarenal (AKA Adrenal) Glands

- Retroperitoneal organs - Lies on superiormedial aspect of the kidney - Surrounded by CT capsule and renal fascia - Has an outer cortex and an inner medulla that have different embryological origins Cortex can be further subdivided into 3 layers: 1. Zona glomerulosa 2. Zona fasciculata ** Occupies the bulk of the gland* 3. Zona reticularis * the medulla has no such subdivisions: is secretes catecholamines (mostly epinephrine and norepinephrine) ----- Arterial Supply 1. Suprarenal artery from inferior phrenic 2. Middle suprarenal from abdominal aorta 3. Inferior suprarenal from renal artery Drains via suprarenal vein which drains into inferior vena cava (IVC) on the RIGHT and the renal vein on the LEFT

Corticosteroids can also be used in Non-endocrine diseases such as

- Rheumatic disorders - Nephrotic syndrome - Allergic diseases - Infectious disease (pneumocystis, H. influenze meningitis) - Asthma/COPD

Pars Intermedia

- Rudimentary region - Found between pars distalis and pars nervosa - Contains weakly basophilic cuboidal follicular cells that contain secretory granules- (it is not known for sure what they secrete but they are thought to secrete melanocyte stimulating hormone (MSH) - Colloid filled cysts known as Rathke's cysts present (remnants of Rathkes pouch)

IgG

- SECOND "late" antibody to be secreted - secreted in large amounts - MOST ABUNDANT isotype in blood and lymph - secreted as a monomer Function: - activate classical complement - opsonization of pathogens (triggering phagocytosis and triggering antibody-dependent cell cytotoxicity- ADCC) - neutralization *** if you only note the presence of IgG- this signifies a NON-current infection, but rather an OLD infection

What are the functions/hormones released from the Ventromedial nucleus of the hypothalamus

- Satiety center - destruction results in obesity and savage behavior ** stimulation- decreased eating, lesion-obesity Hormones: - GHIH (aka somatostatin)

IgE

- Secreted as monomer - binds with high affinity to Fcepsilon receptors on mast cells, eosinophils, and basophils - efficiently triggers degranulation - important in allergy and response to helminths (parasites) **IgE has low levels in serum

Heme excretion

- Secretion of bilirubin-diglucuronide into the bile - removal by bacteria of glucuronic acid makes: Urobilinogen - is mostly oxidized to stercobilin (brown) - some reabsorbed to portal circulation and then converted to yello urobilin and excreted in the urine by the kidneys

What type of iron studies could one do in a hematologic assessment

- Serum iron - Serum Ferritin - Total iron binding capacity [TIBC] - Iron saturation (%)

What type of specific confirmatory tests could be done in a hematologic assessment

- Sickling Test - G-6-PD Assay - Serum Vitamin B12/ Folate levels - Antibodies to Intrinsic Factor (seen in perincious anemia)

Beta- Thalassaemia is due to

- Single base substitutions including frameshifts - Few large deletions or insertions Estimates: about 60,000 ppl with symptomatic Beta-Thal born each year, less than 300,000 alive ** most ppl with this do not survive very long ** notice that the more common type of mutation is different in beta- vs alpha-thalassemia

Primary (central) Lymphoid organs

- Site of development and maturation of lymphocytes into mature, BUT NAIVE (have yet to see an antigen) immunocompetent cells Includes: - Thymus: CFU-L cells leave the bone marrow after "birth" and mature to T cells in the thymus (becomes immunocompetent but niave) - Red Bone Marrow: Where both Tcells and B cells are "born' and where B-cells mature (become immunocompetent, but niave). NOTE: B cells also mature further after leaving the bone marrow

Which drugs have agonist activity on growth hormone

- Somatropin - Mecasermin

A secondary lymphatic tissue/organ is where a naive lymphocyte first comes in contact with an antigen and an immune response is generated. What are some examples of secondary lymphatic tissues

- Spleen - Lymph Nodes - Tonsils - Diffuse Lymphatic tissue (Peyers patches, Appendix etc..)

Ex. of transport globulins that bind a hormone class for blood transport

- Steroid hormones are transported on albumin or specific globulin transport proteins - Transcortin binds progestins and glucocorticoids in blood

Name some signaling biomolecules that are lipophilic

- Steroids - Iodothyronines (Thyroid Hormone) - Calcitriol (Vitamin D) - Eicodanoids) * these have transport proteins to move them through the body- ex albumin and thyroid hromone- binding globulin (TBG) * their plasma half-life is usually long (hours to days) and their receptor is usually always intracellular * MOA: receptor-hormone complexes bind to response elements and act in the nucleus

What occurs in a Vasocclusive Crisis in Sickle Cell Anemia

- Sudden episodes of tissue hypoxia - Ischemia leads to hypoxia which results in infarts (ex: splenic infarts- repeated infarts of spleen heals with fibrosis- left with scar tissue)- can lead to Howel Jolly Bodies (note these are not specific for sickle cell but their presence is indicative of diminished splenic fx.) - Severe pain - Location of pain depends upon the organ involved

Source of Vitamin B12

- Synthesized ONLY in bacteria, NOT in plants- the rarest vitamins - only available from animal products: liver, red meat, eggs, dairy, and enhanced cereals

Effector Cells (elimination of antigens)

- T lymphocytes: activation of phagocytes, killing infected cells - Macrophages: phagocytosis and killing of microbes - Granulocytes: killing microbes ** induction site is where immune cells meet antigen, get activated, and move to effector sites to perform their functions

Beta Thalasemmia Clinical Presentation

- Thalassemia Facies: prominent front and parietal bones and enlarged maxilla ** hair on end appearance/crew-cut appearance- erosion of cortex and new bone formation

The largest secondary immune organ in the body

- The spleen- it is about the size of a clenched fist * it is enclosed by a dense CT capsule from which trabeculae extend into the parenchyma of the organ - the Hilum carries nerves and arteries into the splenic pulp and veins and efferent lymphatic out of it ** like the thymus, the spleen possesses EFFERENT, but NOT afferent lymph vessels **** NOTE: any antigens come from filtereing blood, not lymph

Describe Thymic Involution

- The thymus is fully formed and functional at birth and very active through early childhood - it persists as a alrge organ until about puberty - then T-cell differentiation and proliferation are reduced and most of the lymphatic tissue is replaced by adipose tissue ** this shrinking of the thymus with age is known as thymic involution

Evasion of complement by microbes is possible by

- Thick cell walls preventing the function of the MAC - Recruitment of host complement regulatory factors by microbes to avoid complement activation (factor H, DAF, and CD59) - Production of microbial factors that mimic host complement regulatory factors (C1q-binding protein (E.coli), staphylococcal complement inhibitor, gpC-1 (herpesviruses), gp160 (T. cruzi) and others - Microbial production of inflammation inhibitors, such as the chemokine inhibitory protein of staphylococci (CHIPS)

What values can be looked at when measuring blood concentration?

- Total concentrations - Bound concentrations - Free concentrations (ex. free levels of thyroid hormone T3 and T4 are found in much lower concentrations in the blood as compared to the bound forms)

Morphological cahnges in neutrophila in sepsis or severe inflammatory disorders

- Toxic granules: coarser and darker than normal neutrophil granules, represent abnormal azurophilic (primary granules) - Dohle bodies: dull gray inclusions representing patches of dilated rER - Cytoplasmic vacuoles: phagolysosomes, indicating presence of phagocytosis

Which hormones are produced by the thyroid gland

- Tri-iodothyronine (T3) - Thyroxine (T4) - Calcitonin

Describe the structure of TCR

- Two polypeptide chains (alpha and beta) of roughly equal length - Both chains have variable (V) and constant (C) regions Genes: - the alpha chains has V and J gene segments - beta chain has V,D, J gene segments ----- The TCR is a heterodimer composed of 2 glycosylated polypeptide chains belonging to the immunoglobulin superfamily, and there are 2 types of TCRS: alpha-beta TCRs and gamma-delta TCRS - the alpha-beta TCR is composed of one alpha chain and one Beta chain - whereas the gamma-delta TCR is made up of one gamma chain and one delta chain *** the alpha-beta TCR is the type found on the majority of T lymphocytes, and it binds MHC/antigen peptide complexes (MHC-I or MHC-II)

Name receptors that are part of the Cytokine Receptor Family

- Type I cytokine (hemopoietin) receptors - Type II cytokine receptors - TNF receptor family - IL-1 receptor family (*** key on in inflammation) - Seven transmembran GPCRS (their ligands are chemokines)

General mechanism of action of insulin

- Tyrosine Kinase receptor activity; activates several classes of intracellular messengers - GLUT-4 transporters to cell membrane of select tissues, increases glucose uptake - Increased activity of enzyme that store and/or process glucose - Induction of transcription, increase in protein synthesis - Increased glucose utilization occurs even in target cells with no GLUT4s (remember hepatocytes with GLUT-2s)

What are some NON-physiological inhibitors of coagulation

- Vitamin K antagonists (in vivo) : ex. Warfarin **** mainly related to extrinsic pathway: Vitamin K does carboxylation of glutamate residues in factors 2,7,9,10- so an antagonist would BLOCK this carboxylation ** Warfarin is also an antagonist that is similar to vitamin K- it blocks carboxylation of factors 2,7,9,10 so the extrinsic and common pathways are NOT activated - Calcium chelators - EDTA (ethylenediaminotetraacetic acid) - Citrate - Oxalate

Other effects of glucocorticoids (cortisol)

- Water retention (minor *effect over baseline action) and increased blood proteins (direct) and hematocrit (via increased EPO), so possibility for increased blood volume overall ** licorice can turn "minor" into "dangerously major" resulting in hypertension - mixed effect on water balance, direct mineralcorticoid effect but inhibited ADH effect. Hypokalemia possible - immune depression by many mechanims including decreased prostaglandin production - increased GI growth and function, increased gastric acid secretion - decreased collagen formation, decreased osteoblast activity, increased bone resroption, decreased intestinal calcium absorption, and decreased renal calcium reabsorption- net effect is lowered plasma calcium and likely increase in PTH, calcitriol to compensate - inhibition of many hypothalamo-pituitary-peripheral gland axes - effects on mood and cognition, both positive and negative

Biphasic secretion of Insulin

- When glucose rises, at first insulin secretion goes up dramatically then it drops (0-6min) then it rises slowly to the level at which it was first secreted (expansion/replenishment of the RRP- 6-30min) - Generally this is attributed to an initial release of stored insulin in secretory vesicles (RRP= readily releasable pool for insulin secretion within the beta cell), followed by production of new insulin after a few minutes ------ When insulins effects have successfully reduced BG, the glucose signal for further insulin secretion ends and the metabolism and clearance of the already-secreted insulin rapidly follows. - During this "downtime", the beta cells store a new set of insulin proteins and store them in vesicles, functionally replacing the readily releasable pool of insulin that has been depleted by the end of the first phase

Secondary (peripheral) lymphoid organs

- Where immunocompetent cells can interact with antigen and with each other to mount a response against invading antigens or pathogens Includes: - Spleen - Lymph Nodes - Tonsils and Adenoids, Bronchus, Mesenteric, Peyers Patch..

Growth Hormone (GH)

- a protein hormone, very large (191 AA) - produced and secreted by anterior pituitary Somatotrophs - a major participant in control of several complex physiologic processes, including growth and metabolism *** secretion peaks during puberty and then slowly declines during adulthood GH and IGF1 increas in parallel during puberty, after puberty the levels begin to fall throughout adulthood and then decline somewhat rapidly after apprx age 60 --- During adulthood, GH and IGF regulate and maintain body mass, and facilitate compensatory growth (ex. removal of kidney, increased cell division in the remaining kidney lets it grow until its total mass comes to apprx. the former mass of the two kidneys combined) - thus for most of a persons life, growth hormones ability to help stimulate growth of long bones is secondary to its other effects promoting maintenance of what has already been produced

Normocytic (normal RBCs) can be seen in

- acute blood loss - anemia of chronic disease; ex: infections, malignancy, CT disease

Somatropin

- administered subcutaneously once daily (since it is a protein) - ~70% bioavailable - circulating half-life 20 minutes; biological half-life much longer Indications for treatment/use: - GH deficiency in children or adults - genetic conditions associated with short stature (turner syndrome, noonan syndrome, prader-willi syndrome) - chronic renal insufficiency - children born small for gestational age - children with idiopathic short stature - AIDS associated wasting - malabsorption associated with short bowel syndrome * also used in anti-aging programs/athletic performance enhancement (this is band in most sports) Contraindications: - acute critical illness - evidence of active malignancy - proliferative or severe nonproliferative retinopathy - unsupervised Prader-Willi Syndrome Adverse Effects: - Children: generally well tolerate. Rare side effects (intracranial hypertension, papilledema, visual changes, headache, nausea, vomiting, type 2 diabetes, slipped epiphysis, scoliosis) - Adults: occur more frequently (peripheral edema, carpal tunnel syndrome, arthralgias, myalgias) Drug Interactions (that may cause reduced effects) - Estrogen - Glucocorticoids

Calcium dietary needs increase throughout the life cycle

- after menopause, stable body calcium is dramatically reduced each yr in healthy women - vitD production is reduced in the elderly as renal 1-alpha-hydroxylase enzyme function decreases ------- bone density peaks in early adulthood in both males and females - males have higher peak bone density - with aging, bone density decreases - women reach the "fracture threshold decades earlier then men on average" * reason for mens stronger bones= estrogen vs testosterone

Hematopoiesis

- all blood cells, including the cells of the immune system are derived from pluripotent hematopoietic stem cells - the type of mature cell that develops is determined by exposure of progenitor cells to specific growth factors - a recombinant form of the growth factor erythropoietin (EPO) is used to treat some types of anemia

short feedback loops

- anterior pituitary hormones provide negative feedback on the axis - under physiological conditions only GH and Prolactin provide short-loop feedback ** others can do so under pathological condtions (ex. ACTH) - ACTH can provide this in Addisons Disease aka primary adrenal insufficiency *** the hormone from the pituitary gland goes back and does negatice feedback on the hypothalamus

COmplement proteins

- are normal serum proteins (about 10% of serum proteins) - there are over 30 known components (most soluble, some membrane bound) - soluble components of complement live as zymogens (an inactive prescursor enzyme that is altered to become an active protease that celaves and thereby induces the proteolytic activity of the next complement protein in the cascade) - they are also heat labile (sensitive to heat): can be inactivated by heat (56 degrees celsius for 30 minutes)- some diagnostic tests rely on inactivating complement to not interferes with measurements

Causes of Anemia

- blood loss - decreased erythrocyte production (due to iron deficiency, folate or B12 deficiency, thalassemia, or cancers) - hemolysis

What are some procedures that could be done in bone marrow examination

- bone marrow aspiration (this gives better cytologic details- with the report available on the same day) - bone marrow biopsy ( gives better architectual details but the report is available only after 5-7 days; more painful procedure- Helps with identification of hypocellular vs normocellular vs hypercellular marrow on biopsy image ) ** these are mainly done in pelvis and axial skeleton in an adult- less commonly it is done in the sternum When would you do this? - Evaluation of unexplained CBC results - Diagnosing Malignancy (cancer): primary bone marrow cancers (Leukemia and Myeloma) and secondary bone marrow malignancies or metastatic cancer - Evaluation of iron stores: Myelodysplastic/Myeloproliferatic disorders - Evaluation of disseminated infection (Tuberculosis, Fungal disease) - Bone marrow donor harvesting (aspiration)

In brainstorming a list of possible changes?

- brings people together to get diverse viewpoints - everything is up for discussion- no ones ideas are maligned - uses a discovery method to establish ideas for change - creates a list of possible changes after possible problems are identified with process modeling

Foods that contain both phosphate and clacium

- cheese - wheat - cod filet - nonfat milk

Name some characteristics of the constant region of immunoglobulin (Fc)

- constant sequence - crystalizable - carboxyl terminal - cell binding - complement binding - complement activating

"anti-anabolic" effects of cortisol

- converts protein to glucose - accelerate protein mobilization and degradation (except in the liver) - converts AAs into glucose precursors - inhibits protein synthesis - inhibits glucose uptake and decreases glucose utilization during hypoglycemia - enhances glucagon release - tendency to raise blood glucose

Name some steps in improvement process

- creating a focused aim statement - process modeling - brainstorming a list of possible changes - identifying mesures - performing PDSA cycles

Leukopenia (low WBC dount)

- decrease in neutrophils (neutropenia or granulocytopenia, and agranulocytosis) - decrease in lymphocytes (lymphopenia)

PTH effects on phosphate (in a low plasma concentration state)

- decreased renal tubular reabsorption of phosphate - increased urinary exretion of phosphate - decreased plasma phosphate concentration * PTH increases plasma Ca++ and decreases plasma phosphate

From the endocrine system replacement therapies of peptides and protein hormones are

- degraded in the GI tract (require parenteral administration - rapidly metabolic (short half-life) - primarily fast-acting via membrane receptors

Albumin functions to

- determine oncotic pressure - transport of fatty acids, bilirubin ( a break down product of heme) etc. - drug transport (salicylates, barbiturates, sulfonamides, warfarin, penicillin)

Rhesus Blood Group

- differs in presence (Rh+) or absence (Rh-, autosomal recessive) or the rhesus antigen (protein) - determined by presence or absence of polypeptide D (different AA varients in the polypeptide explain subgroups of Rh+) - 15% of North americans are Rh- (variation between populations) - No antibodies against Rh+ in Rh- people (different from the situation in ABO blood group system) *** the antigen here is a protein ** also Rhesus, Rh, and D are used interchangebly

From the endocrine system replacement therapies of steroids are

- efficiently absorbed by any epithelial surface - circulate bound to binding proteins - longer half-life than peptides and proteins - primarily regulate gene transcription via intracellular receptors

Immune System

- effort to combat potentially hazardous materials - restoration of normal structure and function Role of the immune system is: - defense against infections or against tumors - can injure cells and induce pathologic inflammation - recognizes and responds to tissue grafts and newly introduced proteins NOTE: the immue system can do both protection AND destruction

Heme Degradation

- erythrocytes last ~120 days - most lost heme is from erythrocytes (85%) with the remainder from hepatic P450 and other cytochromes - Heme is oxidized, iron released, and the macrocycle broken - converted to bilirubin - sent to liver for excretion in the bile as a diglucuronide adduct - after transport to the liver: proprionic acids are modified, reacted with UDP-glucuronide then secreted as Bilirubin diglucuronide into the bile

Calcitriol

- facilitates calcium and phosphate absorption in small intestine - interacts with PTH to enhance mobilization from bone - decreases renal excretion of calcium and phosphate * Actions are mediated via Vit D receptor (VDR) - cytosolic VDR binding - translocates to nucleus - interacts with DNA to modify gene transcription Other effects: - Affects mauration and differentiation of mononuclear cells; influencing cytokine production and immune function - inhibits epidermal proliferation and promotes differentiation (skin related therapies) ---- - Oral absorption is rapid - highly protein bound (99.9%) Adverse effects: - hypercalcemia with or without hyperphophatemia - hypervitminosis D - Use caution in renal patients with rapidly progressive disease or hyperphosphatemia

Signs of severe Iron Insufficiency- Anemia

- fainting - chest pain - angina - heart attack other main symptoms: - fatigue - weakness - pallor - palpitations - headache - cold hands and feet - sore or inflamed, swollen tongue - brittle nails - restless leg syndrome - hair loss

How does the innate immunity function in the genitourinary tract

- flushing action of urine (flushes out toxins) - urine acidity (antimicrobial) - vaginal secretions, lysozyme - Tamm-Horsfall protein (THP; antimicrobial-immunomodulation)-this helps to prevent UTIs

Carbohydrate Metabolism during extended fast (early starvation 4-24hr) - increased glucagon/ epi/norepi

- glycogenolysis- slows as liver glycogen stores are depleted - gluconeogenesis (glucose during fasting is made in the liver and the kidney)- precursors are alanine and glutamine from protein breakdown, lactate from anaerobic metabolism, and glycerol from trigyceride lipolysis (glycerol, alanine, glutamine, and lactate are precursors) - FA oxidation - Proteolysis (occurs to support gluconeogenesis) * Fat feeds the body during fasting- the action of epi/norepi on adipose releases free fatty acids. Many tissues use fat as the main energy source, including skeletal muscle. Some FFA are converted to VLDL

There is a wide distribution of H1 and H2 receptors in the periphery and the CNS; what are the different functions of histamine in these

- histamine can exert local or widespread effects depending on where it is released and how much is released - histamine contracts many smooth muscles (ex. bronchi and gut) - histamine relaxes some smooth muscles (ex. those in small blood vessels) - bronchoconstriction and contraction of the gut are mediated by H1 receptors. In the CNS, H1 activation inhibits appetite and increases wakefulness

Factors inhibiting GH secretion

- hyperglycemia (this stimulates insulin, a noraml person with transient hyperglycemia will be accompanied by a higher insulin that has been secreted to deal with the excess glucose and a reduction in GH that would otherwise help to keep blood glucose too high. - increased blood free fatty acids - aging - obesity - GH (exogenous) - GHIH (somatostatin) - somatomedins (IGFs)

Factors stimulating GH secretion

- hypoglycemia - decreased blood free fatty acids - high levels of AA (used as substrates for protein productiona nd eventual growth) - starvation, especially with severe protein deficiency - stress, trauma, and/or excitement - exercise - testosterone, estrogen - ghrelin (secreted when stomach is empty) - deep sleep - GHRH

Catecholamines help to ensure that the oxygen and nutrients are available for a person to meet the challeneges of an acute stressor such as those associated with exercise, because if not compensated it can lead to

- hypoglycemia (from rapid glucose intake by muscle) - hypoxia (from inadequate ventilation) - potentially shock (by large-scale production of vasodilators) -------- Fixed by sympathetics 1. Brochodilation mediated by beta-2-receptors: ensures adequate oxygen in the blood 2. Inhibition of smooth muscles (i.e. gastric smooth muscles) that are not necessary for this response (redirects oxygen and nutrients to those tissues which do require more oxygen and nutrients) 3. Catecholamines help to mobilize energy resources in the blood to accompany increased oxygen to working tissues (direct) 4. Catecholamins indirectly increase blood glucose by altering secretion of other hormones 5. Sympathetic stimulation including adrenal catecholamines increase 3 different aspects of heart function - increase strength (contractility) this is called (inotropy) by which it contract by altering ca2+ release and uptake in cardiac myocytes - increase in heart rate (chronotropy) - decrease length of time during which the heart actively contracts (lusotropy) 6. Vasculature is affected by sympathetic stimulation and adrenal catecholamines - alpha-receptor mediated constriction of veins and lymphatic vessels hels to maintain venous return (req. for adequate cardiac output) - constriction of many of bodys arterioles through alpha receptors help to maintain blood pressure so that blood flow is maintained and with it delivery of nutrients to working muscles

In the stage of pro-B cell to pre-B cell

- if a functional heavy chain is expressed after Pro-B cell stage - it will complex with surrogate light chain to form a (pre-B receptor) - the surrogate light chain has VpreB and gamma5 ** surrogate light chain is needed bc the light chain is NOT yet arranged- this is present before IgM is expressed ** if function, then you have progression to pre- B cell

Sodium-Glucose Transporter (SGLUT-1) is

- important in absorption of glucose in the SI and of reabsorption of glucose in the PCT, but it is NOT intended to support metabolism directly - it doesnt seem to fall directly into either class I or II because of its cotransporter function ** expressed in intestinal mucosa, kidney tubules

Methyl malonyl CoA mutase (MCM)

- in the mitochondria - isomerizes methylmalonyl-CoA --> succinyl-CoA * MCM is involved in metabolism of branched-chain AA isoleucine, valine as well as methionine, threonine, thymine, and odd-chain fatty acids ** it requires the deoxyadenosyl form of Vitamin B12

Diabetes Insipidus

- inability of the body to produce or release ADH - inability of the kidney to respond to ADH ** either results in polyuria (excess production of urine) - this urine is very hypotonic and typically contains no glucose - if not countered with increased water intake, dehydration will occur 2 types: Central: inability of body to produce or release ADH from the posterior pituitary - Tumors - Trauma - Surgery Nephrogenic: inability of the kidneys to respond to ADH (treatment is to correct the underlying renal disorder) - Renal diseases - ADH-unresponsive kidney - Drugs (lithium)

alpha2-globulin

- includes protease inhibitors and transport proteins Main one: ** alpha2-macroglobulin (transcuprein)- a protease inhibitor of plasmin (breaks down clots formed in blood), thrombin and kallikrein, carrier of cytokines and growth factors, zinc and copper transporter also have - Haptoglobin: binds free Hb, haptoglobin-hemoglobin complex targets hb for removal by spleen - ceruloplasmin: transports iron and copper - thyroxine-binding globulin: highest affinity T3 and T4 transporter - alpha2-antiplasmin: inhibits plasmin and neutrophil elastase - protein C (autothrombin IIa, factor XIV): activated protein C (APC) inhibits Factor Va and VIIIa

"Shift to the left"

- increased number of immature neutrophils in the blood - large number of BAND CELLS appear in the blood this is called a "shift to the left" and it is an indication of a bacterial infection *** Unlike erythrocytes, mature and near-mature neutrophils are stored in bone marrow - ratio of these neutrophils in bone marrow to bloodstream is ~5:1 - this reserve pool can be released abruptly into the circulation in response to inflammation, infection, or strenous exercise This can be visualized by looking at a blood smear stained with Wright stain; doing a differential WBC count orr today most moder, urban medical labs have an automated hematology analyzer which count, measure, and analyze RBCs, WBCs, and platelets as well as measure the amount of hemoglobin in the blood and within each red blood cell

What affects of thyroid hormone increase heat production in the body

- increased uncoupling protein-1 (UCP-1) in brown adipost tissue - increases sodium-potassium pumps

Risk factors associated with Vit D Deficiency

- indoor environemnt with little to no sun exposure - vegan diet lacking supplements - darker skin color - living in polar regions, either north or south of the equator

Th2 migrate to the tissues where they can

- induce eosinophil production (bone marrow) and activation in the affected tissues-- this is IL-5 dependent - mucus-production by intesetinal goblet cells and intestinal smooth muscle contraction (peristalsis) to expell dying or dead worms--- IL4 and IL-13 dependent some Th2 cells can also - remain in secondary lymphoid tissue to further specialize into Tfh cells after migrating towards C cell-rich areas; once back in the primary follicl, Tfh cells induce germinal center (secondary follicle) formation and maintenance, and trigger IgE isotype-switching (mainly) and affinity maturation in B lymphocytes for the purpose of eosinophil and mast cell sensitization (binding of IgE to mast cell and eosinophil FcepsilonR)-- having more than one FcepsilonR stimulated at once which is possible for large Ag such as a worm- triggers degranulation on the part of the eosinophil to release molecules (ex. Major basic protein) that damages the worms surface - Th2 in some circumstances can also trigger alternative macrophage activation; which serves to repair damaged tissues through release of polyamines and proline, which induce proliferation and collagen production, respectively

Target cells of cytotoxic T cells include

- infected cells - tumor cells

What are some causese of a Thrombus

- injury to a blood vessel or build-up of fatty plaques (both create rough surfaces inside vessel, which may activate platelets - poor blood circulation (cloothing factors accumulate) ** NOTE: immobility increases the risk of deep vein thrombus in the legs

Diagnosis of Congenital Adrenal Hyperplasia

- intersex phenotype of genotypic females - precocious puberty in males (testosterone --> estradiol) - adrenal glands enlarged at birth - elevated 17-OH-progesterone and 17-ketosteroids - elevated ACTH - electrolyte abnormalities - salt craving in 21-hydroxylase deficiency Treatment: - cortisol, even prenatally after prenatal diagnosis

Aldosterone Mechanism of Action

- intracellular receptor in nephrons distal tubule and collecting tubules/ducts- in renal principal cells - mRNA production there Aldosteronr have to work on 3 proteins to get its effects: - increased # of Electrogenic Sodium Channels (apical)- Na+ in - increased Na/K pumps (basal)- sodium out of cell, K+ into cells * more ability to reabsorb Na+, water follows Na+ - increased apical potassium channels- K+ leaks into cell ---- There are target tisssues of aldosterone other than renal principal cells, such as cells in the salivary ducts and others in the colon, but the most important of aldosterones effects take place in the kidney * the mechanism in these other tissues are functionally the same as described above, increased sodium transport capacity

Metabolism may

- involve biotransformation (conversion to a different chemical substance- a "metabolite") - result in conjugation of the drug with other molecules changing their chemical properties with the result of - inactivating the drug (which is most common)

Erythropoiesis requires proliferation of cells, heme synthesis, and DNA synthesis and therefore requires:

- iron - folate - B12

Describe the structure of Vitamin B12 (aka Cobalamin) and the two specific reactions it carries out

- it is a cobalt-containing, pyrrole ring system (similar to porphyrins, but not identical) - comes in various forms (-CN, -CH3, -deoxy-adenosyl) Required as an enzyme cofactor for only two known specific reactions: - methylmalonyl-coA mutase- uses the deoxyadenosyl form (to get odd chain fatty acids into the TCA cycle) - methionine synthase (aka 5-Methyl-THF-homocysteine methytransferases)- uses the methyl form

Beta Thalassemia Minor (Thalassemia Trait)

- less severe: one mutated Beta-chain allele - RBCs carry less oxygen than normal - common in mediterranean, middle east, africa - Asymptomatic/mild anemia - selective survival advantage for falciparum malaria Labs: - CBC: decreased RBC, Hb, Hct, MCV, MCHC - increased corrected reticulocyte count - PBS: microcytic hypochromic RBCs and target cells *HbA2 may also be increased and normal- slight increased in HbF

Primary target tissues for insulin

- liver hepatocytes - skeletal muscle cells (+cardiac) - adipocytes

The hypothalamo-pituitary-thyroid axis

- long-loop feedback * two significant peripheral gland hormones that provide this feedback, the two variants of thyroid hormone (T4 and T3) ---- Hypothalamus produces thyrotropin-releasing-hormone (TRH) - anterior pituitary produces thyrotropin, aka TSH - thyroid gland produces two varieties of Thyroid hormone (TH): thyroxine (T4) and triiodothyronine (T3) *** the long-loop negative feedback is by TH (especially T3) on the hypothalamus and pituitary gland

The Hypothalamo-Pituitary-Testis Axis

- looks like the two negative-feedback driven ovarian axes, because it operates the same way * testosterone is the regulated hormone in the plasma of males high amounts of testosterone will lead to a decrease in GnRH and LH & FSH * gonadally produced testosterone always exerts long-loop negative feedback

Overview of innate recognition

- lymph drains antigen and innate cells to secondary lymphoid tissue leads to - activation of B cells and T cells - T cells become effector T cells, B cells secrete antibodies - the effector T cells and antibodies traffic to site of infection and the Killer T cells can kill infected cells and the antibodies & cytokines can go on and trigger additional functions

Follicular hyperplasia

- lymph node architecture is well presereves: secondary follicles (large, oblong) with prominent germinal centers and many mitotic figures "benign- not follicular lymphoma" found in - rheumatoid arthritic - toxoplasmosis - HIV- early stages

Dexamethasone Suppression Test

- measures the response of adrenal glands to ACTH Low Dose Overnight test - pt given dexamethasone at 11PM, cortisol measured at 8AM following morning- suppression of cortisol to less than 1.8micrograms/dL suggests strongly that patient DOES NOT have Cushing Syndrome High Dose Overnight test - Measure cortisol on the morning of the test- then patient given dexamethason at 11pm- draw blood next morning at 8am for a cortisol measurment (normal result= greater than 50% reduction in plasma cortisol)

Complement cascades can result in

- microbe lysis - microbe and apoptotic body opsonization ("tagging") resulting in microbe or apoptotic body phagocytosis by neutrophils and macrophages - soluble byproducts that trigger and further stimulate inflammation

How does innate immunity function in the Respiratory tract

- mucus - ciliated epithelium: cough-sneeze reflex (part of immune defense) - surfactants (collectins): secreted by Type II pneumocytes, lubrication of the alveoli, and binds pathogens for phagocytosis - alveolar macrophages

Of the two daughter cells produced when a stem cell divides:

- one daughter remains a stem cell (will continue to have stem cells throughout life- keeps an available population of stem cells always ) - one daughter goes on to terminally differentiate

The Hypothalamo-pituitary ovarian axis, negative feedback variants:

- ovary with the corpus luteum (yellow body) secretes progesterone, which exerts negative feedback late in the ovarian cycle, just as estradiol does for the early part of the ovarian cycle * their negative feedback inhibits both GnRH and LH, FSH production

Eosinophils function in

- parasitic infections - asthma and allergies (together with mast cells and basophils)

Hypothalamus (a secondary endocrine gland)

- part of the forebrain - involved in many drives (ex. hunger and sex drives) - important relay point between the "higher-brain" cortex and brainstem - important in autonomic nervous system function - has many nuclei with many specialized functions

What are the functions/hormons released from the Arcuate Nucleus of the hypothalamus

- produces hypothalamic releasing factors - contains DOPA-ergic neurons that inhibit prolactin release *** control of anterior pituitar- production of hypothalamic releasing and inhibiting factors Hormones: - GHRH - GHIH (aka somatostatin) - GnRH - DA (dopamine)

Examples of feedback loops that are constitutivels secrete-until-stopped feedbacks

- prolactin regulation - calcium feedback

What are the functions of Treg cells

- promote self-tolerance - tolerance to innocuous Ag - prevent T cell responses - terminate T cell responses - inhibit other leukocyte functions Tools used to do this include: - TGF-beta - IL-10 - CTLA-4 - PD-1 - CD25

What do carrier proteins for plasma transport provide

- protection from destruction in blood - solubility in the blood - limit release into tissues (increases half life in blood) - increase hormone pool and evens out spikes in secretion (ex. Transthyretin, GH binding protein (GHBP), albumin or specific globulin transport proteins, transcortin)

In allergic reactions, Histamine H1 receptors are DIRECTLY involved in

- pruritis (itching) - mucosal edema ("stuffiness") - sneezing ** in addition, H1 receptors cause release of ACH that interacts with muscarinic receptors to cause mucus secretion (so, histamine H1 receptors INDIRECTLY cause mucus secretion) in the skin: urticaria (rashes) exhibit vasodilation, vascular permeability (swelling) and pruritis, all of which are mediated by H1 receptors - in the airways H1 receptor activation causes bronchospasm and edema, which are components of asthma NOTE: elevated plasma and tissue levels are found in allergic responses in the nose, skin, and airways

One may be able to selectively block physiological actions by

- receptor selectivity (specificity) - dose (affinity) ** note that these are not completely independent

Diphenhydramine

- reduce symptoms of nasal and dermatological allergies caused by histamine release - sedation (drowsiness) via antagonism of CNS muscarinic receptors - inhibition of nausea, vomiting, and vertigo via antagonism of histaminergic and cholinergic signals from vestibular system - anti-parkinsonism effects due to via antagonism of CNA muscarinic receptors ------ Systemic administration allows for treatment of: allergic reactions, insomnia (short-term therapy only) and motion sickness Topical administration allows for treatment of: relied of pain and itching associated with bites, poison ivy, poison oak, and posion sumac and other topical allergens *** Found in benadryl, tylenol, dramamine

Hormones that are bound to binding proteins/carriers in the blood have

- reduced activity - increased half-life (ex. Albumin- note when it is bound it is NOT active, only free fraction exerts an action)

Pathogenesis of Eosinophilia (increased eosinophils in the peripheral blood)

- release of eosinophil chemotactic factor from mast cells/basophils in type I IgE mediated hypersensitivity reactions - growth factor IL-5 ------ Causes: - Allergic disorders: asthma, hay fever, drug reaction to penicillin - Parasitic infections - Skin diseases (pemphigus, dermatitis herpetiformis - Certain malignancies (hodgkins lymphoma) - Collagen vascular diseases

The endocrine system sends messages to control and regulate metabolic activity of the body using hormones that are

- released by endocrine secretory cells and - carried by the blood circulatory system (endocrine organs have rich blood supply)

What is the mechanism for Beta-Thalassemia

- severely reduced production of beta-Hb chains - alpha-Hb chains in surplus (cannot produce homo-tetramers, precipitation inside cells- centers for oxidative damage of membrane proteins and lipids) - increased destruction of RBC precursors in bone marrow - shortened RBC lifespan in circulation **** for molecular mechanism of cell damage, focus on the chain that is in surplus

Deletions on Chromosome 16, alpha-thalassemia

- silent carrier: one deletion - alpha-thalassemia trait (mild anemia): 2 copies left, 2 copies deleted- mild sx's - Hemoglobin H disease, moderately severe anemia (3 copies deleted) - Hemoglobin Barts Disease, hydrops fetalis (all four copies deleted) ** Hb H and Hb Barts disease is rare in people of African descent but more common in people from SE Asia bc of the distribution of the two types of alleles

Haptens

- small molecules that, on their own, are NOT immunogenic - but they CAN bind antibody - they generally only have ONE epitope ** to make a hapten immunogenic, it MUST be bound to a protein carrier molecule to form a conjugate

Properties of the Adaptive Immune Response Include

- specificity - diversity - clonal expansion - anamnestic reaction (secondary response and booster response) - memory

Functions of Catecholamines

- stimulates "fight or flight or freeze" reaction - increases plasma glucose levels - increased cardiovascular function - increased metabolic function - decreased gastrointestinal and genitourinary function

How does innate immunity function in the gastrointestinal tract

- stomach aciditiy (not that many bacteria in the stomach because of this) - resident bacteria - epithelium - PANETH cells: secrete- alpha-defensins, lysozyme and phospholipase-A

Requirements of the body in terms of maintenance of blood glucose

- sufficient circulating glucose - resting glucose: near 4-5mM (less than 100mmg/dl) - after eating: ~10mM (less than 200mg/dl) -- Hypoglycemia (serious condition) the body will consider this as a stress response normal fasting glucose: 70-99mg/dL or 3.9-5.5mM normal glucose 2 hr postprandial: <140mg/dL 7.8mM * this leads to increased production of both GH and cortisol A major role of cortisol= stimulation of gluconeogenesis to supply blood glucose from production in the liver - breakdown of protein for gluconeogenic precursors - stimulation of synthesis of gluconeogenic enzymes * reduced insulin and increasing Glucagon, NE, and E are normal responses to fasting * Hypoglycemia produces more acute rises in cortisol and epinephrine

How do epithelial reticular cells (ERCs) form the framework of the thymus

- the ERCs are usually joined to each other by desmosomes, forming a 3-D cytoreticulum that provides structural support for the developing thymocytes

Secondary hypothyroidism

- the thyroid gland is normal but there is little to no TSH coming from the pituitary, therefore TH levels are too low ex. reaction of thyroid following pituitary resection

Secondary Hyperthyroidism

- the thyroid gland responds appropriately to an excessive quantity of TSH, again leading to too much TH * one would expect high levels of BOTH TSH and TH in the plasma ex. Anterior Pituitary Tumor

In Carbohydrate metabolism during the fasted state

- there are low glucose signals which cause insulin to drop and glucagon to increase (also epi/norepi increase) - liver glycogenolysis is promoted to provide circulating glucose for blood and brain More slowly: there is also fatty acid release from adipose and gluconeogenesis ------ In fasting Glycolysis becomes down regulated and fatty acids become the main source of energy (exceptions= brain and RBC which req. glucose) - The liver supplies glucose to glucose-requiring organs (brain and RBCs)- there are 2 sources of glucose: 1. Glycogenolysis: glycogen breakdown to form glucose 2. Gluconeogenesis - early in the fast, liver begins to break down its glycogen stored to keep blood glucose sufficiently high to support brain and erythrocyte function * since muscle lacks the enzyme glucose-6-phosphatase, muscle glycogen stores cant be used to supply glucose to any other organ

Primary Hyperthyroidism

- thyroid gland is overactive and does not respond approriately to TSH presence or absence - T3 and/or T4 levels are too high * one would expect undetectable levels of TSH in the plasma because feedback from the excess TH would reduce its secretion ex. Graves disease, TSH receptors bound by an antibody that stimulates TH secretion

Primary Hypothyroidism

- thyroid gland is underactive, and does not respond appropriately to TSH presence or absence. TH levels are too low as a result * one would expect high levels of TSH in the plasma because feedback from TH would be minimal ex. reaction of thyroid following radioactive iodine therapy or resection ex. chronic iodine deficiency in diet

Lymphadenopathy

-local/generalize enlargement? - tender/non-tender? Reactive hyperplasia: acute lymphadenitis and chronic lymphadenitis OR Neoplastic conditions with lymph node infiltration: primary tumor like lymphoma/leukemia or secondary tumor like metastatic tumor

Parathyroid Glands

-pea-sized, round structures usually found embedded in the POSTERIOR surface of the thyroid gland -a thick CT capsule separates the glands from the thyroid tissue * Most people have 4 parathyroid glands (two superior and two inferior), but occasionally there are more in tissues of the neck or chest ------ Its blood supply is essentially the same as the thyroid gland - Supplied by superior and inferior thyroid arteries and sometimes the thyroid ima (from brachiocephalic trunk but NOT present in all individuals) - Drains via the superior and middle thyroid veins to internal jugular vein and via inferior thyroid to brachiocephalic vein

Describe the circulation of iron in the body

1. <10%; ~1mg of dietary iron is taken up 2. similar small percentage is lost to excretion, loss of skin, etc 3. iron is transported using transferrin 4. iron is stored as ferritin (mostly) 5. only ~3mg of iron is in the circulation 6. iron from senscent RBCs is stored in the reticuloendothelial macrophages in a rapidly deliverable form 7. bone marrow takes up ~20mg/day for use in making RBCs

Describe what occurs in Signal 1 of the TCR

1. APC presents through MHC I and MHC II (whichever it is the TCR function is exactly the same) 2. CD4/CD8 and CD3 come closer together and are phosphorylated by kinase (LCK) 3. This allows docking of ZAP-70 which also gets phosphorylated by LCK also and carries the signal down stream 4. ZAP-70 is involved in activating phospholipase C gamma 1 and PI3-kinase , and the MAP kinase pathway ** this process leads to the activation of transcription factors NFAT, NF-KBeta, and AP-1 ** their main action is to bind the promoter region of IL-2 and its receptors ** NOTE: signal 1 does NOT generate enough NFAT and NFkBeta to really do much and that is why it needs signal 2 (co-stimulatory signal) which uses CD28 to activate PIP3 which gives NFAT and NFkB (this reinforces signal 1 to ensure you get enough transcription factor on IL-2 and its receptor

Strategies for Type II DM pharmacotherapy include

1. Act on the liver, muscle and/or adipose tissue to decrease glucose levels (biguanides (metformin); thiazolidinediones (rosiglitazone)) 2. Act via the suldonylurea receptor to increase insulin secretion (sulfonylureas- glimepiride and glyburide) 3. Act via incretin receptors to increase insulin secretion (Incretin mimetics: exenatide, liraglutide) 4. Slow intestinal carb absorption (Alpha-glucosidase inhibitor- acarbose) 5. Inhibit renal glucose reabsorption (gliflozins)

Disorders of Glucocorticoids

1. Addison Disease: lack of corticosteroids. Most often caused by autoimmune destruction of adrenal cortex 2. Cushing Syndrome: Excess glucocorticoids. Can be caused by an ACTH-secreting pituitary tumor (Cushing Disease) 3. Licorice-induce hypertension: A component of licorice root prevents the oxidation of cortisol to cortisone

What are two main reasons for swollen lymph nodes

1. After exposure to antigen such as a disease-causing organism, lymph nodes make MORE and LARGER secondary follicles (* this makes the lymph node LARGER)- after plasma cells and memory B cells leave the new follicles, the lymph node can shrink back down 2. Cancer cells can be released from a tumor in one site in the body, get carried in lymph to lymph node, get trapped in lymph node, keep dividing (* swollen lymph node can be the first sign of a tumor located somewhere in the body) - the condition of the lymph nodes is very important in cancer staging: it decides the treatment to be used, and determines the prognosis

B cell development goes through certain checkpoints to ensure that the cell meets certain criteria. Can you recall some of these?

1. Are heavy chains rearranged after pro-B cell stage? if no then apoptosis, if yes go on to pre-B-cell receptor 2. Are light chains rearranged properly? if yes ges on to become BCR, if not then apoptosis 3. Is IgM being expressed?

Functions of Monocytes

1. Avid Phagocytes: - in tissues they phagocytose and destroy dead and defunct cells as well as antigens and foreign particulate matter (such as bacteria) 2. Antigen Presenting Cells - they play a major role in the immune response * part of mononuclear phagocyte system

What are the 2 main type of granules that neutrophils contain- which contain hundreds of proteins, "weapons" used to kill bacteria

1. Azurophilic granules (aka primary granules) - These are the LYSOSOMES of the nuetrophil and contain myeloperoxidase, which helps to generate highly reactive bactericidal hypochlorite and chloramines (neutrophil oxidative burst) 2. Specific granules (aka secondary granules) - "neutral"- colored in neutrophils - the smallest granules which contain various enzymes and antimicrobial agents (ex. lysozyme, lactoferrin)

Activated B cells need help. What forms of help do they need?

1. B cells require T cells for them to make that switch (soo T cells help B cells to make antibody) 2. B cell activation also requires 3 signals: - B cell presents peptide to T cell - CD40-CD40L - Cytokines binding to cytokine receptors ** T cells also had 3 signals with APCs-

What is the Immunological sequence that occurs in Bacterial Infections in the Adaptic Immune system?

1. Bacteria (or other antigen) invade the body 2. Antigen presenting cells APCs (macrophages, dendritic cells others) phagocytose bacteria and then present antigen to NAIVE T cells, which acitvates these T cells 3. Activated T cells turn on naive B cells 4. B cells can transform into plasma cells- secrete antibodies specific to invading bacteria 5. Antibodies opsinize invading bacteria; bacteria are then destroyed by adaptive immune system- (also make memory B cells)

Production of T cells in the thymus

1. CFU-L cells from BM in newborn to adult (immuno-INcompetent) (CD4- and CD8-) begin their "education" in the cortex of thymus where they divide by mitosis 2. Thymocyte undergo POSITIVE SELECTION in cortex: must be able to recognize certain MHC molecules and be immunocompetent ** apoptosis if they DONT recogenize these, those that survive migrate to medulla (corpses removed by machrophage phagocytosis) 3. In medulla, they undergo NEGATIVE selection: any thymocyte that recognizes a self-antigen undergoes apoptosis 4. Thus, the thymocytes undergo both positive and negative selection ** over 95% die by apoptosis ** this is why the medulla of the thymus is lighter-staining than the cortex, it contains fewer cells

What are the phases of immunological action

1. Cognitive phase: must be able to see and find pathogen- does this with receptors on cells that bind to microbial molecules this causes 2. Activation phases: activation of a previously silent immune cell which can no move on to 3. Effector phase: kills target NOTE: immune system is expected to NOT be self reactive (Tolerance Induction- this is where we select for cells that are NOT self reactive)

Disorders of Sex steroids

1. Congenital Adrenal Hyperplasia (adrenogenital syndrome) - deficiency of 21-hydroxylase or 11-hydroxylase (or both!) - reduced corticosteroids - elevated ACTH - overproduction of adrenal androgens (since the path from progestins to glucocorticoids is inhibited- pushes towards androgen production) 2. 5alpha reductase deficiency (testosterone is not converted into dihydrotestosterone but rather estradiol--> this is what explains the ambiguous genitalia) - ambiguous external genitalia - virilization at puberty

Factors influencing immunogenicity (what factors make antigen immunogenic)?

1. Dose - very small quantities may get rapidly cleared - very large quantities may inhibit response ** so size must be just right 2. Route: ** best route= blood stream - entry of host for most pathogens by crossing mucosal surface (ex. GI: most are rapidly degraded and do not get much chance to interact with immune cells) - those that enter the blood stream can remain intact and have more potential to drive immune response ** imagine if all the food you at was immunogenic? that would be really bad- this is way any antigen taken orally is usually non-immunogenic 3. Adjuvants: - chemical substances that enhace the immune response to an antigen (augment immunogenicity) they are thought to: (bc were not sure how they work) - prolong the persistence of the antigen - stimulate or modulate immune cells - enhancing macrophage function

Neutrophil Oxidative Burst

1. During Phagocytosis, NADPH oxidase causes a burst of O2 consumption that leads to the formation of: - superoxide (O2-) anions and - hydrogen peroxide H2O2 (* both are destructive by themselves) 2. H2O2 used by myeloperoxidase (MPO) plus Cl- to form HOCL, which then produces the strongly antiseptic hypochlorite ion (OCl-), the active ingredient in bleach! ** this "bleach" denatures proteins and membranes of microorganisms and kills them * it can also kill other cells of the body, "collateral damage" of fighting infection

What are two main functions of the spleen?

1. Filters blood: mounts an immune response to antigens, particularly bacteria, circulating in the blood 2. Removes aged and damaged erythrocytes from the blood circulation

Resting Phagocytes get their energy from glycolysis- they can not kill and they can not make powerful radicals- in order to do so they have to go through induction. What are 3 enzymes that allow this to occur?

1. G-6P dehydrogenase (shifts metabolism to Pentose phosphate pathway) 2. NADPH oxidase (this is critical for the phagocyte to kill) *** clinically a NBT (nitro blue tetrazolium) test can be used to measure a phagocytes killing capacity by ROS - an increased NBT= phagocyte can kill (strong blue) - decreased NBT= phagocyte CANT kill (faint blue) 3. Myeloperoxidase: generates HOCL ion- clinically this is not necessary so once you have NADPH oxidase you are already a 90% affective macrophage

Endocrine system includes

1. Glands: pituitary, thyroid, parathyroids, adrenals, pineal (also testes and ovaries but not worrying about that much now) 2. Clusters of endocrine cells within an organ (ex. islets of langerhans (pancreas) 3. Isolated endocrine cells in tissues (ex. mucosa of GI)

Describe the main pathway fro insulin secretion

1. Glucose entry via GLUT-2, other nutrients too - Other energy sources such as fatty acids or amino acids such as leucine or arginie also increase ATP levels in the cell, turning on the intracellular signal- 2,3. Metabolize glucose or other nutrients 4,5. ATP, NADH levels are up - the levels of ATP produced within the cell cause it to become and intracrine messenger- ATP acts inside the cell as a messenger via closing potassium channels which then produce the membrane potential changes and subsequent exocytosis of insulin- 6. K+ channel closes (depolarizes cell and opens the voltage-gated calcium channels) and Ca2+ channels open (depolarizes cell more) 7. This Ca2+ along with other calcium from intracellular stores then binds to motor (exocytosis) proteins that "drag" vesicles containing insulin to the basolateral membrane resulting in exocytosis of insulin molecules 8. Exocytosis of insulin ---- So the extracellular conc. of glucose alters concentration of ATP and that proportionally increases intracellular calcium. If ECF glucose is up, then ATP is up, calcium is up, and insulin secretion is up

The integral membrane proteins of RBCs are of what two major families

1. Glycophorins 2) Band 3 proteins - the carbohydrate groups on glycophorins and band 3 proteins (and on glycolipids) form the ABO blood group antigens (sugar transferases determine ABO blood group) - sugar transferase A (type A blood), B (type B blood) , AB (type AB blood), or None (type O blood)

Tonsils (like ALL secondary lymphoid tissue) have

1. HEVs to bring in naive T and B cells from the blood (** remember there were no HEVs in the spleen, why was this?bc whole components of blood get dumped there and they can just find where they need to go they dont need a special thing to bring them in) 2. secondary follicles/nodules, follicular dendritic cells in germinal centers (also primary follicles) 3. reticular cells/fibers to make the framework

What are 3 types of Hormone Control

1. Homeostatic feedback, almost always negative - physiological response-drive vs. endocrine axis-driven Ex. of Physiological response driven feedback-- If plasma glucose rises too high (hyperglycemia), insulin is secreted to reduce it. If it drops too low (hypoglycemia), glucagon and/or catecholamines (epinephrine) are secreted to increase it- each activates a series of generally oppossing biochemical processes to produce its change in blood glucose 2. Neural control: - includes adrenergic (epi/norepi), cholinergic (ACh), serotoninergic - can serve homestatic feedback - Nervous system directly commands hormone release- often involves neurons or related neural tissue cells as secretagogues Ex: the cells in the adrenal medulla that secrete catecholamines are derived from neural crest cells 3. Chronotropic control (modulation) - includes pulsatile (such that chronotropic modulation influences the quantity of hormone released at each time), diurnal, mentrual, seasonal and developmental rhythms - involved neuronal signals - can modulate homeostatic feedback Ex: Circadian cycle of cortisol secretion: cortisol is the primary human glucocorticoid- its secretion peaks at 9-10am and is minimal at midnight - note that Growth hormone on the other hand which supports cortisol catabolism actually peaks at midnight (kids growth at night)

Therapeutic uses of pharmacology in endocrinology

1. Hormone replacement therapy 2. Controlling inappropriate hormone secretion 3. Evoking or blocking the action of a hormone in order to achieve some desired metabolic effect

What are some proteins found in innate immunity (humoral function)

1. IFN-alpha, beta, gamma, and lambda - these do inhibition of viral replication and activation of NK cells (these do not prevent viral infection BUT they do prevent viral replication) ** Type I IFNs: IFN-alpha and IFN-Beta Type II IFNs: IFN-gamma Type III IFNs: IFN- lambda - Type I and III have very similar functions and are primarily involved in antiviral defense - IFN-gamma is also involved in defenses against intracellular pathogens, BUT it is associated more with cellular immunity 2. Complement: proteins in serum that augment the immune system 3. Acute phase proteins - C-reactive protein (CRP) - Mannan binding lectin ( a type I PRR) *** NOTE: there is always a rise in acute phase proteins just before inflammation is about to occur 4. Defensins

Describe the process of clearance of immune complexes as a function of complement

1. Immune complexes activate complement (leads to deposition of many molecules of C3b on the immune complex) 2. These immune complexes can be bound to erythrocytes through C3b/CR1 interaction 3. In the spleen, splenic macrophages uncouple erythrocytes from immune complexes; immune complexes are phagocytosed and destroyed by splenic macrophages, and erythrocytes are recycled

Actions of Insulin on Fats (lipids)

1. Increases transport and conversion of glucose into fat 2. Promotes transport of fatty acids from the blood into adipose tissue 3. Inhibits lipolysis. Instead promotes TAG formation in adipocytes 4. At adipocytes, this decreases FA (and thus glucose) output and promotes storage of both ingested and de novo TAGs (one of many reasons why someone on high carb diet, nearly-no-fat diet with excess caloric intake can become obese)

Pathogenesis of Sickle Cell Anemia

1. Initial sickling: reversible with administration of O2 2. Recurrent sickling: irreversible sickling due to membrane damage (from repeated cycles of deoxygenation)- increased adherence to endothelium 3. Irreversibly Sickled Cells: increased RBC adherence to endothelial cells in micro-circulation, increased RBC adhesion molecules- RBCs sticky in slugglish blood flow, gives inflammation (decreased NO), micro-vascular occlusions (vaso-occlusive crises)- ischemic damage ** changes in phospholipids of the membranes results in stronger adherence to endothelial cells, which further impairs blood flow

2 phases of an immune response include

1. Innate phase: triggered upon antigen exposure and remains active until antigen is eliminated 2. Adaptive phase: takes hrs to days to fully develop after antigen exposure (this is triggered by cells of the innate immune system like dendritic cells and macrophages) & many cells acting during the innate phase are also called upon to act during the adaptive phase (ex. Neutrophila, macrophages, NK cells)

Actions of Insulin on Carbs

1. Insulin promotes glucose transport into most cells in the body (using GLUT-4 and facilitated fissusion- needs a carrier protein) 2. Stimulates glycogenesis, the production of storage polysaccharide, glycogen from glucose in skeletal muscle and the liver 3. Insulin inhibits glycogenolysis- decreases glucose output by the liver and promotes storage of glucose as glycogen 4. Insulin inhibits gluconeogenesis- conversion of AAs or FAs into glucose by the liver Overall: - Glucose is stored, not produced. Combined with increased glucose uptake and cellular respiration, this has the net effect of reducing plasma glucose

4 types of cell adhesion molecules

1. Integrins (Heterophilic- bind cell to ECM) 2. Cadherins (Homophilic- bind cell to identical cell) 3. Ig-superfamily (IgSF) (mostly Homophilic): although exploited extensively for functional roles in immue recognition, such as for antibodies and T-cell receptors, the immunoglobin fold is also found in a wide variety of structures employed in cell-cell interaction (ALL members contain a domain known as an immunoglobulin domain or fold **) 4. Selectins (Heterophilic): binds cell to CARBOHYDRATE on another cell (there is L, P and E selectins)

Major sites of iron storage in the body are

1. Liver (~1g): it is stored here as ferritin 2. Reticuloendothelial macrophages (~0.6g) - senescent RBCs are degraded in macrophages

General Rules involving hormonal half-lives

1. Locally-acting biomolecules are often metabolized by locally-produced degrading enzyme and therefore exhibit a short half-life (ex. vasoconstrictors degraded by endopeptidases) 2. Small peptides typically act locally and exhibit the shortest half-lives 3. Hypothalamic hormones exhibit relatives short half-lives 4. Hydrophilic biomolecules have shorter half-lives than hydrophobid biomolecules (hydrophobic hormones typically bind to serum proteins which extends half-life) 5. Pro-hormones and break-down metabolites exhibit a longer half-life than the most active biomolecule/hormone (ex. T3 (the more bioactive thyroid hormone) has a shorter half-life than T4 (the hormone found in higher quantities)

Describe the life cycle of RBCs

1. Low O2 levels in blood stimulate kidneys to produce EPO 2. EPO levels rise in the blood 3. EPO and necessary raw materials in blood promote erythropoiesis in red bone marrow 4. New erythrocytes enter bloodstream; function ~120days 5. Aged and damaged RBCs are engulfed by macrophages of LIVER, SPLEEN and BONE MARROW; the Hb is broken down

Describe how lymph flows through a lymph node

1. Lymph enters the lymph node through AFFERENT lymphatics 2. The lymph is filtered through a reticular fiber network and the "filtered bits" are exposed to APCs (mainly dendritic cells), T and B cells, and other cells of the immune system *** begins an antigenic response** 3. The now filtered lymph exits the lymph node through EFFERENT lymphatics ----------- Lymph containing micro-organisms, soluble antigens, APCs, and a few B cells, enters the lymph node via AFFERENT lymphatic vessels which enter endothelial lined: 1. Subscapsular sinuses and 2. Peritrabecular sinuses, which lead to a meshwork of 3. Medullary sinuses in the medulla. These medullary sinuses become larger channels that combine to form the 4. Efferent lymphatic vessels that exit at the hilum

List and describe the three groups of adrenal steroids

1. Mineralcorticoids - Prototype: aldosterone - produced in Zona Glomerulosa - Needs 21-Hydroxylase (ZG/ZF) and aldosterone synthase (ZG only) - Function: increase salt and water retention, mostly through renal action 2. Glucocorticoids - Prototype: Cortisol (aka Hydrocortisone) - produced in Zona Fasciculata (minor production from ZG) - Needs 21-Hydroxylase (ZG/ZF) and 17 alpha hydroxylase (ZF/ZR) - Function: many ex. Increase energy mobilization from all sources including proteins, and anti-inflammatory effects 3. Adrenal Androgens - Prototypes: DHEA, Androstenedione - Produced in Zona Reticularis - Needs 17-alpha hydroxylase (ZF/ZR) and 17,20 lyase, (ZR only) - Weak androgenic effects, precursor to gonadal androgens and estrogens

Can you give two examples of chemotactically active factors

1. N-formylated Oligopeptides of Bacterial Origin: - mitochondria also make N-formylated proteins when they translate proteins inside mitochondria (just like bacteria), - ruptured mitochondria release these proteins (13 proteins with N-formyl groups) - they are chemotactic for phagocytic cells because the body thinks it is being invaded * one main reason that necrosis causes inflammation * this is part of the INNATE immune system (neutrophils will recognize any bacterium, regardless of whether they have ever seen this particular strain before (if the bacteria is opsonized with antibodies, it is an even better target) 2. Chemokines: a subset of cytokines which can induce chemotaxis of a leukocyte (a cytokine is any number of substances, such as interferon, interleukin, and growth factors, which are secreted by certain cells of the immune system, and have an effect on other cells)

Describe the Dual embryological origin of the pituitary gland

1. Neurohypophysis - from nervous tissue that migrates inferiorly from the floor of the diencephalon - subdivided into PARS NERVOSA (posterior lobe) and INFUNDIBULUM/STALK (stem and median eminence) 2. Adenohypophysis - from oral ectoderm - subdivided into PARS DISTALIS (anterior lobe), PARS TUBERALIS (surround stalk), and PARS INTERMEDIA

Functions of Antibody secretion by plasma cells

1. Neutralization: antibody preventa bacterial adherence by binding the pathogen 2. Opsonization: antibody promotes phagocytosis by binding pathogen 3. Complement activation: antibody activates complement, which enhances opsonization and lyses some bacteria via the classical pathway

5 functions of complement

1. Opsonization - tagging of targe so immune system knows what to kill (C3b is main one that triggers for phagocytosis) 2. Inflammation - C3a and C5a bind mast cells and trigger release of inflammation 3. Microbial lysis: - form a pore in the membrane- the insides leak out (bacteria swells leading to lysis) 4. B lymphocyte activation - complement serves as a signal for B cells to make specific antibody (specificity provided by BCR)- * note BCR has CR2 5. Clearance of immune complexes - increase accumulation of antigen from microbe. Antibodies will bind the antigen

Intestinal Calcium Absorption occurs via

1. Paracellular transport (rare): pass through tight junctions from the lumen into the ECF from there into the blood 2. Apical and basolateral membranes - Apical: Ca2+ channels (TRPV6) - Basolateral: Sodium/Ca2+ exchanger and Primary active calcium transport

Parathyroid hormone, Calcitonin, and Vitamin D- related drugs are used in

1. Prevention and treatment of osteomalacia/rickets 2. Regulation of parathyroid hormone secretion in hyperparathyroid clinical situations Ex. Renal failure, primar hyperparathyroidism 3. Treatment of Hypercalcemia, osteoporosis and other diseases of high bone turnover

Classes of steroid hormones

1. Progestins - Formed during menstrual cycle (by the corpus luteum) and pregnancy (by the placenta) - Most important: PROGESTERONE 2. Glucocorticoids - "Stress Hormone" from the adrenal cortex that regulates major metabolic pathways - CORTISOL 3. Minceralcorticoids - Regulators of renal sodium and potassium excretion, from adrenal cortex - ALDOSTERONE 4. Androgens - The virilizing hormones from the testis, also formed in the adrenal cortex - TESTOSTERONE 5. Estrognes - Regulators of female reproductive function, from ovary and placenta - ESTRADIOL

Actions of Insulin on Proteins

1. Promotes transport and incorporation of AAs from the blood into muscles and other tissues - this decreases blood AAs levels and prommotes protein synthesis in target cells 2. Insulin inhibits protein degradation 3. Net anabolic effect in the body (since neither GH nor IGF-1 significantly increase glucose uptake into muscle, this ability of insulin is necessary for protein synthesis to take place in high enough quantities to produce a net anabolic effect body-wide) ------- ** this is the opposite effect of cortisol- stimulates release of muscle-based AAs and their hepatic conversion into other fuel sources, promotes catabolism more than anabolism

The 3 formed elements that make up blood

1. RBCS (erythrocytes): 5-6million per microliter of blood- work to transport oxygen (and CO2) 2. White blood cells (leukocytes): 5,000-10,000 per microliter of blood- work in defense and immunity - Basophil - Eosinophil - Neutrophil - Lymphocyte - Monocyte 3. Platelets: 250,000-400,000 per microliter of blood- function in blood clotting *** In the body, these formed elements are suspended in PLASMA, when taken outside of the body- blood will clot, leaving (the liquid) serum behind

What are the 3 things the immune system can distinguish between?

1. Self vs. nonself 2. Micro vs. Macroscopic invaders - micro: bacteria, viruses, protazoans, fungi (small enough to be phagocytosed) - macro: (metazoans) ex. worms (not big enough to be phagocytosed 2. Intra vs. Extracellular invaders (immune system needs different paths for each -----these distinguishing elements dictate the type of immune response---- - Extracellular Microscopic Organisms: Unicellular- can be physically flagged by molecules present in body fluids and destroyed by lysis or phagocytosis - Intracellular Microscopic Organisms: (these are found hidden inside of cells- shielded from molecules of the immune system meant to flag them for destruction)- destroyed by killing the cells harboring them - Large extracellular organisms (multicellular- too large to be phagocytosed or lysed) these are destroyed by hordes of cells releasing corroding molecules on them

Describe the 2 components of Red Pulp

1. Sinusoids (sinusoidal capillaries) - the blood vessels, (the "sea" - NO reticular fibers/cells in blood sinuses (unlike lymph sinuses) 2. Splenic Cords (of Bilroth) - made of Reticular Fibers (Type III collagen), (the "land")- alot of resident macrophages and dendritic cells ** in the splenic red pulp, all the blood is dumped here and then has to reenter the sinusoids through slits in walls of sinusoids to re-enter the bloodstream

What are some properties that make a good antigen?

1. Size- at least 6,000-10,000 daltons (6-10kd): anything smaller than this is a Hapten (non-antigen) 2. Complex: - Proteins are the BEST antigens because of their complex nature - Polysaccharides also make good antigens - Nucleic acids and phospholipids are weak antigens - small molecules (hormones, lipids, simple sugars) usually must be conjugated to a larger macromulecule to be antigenic 3. Foreignness: if it does not look foreign, it is not a good antigen (you want the immune system to bind non-self) 4. Solubility: - molecules that are easily solubilized are better antigens - insoluble molecules tend to pass through body unrecognized

Blood flow through the red pulp

1. Some penicillar arteries in spleen are open-ended, dumping blood into the splenic cords (of Bilroth) "open circulation" 2. Plasma and formed elements of blood must pass between stave cells lining sinusoid to reenter blood circulation inside sinusoids "closed circulation" ** NOTE: the spleen is the only human organ where blood passes through spaces NOT lined by endothelia or other barrier-forming cells

Describe the process of B cell development

1. Stem cell in the bone marrow - B-cell rearrangments of the heavy chain (VDJ rearrangement in the next 2 steps- 2. Early pro-b cell 3. Late pro-b cells -B-cell rearrangement of light chain V-J in next two steps-- 4. Large pre-B cell 5. Small pre-B cell -- At theend of pre-B cell you have heavy and light chain- you have IgM-- 6. Immature B cells 7. Mature B cell ( also has IgD along with IgM so- whole process must be repeated again for IgD) ** NOTE: a cell will be B cell when it begins to express certain markers along with the BCR these markers include - CD19 (one of the early markers on a B cell) - CD21 - CD20

4 classic symptoms of inflammation (swollen reddened state) produced in an area of the body as a reaction to injury or infection

1. Swelling- caused by edema 2. Redness- caused by increased blood flow 3. Heat- caused by increased blood flow 4. Pain- caused by irritation of nerve ends 5. Inhibition of the affected area (seen sometimes) ** acute inflammation is a rapid host response that serves to deliver leukocytes and plasma proteins (such as antibodies) to sites of infection or tissue injury)

List the steps in Thymocyte Development

1. T lymphocyte progenitor is found in the bone marrow - this migrates to the thymus (specifically the corticomedullary junction of the thymus) where it becomes a... 2. Thymocyte - this migrates towars the cortex and once here goes through... 3. Thymocyte proliferation - this occurs from thymic stromal cells cytokine secretion of IL-7 and Notch 1, 1 week later there is acquisition of the adhesion molecule CD2 making the cell a... 4. Double Negative (DN) Thymocyte: meaning it expresses CD2 but niether CD4 or CD8 - this cell then migrates towars the subcapsular region in the thymus where it goes through 5. DN Thymocyte TCR gene rearrangement (rearrangement of its genes)- this is RAG-1/RAG-2 and TdT-dependent - Successful TCR beta-chain rearrangmenet occurs as well as association with pre-T-alpha-chain and CD3, then in the subcapsular region you have.. 6. DN Thymocyte pre-TCR proliferation (and at this point the expression of CD4 and CD8 begins, alone with successful TCR-alpha-chain rearrangement) the cell now becomes a 7. Double Positive (DP) Thymocyte (meaning it expresses CD4 and CD8) in the cortex - At this point you have positive selection (ensure TCR can interact with self-MHC), Ag presentation by thymic cortical epithelial cells, and CD4/CD8 lineage commitment- MHC class preference this leads to 8. Single Positive (SP) CD4+ of CD8+ Thymocyte (in the cortex) - At this point these move through to the medulla where they undergo Negative selection(ensure that the TCR does not respond to self antigen), Ag presentation by BM-derived DCs and macrophages, and Central Tolerance- which finally yields a 9. Mature, naive, and resting CD4+ or CD8+ T lymphocyte leave the thymus from its medulla and go on to move to the periphery ** NOTE: this cells migration in development is cortex to subcapsular zone to cortex to medulla

Describe the schematic of ABO production

1. The cell with a precursor with alot of carbohydrate receives a fucose via fucose transferase - this gives substance H with an L-fucose attached (this is also an antign) - 2. Next Glycosyl Transferase can place the following terminal sugars (the A/B/O antigens are N-linked and O-linked oligosaccharides in either glycoproteins or sphingolipids found on the plasma membrane): - N-acetylgalactosamine: to yield A - D-galactose: to yield B - or Glycosyl transferase is inactivated to yield O- the terminal sugar is missing (due to a framshift mutation at delta G258)- the inactive fucose transferase is NOT allelic even though the phenotype looks like an "O" (locus heterogeneity) * NOTE: this is on ANY cell not just RBCs & that these sugar structures attached to the cell membrane differ at the terminal membrane because the allelic Glycosyl transferases producing A or B blood type differ in 4 amino acids (the two alleles differ in substrate specificity) *** If fucose transferase is absent- you will NOT get A, B, O but you will get the blood type Oh (Bombay phenotype)- higher incidence in people from India subcontinent- this is still part of the O blood type ** most other blood groups have antigens that are proteins

Neutrophils are active phagocytes of bacteria and other small particles- what are two reasons that they select bacteria/particles to be phagocytosed?

1. They are coated with antibodies and/or complement (i.e. opsonized with "eat me" signals or, 2. bc they are emitting chemoattractors ** chemoattractors/chemotactically active factors are important mediators of a number of processes because they attract the needed cell types to the area where they are needed. they function in: 1. immune responses 2. inflammation 3. wound healing 4. embryogenesis

B cells play a critical role in adaptive immune response. What are the main features that allow it to do this?

1. They recognize and respond to antigen 2. Secrete antibodies 3. Present antigen to T cells

Main cell types found in the thymus include:

1. Thymocytes (developing T lymphocytes) 2. Epithelial reticular cells (ERCs) - Which are stellate cells (arranged in a radiating pattern like that of a star), have light staining oval nuclei, prominent nucleoli, eosinophilic cytoplasm, contain KERATIN intermediate filaments in their cytoplasm (like epithelial cells) * 6 different types- that performs many diff. function in thymus 1. Forming Framework of thymus 2. Forms blood thymus barrier 3. Forms Hassal's (thymic) corpuscles

List the functions of blood

1. Transports O2, CO2, hormones, waste, nutrients, enzymes 2. Stabilization of pH and electrolyte concentrations in interstitial fluids 3. Regulation of body temperature 4. Blood acts as a pathway for migration of white blood cells between various connective tissue compartments of the body

What 3 major events occur in Hemostasis

1. Vasoconstriction 2. Platelet plug formation 3. Coagulation of blood - ALL beginning the moment the vessel is damaged- * coagulation takes longer, and is completed after vasoconstriction and platelet plug formation occur

What are the two classes of TCR

1. alpha:beta TCR on alpha:beta T cells** (will mostly be looking at these) - T cells that express alpha:beta TCRs recognize antigen in the form of peptides - peptides MUST be presented in the context of MHC (MHC-restricted) 2. gamma:delta TCR on gamma:delta T cells - gamma:delta T cells recognize peptide and non-peptide antigens - recognize antigen WITHOUT MHC - ex: IELs

Acute inflammation has 3 major components that occur in sequence- what are they

1. alterations in vascular caliber that lead to an increase in blood flow 2. structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation ** loosening of capillary endothelial cell tight junctions (Histamine increases the size of blood vessels) 3. MIGRATION of the leukocytes from the microcirculation (diapedesis), their ACCUMULATION in the focus of injury, and their ACTIVATION to eliminate the offending agent

3 direct tissue-specific effects of GH

1. decreases fat mass- puts it to work 2. increases glucose production and release at liver 3. increases protein synthesis in muscle

2 important properties of iron

1. electron carrier in redox reactions it can be converted from Fe3+ (Ferric form) and Fe2+ (Ferrous form) *** it can switch between the ferrous and ferric states to facilitate reduction/oxidation and electron transfer 2. Reversible oxygen binding Fe2+ + O2 --><--- Fe2+...O2 ** only ferrous iron (Fe2+) binds O2, ferric iron (Fe3+) does not

List the Cells of innate immunity

1. epithelial cells 2. phagocytes - macrophages - neutrophils - dendritic cells 3. NK cells, intraepithelial lymphocytes *** Note that generally lymphocytes are part of the Adaptive immune system but these are special lymphocytes that are innate

Iron is found in circulation or use in

1. erythrocytes ~1.8g 2. bone marrow ~0.3mg (marrow uses ~20mg/day) 3. myoglobin- 0.3-0.5g

Which hormones are produced in the Pars Distalis (Denohypophysis or Anterior pituitary)- larger part of the pituitary gland

1. growth hormone (GH) 2. prolactin (PRL) 3. luteinizing hormone (LH) 4. follicle stimulating hormone (FSH) 5. thyroid stimulating hormone (TSH) 6. adrenocorticotrophic hormone (ACTH)

Actions of Glucagon on Carbs

1. increase in glucose production by the liver and thus raises BG level 2. decreases glycogen synthesis 3. stimulates glycogenolysis 4. stimulates gluconeogenesis (mostly in liver)- the conversion of AA's into glucose, glycerol from TAG breakdown can also enter into gluconeogenesis ** many metabolic functions performed by the liver, that cells in the kidney have some reserve capacity to perform the same functions (this typically only manifests in sig. way only in extreme circumstandes (ex. some degree of renal gluconeogenesis during extended fasting) or in certain pathologies

What are the phases of Antigen Elimination

1. inject the antigen (this is when the amount of circulating antigen is at its highest) 2. Equilibrium phase: distribution of antigen between vascular and extravascular compartments 3. Catabolic Decay phase: elimination of antigen by innate cells; processing and presentation of antigen to T cell 4. Immune Elimination phase: the formation of antigen-antibody immune complex and removal of complex ( T cells activated- no free antibody, it is bound by remaining antigen- forms immune complex) ** after this there is NO more antigen- and any antibody produced will be noticed 5. The apperance of free antibody in serum ( Detectable antigen specific antibody) *** NOTE: antibody production starts at the end of phase 2 but there is NO free antibody during formation of immune complex in phase 3

Describe insulin receptor action

1. insulin binds insulin receptor 2. this recruits insulin receptor substrate 1 (IRS-1) 3. IRS-1 activates PI3-kinase, which then phosphorylates PIP2 to PIP3 4. PIP3 binds PKB aand phosphoinositide-dependent kinase 1 (PDK1) resulting in phosphorylation of PKB, and its activation 5. PKB phosphorylates TBC1D4, permitting rab activation on vesicles, and vesicle fusion with the plasma membrane

What are the main four things found in erythrocytes (RBCs)

1. plasma membrane 2. cytoskeleton 3. hemoglobin (this makes up 95% of RBCs protein content, 30% weight of RBC and its gives them their red color) 4. Glycolysis enzymes: since during formation in the bone marrow (erythropoeisis), developing RBCs lose their nucleus and organelles (only keeping their cytoskeleton)- this means RBCs also do not have any mitochondria, soooo the mature RBCs actually make ATP exclusively through cytoplasmic glycolysis using glucose in the blood plasma

Steps in making a blood smear

1. prick finger and collect a small amount of blood using a micropipette 2. place a drop of blood on a slide 3a. using second slide, pull the drop of blood across the first slides surface, leaving a thin layer of blood on the slide 3b. after blood dries, apply a stain briefly and rinse. Place a coverslip on top 4. When viewed under the microscope, blood smear reveals the components of the formed elements

2 components of Red bone marrow are

1. stroma: where the blood cells develop "land" 2. sinusoids: blood vessels where the mature blood cells enter the blood stream "SEA" ** in bone marrow both are inside the bony spicules

The way that eosinophils attack their prey is based on two considerations

1. their prey are (usually) eukaryotes like themselves 2. their prey are (usually) much bigger than they are, and too big to be phagocytosed

Describe the proscess of leukocyte migration in inflammatory response

1. there are signals that are sent to alert phagocytes when there is an infection (recieves inflammatory stimulus) 2. WBC moves to the margin this is called Margination- the WBC is "Rolling" along bc it is in a low-affinity state with integrins 2. Expression of adhesion molecules such as the integrine and selections by chemokines 3. Pavementing: WBC sticks to the endothelium - now there is a higher affinity state for the integrin - WBC stops at a junction and does diapedesis (exits from the blood vessel into the extracellular space) *** the margination and pavementing are due to high expression of selectins and integrin, leukocyte adhesion, and CD18/ICAM-1 ( a patient could have Luekocyte Adhesion deficiency due to lack of CD18) ** NOTE: there are some diseases where the WBC is UNABLE to squeeze through the endothelium and these individuals are more prone to infection 4. Once in the extracellular space Chemokines (ex. IL-8) drive chemotaxis of the phagocyte in a directional motion (the phagocyte moves in a straight line) to the microbe (other chemokines include: C5a, TNF-alpha, PG-E2, IL-1)

Under normal circumstances, how much calcium and phosphate is contained in bone

1.5kg

Concentration of calcium inside the cytosol is

10000 times lower than the outside - makes a powerful electrochemical gradient - to remove calcium from the cell against such a large concentration gradient, either primary or secondary transport (Na+/Ca2+ exchanger, Ca/Mg ATPase transporter)

All Hb proteins (should) consist of

2 alpha-like and 2 Beta-like subunits in one terameric protein ** if the production of Beta-Hb is reduced 10%, so will production of alpha-Hb *** if production of one is reduced more then 50% then a surplus of the other type will be seen (the surplus of the othery type of Hb chain often is at the center of the molecular mechanism of disease) ** remember that Hb is found in RBC with normal lifespan of ~120 days --> constant life long production - RBC lifespan is usually reduced in Hb diseases

Parvicellular hypothalamic-anterior pituitary system

2 diff hormones produced in the hypothalamus: - Growth hormone releasing hormone (GHRH): producing neurons in the arcuate nucleus of the hypothalamus- regulation of pituitary growth hormone (GH) secretion from the anterior lobe - Somatostatin (GHIH, SST) is mainly produced by neuroendocrine neurons of both the arcuate and periventricular nuclei of the hypothalamus- inhibition of pituitary growth hormone (GH) secretion from the anterior love

In person consuming a normal diet containing iodine, apprx what percent of this persons iodine is stored in the thyroid gland

2/3 or 67%

Who is mostly affected by iron deficiency anemia

20-25% of worlds babies have iron deficiency anemia - Normal infants: Hematocrit of 50-60% at birth, 35-40% at 6 months NOTE: breast milk has more bio-available iron in lactoferrin than cows milk 42% of women worldwide and 26% of men are "anemic" according to WHO - daily allowance in US is 8mg/day for men and 18mg/day for menstruating women ** iron supplements are given routinely during pregnancy (you need about a 4g increase to compensate for blood loss at birth and other costs of preganancy that req iron- note that you do save some iron via not menstruating, and contraction of maternal RBC mass after birth) In US, 9-11% of toddlers, adolescent girls and women of childbearing age or "iron deficient"

Congenital Adrenal Hyperplasia (CAH) is a deficiency of an enzyme involved in the synthesis of gluco- and mineralcorticoids, which is the most common type

21-hydroxylase deficiency is the most common MOA: cortisol deficiency --> leads to increased serum ACTH --> bilateral adrenocortical hyperplasia (hypersecretion of androgens) Presents as - female neonates with ambiguous genitalia - boys with precocious puberty (large penis, deeper voice etc) - possibilitity of life-threatening salt wasting, hyponatremia and hyperkalemia (since decreases aldosterone- sodium not being absorbed, but there is increase in K+ --> this is life-threatening!)

Antigen Presentation for T cell Activation requires

3 signals 1. Activaton (Antigen Presentation): engagement of TCR with MHC molecule 2. Survival (Co-stimulation): via CD28 engagement with CD80/CD86 (AKA B.7.1 and B7.2) 3. Differentiation: from cytokines (which will determine which effector T lymphocyte you develop into depending on which microorgnism you are dealing with. Ex: TH1, TH2, TH17, Tfh, Treg) NOTE: CD8 T cells require MORE co-stimulation than CD4 cells hence the CD4 help CD8 activation comes from CD4 TH1 cell help - CD40L present on the surfacre of activated CD4 cells *TH1 engage CD40 on the surface of the pAPC and, with cytokines such as IL-2 and IFN-gamma, leads to high enough pAPC CD80/CD86 expression to activate CD8 cells into becoming CTLs

The key to identifying neutrophils is the shape of their nucleus which is

3-5 lobed nuclei - they also have azurophilic non-specific granules (lysosomes) and neutral-staining specific granules

An antigen with 4 epitopes, has a valency of

4 ** so 4 antibodies can bind specific for an epitope

Basic structure of an antibody

4 chains: 2 heavy, 2 light Fab portion= amino terminal: increased variability to generate specific combos and it binds antigen ** Fab portion is made of both the heavy and light chains Fc portion= constant domain Hinge region: allows flexibility

How many liters of blood does the average adults have

5-6 liters of blood; About 7% of total body weight

Class I MHC bind to

8-10 AA long Antigenic peptides Class I MHC has 3 domains on alpha chain (AKA heavy chain): alpha1 & alpha 2 which make the peptide binding cleft (where the antigenic peptide binds to present TCR) and alpha 3 ** the whole molecule has 4 domains- the 4th domain contributed by Beta2m It is a heterodimer: 2 polypeptide chains: one alpha chain (variable ~6 diff. kinds- this gives specificiy)- it is associated with Beta2m (and this is same for every MHC-I)

Plasma is made up of

92% Water 7% proteins - 58% Albumins - 37% Globulins - 4% Fibronogen ** - 1% Regulatory proteins 1% other solutes - electrolytes - nutrients - respiratory gases - waste products

Metformin

A Biguanide MOA: reduced hepatic glucose production by limiting gluconeogenesis, stimulating hepatic fatty acid oxidation and reducing lipogenesis - also decreases intestinal glucose absorption and improves peripheral glucose uptake and utilization Pharmokinetics: - Oral bioavailbility= 70-80%, NOT protein bound, half-life 4-5hrs (taken twice a day), renal elimination NOTE: - Not likely to cause weight gain or hypoglycemia - Delayed progression to DM in those with IGT (impaired glucose intolerance) - Polycystic ovarian syndrome- infertility treatment

the O blood type is defined as the absence of

A and the absence of B

Describe the structure and composition of the Parathyroid Gland

A connective tissue capsule sends septa/trabeculae (T) into substance of gland; within which are located blood vessels 2 main types of cells within the gland 1. Chief cells (AKA principal cells) - more numerous and smaller than oxyphil cells - darker staining cytoplasm 2. Oxyphil cells -stain lighter, usually larger than chief cells -cell membranes clearly visible ** With increasing age- secretory cells are replaced by adipocytes - chief cells on EM examination contain secretory granules containing parathyroid hormone - the fx. of oxyphil cells is unknown

A chemical compound used to achieve some type of clinical goal

A drug- it can be: - inorganic compounds (ex. metals) - small or large organic molecules (comprised of C,H,O with minor additions of other elements) - bio-macromolecules (recombinant proteins; antibodies; polysaccharids; nucleic acids; etc.- also mostly organic molecules; some very large

Zellwegers syndrome

A general peroxisomal disorder - failure of peroxisomes to oxidize very long chain fatty acids Can lead to: - failure to thrive in infants - hepatomegaly - high levels of iron and copper in the blood - vision problems

Mifepristone

A glucocorticoid receptor antagonist - Progesterone receptor antagonist: pregnancy terminantion - At high doses: inhibits glucocorticoid receptor, NO effect on mineralcorticoid activity Use: - treatment of elevated blood sugar in patients with Cushing's Syndrome and type II Diabetes who failed or are not candidates for surgical treatment --- - this is well absorbed orally. Has a long half life 18-21 hrs. Hepatic metabolism to active metabolites. Fecal and renal elimination Side effects: - Nausea, loss of appetite, muscle and joint pain, fatigue, hypokalemia, irregular menstrual bleeding DO NOT USE in women who are or have any interest in acheiving pregnancy

Calcitonin

A hypocalcemic (and hypophosphate) hormone whose actions oppose PTH - released by thyroid parafollicular C cells - most potent peptide inhibitor of osteoclast mediated bone resorption - secretion mediated by serum calcium levels (level high= calcitonin increase, level low= calcitonin decrease) USES: - hypercalcemia - Paget's disease - Osteoperosis GIven via injection of nasal spray effective duration= 6 hrs - tolerance develops after a few days (for hypercalcemia) side effects: nauses, cramping, swelling, hypersensitivity reactions Added benefit to therapy: analgesis properties ** calcitonin inhibits osteoclastic activity via direct suppression of osteoclastic activity

What does a mature B cell express

A mature B cell expresses both IgM and IgD - they are considered "naive" or a "virgin" until it encounters its specific antigen And these Naive, mature B cells recognize antigen through BCR (surface IgM or IgD) - binding to antigen causes clustering, or cross-linking of BCR - this cross-linking results in generation of signals sent through BCR complex - the signals lead to changes of gene expression

Parathyroid hormoner (PTH)

A peptide hormone Low extracellular Ca2+: increases PTH - This also regulated secretion of PTH indirectly by increasing calcitriol production - High levels of calcitrol inhibit PTH secretion indirectly (by increasing plasma Ca2+)- So (high calcitrol; low PTH) * the higher the calcium ion conc. outside the parathyroid cells, the lower the cAMP and the higher the Ca2+ inside the cell - Gi inhibits adenylyl cyclase - Gq activates release of calcium * these brind down PTH concentration High extracellular Ca2+: decreases PTH - When calcium is low, there is high cAMP and low Ca2+, which stimulated PTH secretion - Gs activates adenyly cyclase: high cAMP - Gq is inhibited; low Ca2+ *** usually this hormone is in a tight range with calcium concentration cAMP= Ca2+ (normal PTH levels)- this is the "just-right" point

Why would you get a spleenectomy

A ruptured spleen can lead to life-threatening internal bleeding - because of open circulation in red pulp; if the splenic capsule is puncuted, the blood will flow directly out of the spleen - common inury-related causes of a ruptured spleen include MVA and severe blows to the abd during contact sports, such as football or hockey AFTER a spleenectomy: - aged RBCs are removed by macrophages in the sinusoids of the liver and bone marrow (RBCs still express PS eat my signal at end of lifespan) - diminished responsiveness to some vaccines - increased susceptibility to infection by bacteria and protozoa

Hypoglycemia

A serious and potentially fatal situation 3 clinical scenarios: - Insulinoma and nonislet tumor - treatment of diabetes mellitus - use or ingestion of a glucose lowering agent by a nondiabetic Treatment: Mild to moderate symptoms: oral glucose and 15-20g of carbohydrate Severe: IV glucose (dextrose) or glucagon injection --- Glucagon - produced by rDNA technology - interacts with glucagon receptor of cells (hepatocyte and other) - IM or IV injection for hypoglycemia by patient, family, friends - need adequate glycogen stores in liver - after parenteral dose, give glucose or food - side effects: nausea, vomiting

HbE

A substitution GAG --> AAG in codon 26 leading to Glu26Lys - this substitution leads to altered splicing (slow removal of intron 1, partial use of alternatic splice donor around codon 26--> some products are non-functional --> reduced concentration of Hb ** common in India and South east Asia, up to 30% allele frequency in some areas- most common Hb variant in california - Heterozygotes HbAE some protection against P.falciparum malaria *** this is a mixed occurence becuase HbE both changes an AA and reduces production HbE/HbA heterozygotes: near normal MCV HbE/HbE homozygotes: frequently benign (mild hypochromic microcytic anemia)- can be classified as mild Beta+ Thalassemia (Hb > 10g/dL)

Positive selection

A test of TCRs to ensure it can interact with self-MHC * this occurs deep in the thymic cortex * & the cells involved in this process are thymic cortical epithelial cells This process leads to - maturation of cells that can sufficiently react with the persons MHC allotypes and - also determines if a double-positive cell becomes a CD4+ cell or CD8+ cell - if TCR preferentially interacts with class I MHC molecule: cell commits to CD8+ lineage - if TCR preferentially interacts with class II MHC: cells comits to CD4+ lingeage ** if the TCR fails to interact with either MHC-I or MHC-II the cell dies

Negative selection

A test of TCRs to ensure that they do NOT respond to self-antigen ** mostly occurs in the medulla ** once key factor in this process is the ability of the cells to provide co-stimulation (CD80/86); thymocytes specific for self-MHC: self-peptide complexes that receive co-stimulation in the thymic medulla are signaled to die, thereby eliminating those positively selected thymocytes that are self-specific and could potentially lead to autoimmune disease ** Negative selection is the main driving force behind the development of central tolerance, i.e. the process by which one's immune system tolerates one antigens by eliminating most self-reactive T lymphocytes in the thymus

Which donors would be compatible with a 24 year old women with blood type A, Rh-

A, Rh- O, Rh- *** Type A blood means it excludes anything with a B *** Rh- means it CANNOT recieve Rh+

What are 2 ways of shutting off a T cell if it is NOT going to die on its own?

A. Cell intrinsic inhibitory signal - Once T cell activated by APC it expresses CD28 which responds to B7, but once activated it also starts to express CTLA-4 - CTLA-4 uses the same ligand as CD28 so there is a competition between the two - If the affinity for CTLA-4 for B7 (AKA CD80/CD86) is much greater than that of CD28- this switched off the T cell activation (signal is blocked) * CD28 usually provides T cell activation * if you increase the avidity of CD28 that would maintain the T cell active * As long has you have increased inflammation, you have increased B7 this increases the chance that CD28 will bind rather than CTLA-4 * decreased inflammation, decreased B7 switch back to CTLA-4 being more likely to bind and you turn off the CD8 or CD4 cell --- B. Blocking and removing B7 on APC - increased CTLA-4 captures B7 becfore the activated T cell gets its CD28 engaged (this is a treatment used in many autoimmune diseases and tumors) - this reduces B7 costimulation ex. Activated T lymphocytes also express other types of inhibitory receptors, PD-1 and PD-2, whose ligands are PD-L1 and PD-L2 respectively; PD-1/PD-L1 is particullary important in therapeutics - engagement of PD-1 by PD-L1 leads to termination of T cell activation in a manner that is similar as that seen for CTLA-4

Insulin activates protein phosphatase, which dephosphorylates acetyl CoA carboxylase (ACC). This activates

ACC and generates malonyl CoA, the substrate for fatty acid synthesis. - The malonyl CoA also will inhibit Carbitine Palmitoyl transferase I (CPT1)

CRH from the hypothalamus causes release of

ACTH (aka corticotropin) from the anterior pituitary - works on the adrenal cortex to release cortisol and androgen

Cortisol has feedback inhibition on

ACTH from the anterior pituitary and CRH from the hypothalamus

ACTH activates what enzymes that is responsible for increasing glucocorticoids

ACTH from the pituitary activates desmolase Cholesterol is converted to progestins via desmolase - progestins than can become Androgens or glucocoritcoids ** all in the adrenal gland ***** glucocorticoid then have feedback inhibition in the pituitary to decrease the amount of ACTH that is secreted

Hormone action is dependent on the concentration and the receptor density at the site of

ACTION, not in the plasma - Systemic (plasma) concentrations of "locally-acting" biomolecules likely do not represent the true level acting at the target site beacuse the biomolecules binds rapidly with receptors upregulated at the site of release, thereby keeping "escape" into the systemic concentration at a minimum ** systemic concentrations of endocrine (hemocrine) "hormones" represent the level of hormone acting on most tissues distributed throughout the body *** For most water-soluble hormones that ARE classic endocrine hormones, the amount in the plasma should be proportional to that in the fluid surrounding the target cells

What is the function of Factor I?

AKA C3b/C4b inactivator - it is a trypsin-like serine protease that accelerates the decay of C3b and C4b; it acts by cleaving C3b to yield iC3b and C3f (membrane-bound and fluid phase), as well as C4b to yield C4c and C4d

Addisons disease

AKA primary adreal insufficiency (primary adrenal hypofunction) Adrenal tissue does NOT respond to ACTH - low production of aldosterone and cortisol - little to no feedback of ACTH secretion - ACTH levels in plasma are far above normal

BCRs bind antigen

ALONE * they do not have MHC restricted presentation like TCRs

Which is elevated in bone disease GGT or ALP

ALP!! GGT and ALP are BOTH increased in bile duct disease but GGT is NOT elevated in bone disease like ALP is sooo.. - In diseases of the bile duct BOTH GGT and ALP are raised - In diseases of the bone the GGT is NORMAL and the ALP is raised

The lysosomes (primary granules) of all leukocytes stain

AZUROPHILIC ** a reddish blue from binding to azures, substances formed when methylene blue is oxidized ** RBCs DONT have lysosomes so they DO NOT stain with this

Hematocrit or Packed Cell Volume (PCV)

Accurate, simple screening test for anemia - volume of blood occupied with cells as opposed to serum-

Conversion of acetyl CoA to malonyl CoA is the rate limiting step in fatty acid synthesis. Which enzyme catalyzes this reaction

Acetyl CoA carboxylase

Name of an enzyme that was previously used to diagnose prostate cancer

Acid phosphatase (ACP) * Alkaline and acid phosphatases are a group of enzymes that display maximum activity at pH 5 or 10 * they are attached to the cell membrane, suggesting an association between their activity and membrane transport It is found in the cells of the: - Prostate (prostate specific antigen- PSA: tumor marker) - Liver - Erythrocytes - Platelets - Bone

Growth Hormone and Prolactin are

Acidophils (body and breast are pink)

What occurs post- activation of the B cells

Activated B cells undergo proliferation and clonal expansion (make lots of copies of themselves) and Activated B cells undergo specialized method of improving antibody molecules such as: - somatic hypermutation (IgM --> IgD) - driven by AID - affinity maturation (IgD has higher affinity)- increasing the number of hot spots available making the antibody molecule more AVID, also increasing the number of CDRs (After 2 weeks after primary immunization you have IgM/IgG- IgG has high affinity and high half life) - isotype (class) switch: this process involves looping out fragments in order to switch isotype class (remember you go with the C that is closest to VDJ when deciding isotype)- in this process the Fab region stays the same- you are just switching class.

The process of somatic hypermutation and isotype switching are mediated by what enzyme

Activation-induced cytidine deaminase (AID) - the synthesis of this enzyme is controlled by IL-4 and CD-40 activation signals ** remember CD40 and CD40L are what interact ** these above conditions are needed for hypermutation to occur -------- AID functions in activation induced deamination of cytosine to uracil which leads to hypermutation- these mutations result in changes of the affinity of the antibody I.e. - These base changes lead to altered binding affinities - those B cells with improved affinity will be clonally selected and will proliferate ** if affinity had become lower the cells would be deleted ** if the affinity has increased you could make a high affinity antibody

Aquired/ Adaptic Immunity can be further subdivided into what two types of responses

Active and Passive Response (both can be natural or artificial) Active (make own antibodies) - Natural: exposure to infectiour agent (ex. cold/infection) - Artificial: immunization (ex. vaccine) Ex: all residents of a nursing home inoculated with an H3N2 influenza-A preparation. What type of immunity is stimulated by this procedure= artificial active **** this gives memory Passive (recieve ready made anitbodies- serum (antibodies) from an immune individual) - Natural: maternal antibodies (ex. breast feeding) - Artificial: antibodies from other sources (ex. recieving anti-tetanus shot after cutting yourself with something rusty) ** passive DOES NOT have memory BOTH ACTIVE AND PASSIVE HAVE SPECIFICITY

Difference between acute (overdose) and chronic (hemochromatosis) iron toxicity

Acute (overdose): - most common in young children who accidently ingest iron tablets (as few as 10 can be lethal) - children experience necrotizing gastroenteritis with vomiting, abd pain and bloody diarrhea. In some cases severe metabolic acidosis, coma, and death may occur - whole bowel irrigation should be used to remove unabsorbed pills and Deferoxamine can be given to bind iron - activated charcoal binds to most toxins but does NOT bind iron Chronic (hemochromatosis): - excess iron is deposited in heart, liver, pancreas and other organs (can cause damage to these) - most commonly seen in pts. with inherited hemochromatosis and pts who receive many red cell transfusions over a long period of time (ex. individuals with beta-thalassemia) - Chronic iron overload can be treated with oral Dferasirox or parenteral Deferoxamine - Chronic iron overload in the absence of anemia is most efficiently treated with intermittent phlebotomy. One unit of blood can be removed every week until the excess iron is removed

Neutrophilic Leukocytosis can be due to

Acute bacterial infections, especially those caused by pyogenic organisms; sterile inflammation caused by for exampl, tissue necrosis (myocardial infarction, burns)

IL-1 and IL-6 when acting on the liver produce

Acute phase proteins which further assist the immune response

Anything that is a product of T lymphocytes is part of the

Adaptive Immune System

Chronic therapy for cushing disease (or syndrome) cannot be stopped abruptly because one could end up with

Addisionian Crisis (so must taper off the dose) * Treatment for Cushing Syndrome or Disease include: - Surgical options to remove primary cause of tumor (must give steroid post surgery) - Slow tapering of pharmacologic glucocorticoid - Inhibitor of ACTH secretion - Inhibitory of adrenal steroidogenesis

Chronic Adrenal Insufficiency

Addisions Disease - hair loss - blurry vision - abd pain - decreased appetite - darkening of skin (hyperpigmentation) - shaking or tremors - anxiety Congenital Adrenal Hyperplasia ** similar symptoms as acute but with lesser severity than acute adrenal insufficiency Require chronic - Glucocorticoid: increase dose in times of illness, stress, or surgery - Mineralcorticoid: increase does in times of intense exercise, sweating, or diarrhea - Liberal salt intake diet

L-selectins on lymphocytes bind ______ on HEV endothelial cells so they will leave bloodstream (*Lymphocyte Homing)

Addressins ** these are what attracts lymph out of blood

Lipoprotein Lipase mediates uptake of fat in the fed state principally in

Adipose tissue ** lipoprotein lipase is located in the capillary lumen of the target tissue - there is can interact with lipoprotein particles and execute its enzymatic activity on the TAGs in the core of the lipoprotein particles. It is tethered by binding to heparan sulfate glycoproteins or binding to a specific binding protein

Treatment for Adrenogenital Syndrome (aka congenital adrenal hyperplasia)

Administration of cortisol - causes the feebadk inhibition on the pituitary needed to drop ACTH levels ** remember this syndrome was caused by an inhibition of glucocorticoid production (which would usually feedback inhibit pituitary to stop ACTH buildup- butt in this syndrome ACTH is accumulating along with increased production of androgens)

Describe the integration of the Adrenal Medulla and the Adrenal cortex in the stress response (stress response is mediated both acutely and chronically by adrenal gland hormones)

Adrenal Medulla (*acute- first to respond in sympathetic response)- short term flight or fight or alarm stage with use of epinephrine and norepinephrine - changes end immediately when stressor ends Adrenal cortex- long term adjustment or resistance stage (CRH from hypothalamus --> ACTH from pituitary --> Cortisol released from adrenal cortex) - AA turned to as primary food source for cells - muscle wasting and weakness - inhibition of functions that are not essential to the body like reproduction (via inhibiting the hypothalamus' release of hormones) ** NOTE: processes induced by glucocorticoid are long-term because once the proteins causing these functions are made, theyll kepp working until they break down themselves or are recycled- which can take a while ** best to think the EPI, NE, and cortisol all work together to respond to stress

11-Hydroxylase deficiency

Adrenal androgens are overproduced Accumulating deoxycorticosterone acts as a mineralcorticoid - virilization - hypokalemia (opposite of the hyperkalemia that was caused by 21-hydroxylase deficiency) - edema, hypertension (because the accumulating deoxycorticosterone retains sodium and water)

How tightly a drug binds to its receptor

Affinity - potency of a drug is directly related to its affinity for the receptor producing the pharmacological effect

Affinity vs Avidity

Affinity: how tight a molecule binds another molecule (how tight is the interaction) vs Avidity: how much binding there is.. (thought of in terms of valence) - this is "How many things are grabbing" (ex: grabbing something with 5 fingers will ensure that you can lift it)

In peripheral tissue, such as an infection site, TH1 cells are presented

Ag by macrophges (MHC-II restricted) and in return, TH1 cells provide CD40L, IFN-gamma, and TNF-alpha among others to the requesting macrophage to help it increase its microbicidal capacithy ** CD4 T lymphcyte helper (TH1) cells also help to activate CD8 cells via stimulating APCs with their CD40L to increase B7

Which live longer: agranulocytes or granulocytes

Agranulocytes live much longer!!! (lymphocytes and monocytes) - Lymphocytes can live a few days to a number of years if they become memory lymphocytes - Monocytes can live a few days in the blood, but several months to years in connective tissues

Describe a model for improvement

Aim: What are we trying to accomplish? Measures: How will we know that a change is an improvement? Change: What change can we make that will result in improvement?

Colloid Osmotic Pressure refers to

Albumin trying to pull H2O into the blood- this opposes hydrostatic pressure which is H2O trying to get out of the blood vessels * on the arterial end: you have more hydrostatic pressue than the venous end - but the oncotic pressure stays SAME on both sides- because amount of Albumin does not change ex: An alcoholic patient with low albumin in blood will have a low oncotic pressure so he will be losing alot of H2O= edema ex: Pt bleeding profusely, do they have less oncotic pressure? NO! bc the concentration of Albumin does not change- it is only the amount that is less

An AST/ALT ratio of 2.0 or higher is indicative of

Alcoholic liver disease * the normal AST/ALT ratio is approximately 0.8

The primary mineralcorticoid

Aldosterone - exclusively synthesized in Zona Glomerulosa - essential for life - promotes sodium retention and potassium excretion by the kidney, in the collecting duct - it also increases H+ excretion there - other tissues affected: GI tract, sweat glands, and salivary glands epithelil cells, to enhance absorption in the former and modify exocrine secretions in the latter - expands ECF volume (thus increase blood volume & blood pressure) ---- NOTE: both cortisol and corticosterone have significantly less potent mineralcorticoid effects but they too can slighlty affect sodium and water retention under physiological conditions (about 10% of the total mineralcorticoid activity), and to a greater degree in certain pathologies (ex. Cushings syndrome)

Mineralcorticoids include

Aldosterone (from ZG)

What enzyme can be used to diagnose bone and bile duct disorders

Alkaline phosphatase (ALP)

Describe Hb Gene Clusters

All alpha-like genes in one cluster, all Beta-like in another (on different chromosomes) - the locus control region (LCR) upstream (5') of it all - progression so that more downstream genes are more heavily expressed later in development

What property is exhibited by the fact that each B cell productively rearranges a single H and L chain allele

Allelic exclusion

Eosinophilic leukocytosis (eosinophilia) can be due to

Allergic disorders such as asthma, hay fever, parasitic infestations; drug reactions, certain malignancies (ex. Hodgkin and some non-hodgkin lymphomas); autoimmune disorders (ex. pemphigus, dematitis herpetiformis) and some vasculitides; atheroembolic disease (transient)

Class II MHC consist of 2 polypeptide chains which are

Alpha and Beta chain (both polymorphic) - both chains are also membrane-spanning polypeptide chains and both contain two domains: alpha1 and alpha2, as well as the Beta1 and Beta2 domains - Once again, the complete class II MHC is a heterodimer - Peptide binding domains are the alpha1 and beta1 domains - Class II MHC bind short peptides of at least 13 AA and up to 21 AA in length (hence there is a greater variation in the lengths of peptides presented by MHC-II, as compared to those presented on MHC-I

What are the main differences in Severe alpha and beta Thalassemia

Alpha thalassemia: surplus beta chain (and gamma chain), forms homotetramers and has precipitation but less of the surplus Beta thalassemia: surplus Alpha chain, does NOT form homotetramers, has precepition all surplus

Decreased alpha-globulins can lead to

Alpha1-antitrypsin deficiency

Erection thats lasted for >5hrs accompanied by penile pain and tenderness could be caused by

Alprostadil - given intraurethrally

What is the first complement cascade to be activated

Alternative Pathway 1. C3 spontaneously cleaves "tick over"- if this takes place close to the membrane then C3b binds the membrane and Factor B comes in and binds C3b 2. Factor D (a plasma serine protease) comes in and cleaves Factor B- stabilization is done by properdin - this cleavage yields C3 convertase *** C3 convertase is the first amplifying stage of complement- it takes more C3 and deposits more C3b and releases more C3a - C3b: increases opsonization and increases opsonin on the surface of target - C3a: drives more inflammation 3. C3b covalently binds to cell surface and binds to C3bBb to form C5 convertase *** C5 convertase is the 2nd ampliflying step- increases that amount of C5 being cleaved to C5b and C5a - C5b goes to the late stage and triggers formation of the pore that is meant to lyse the bacteria NOTE: - These alternative pathway amplification stages (C3 convertase and C5 convertase, also yield a great amount of soluble C3a and C5a respectively, thereby stimulating further inflammation) - C5b initiates the terminal phase of complement activation resulting in membrane attack complex (MAC) and the creation of pores in surface that trigger cellular lysis

3 major classes of "hormones" based on structure

Amines: derived from one or two modified AA's, usually tyrosine (or tryptophan). Can be hydrophilic or hydrophobic (ex. Epinephrine) Peptides: derived from 3 or more linked AA. Usually hydrophilic (ex. Oxytocin) Steroids: derived from cholesterol, includes Vitamin D3. Hydrophobic (ex. Cortisol) --- Plus 2 "hormone-like" classes: - Prostanoids: derived from fatty acid (arachidonic acid), most are cytokines - Gases: ex. Nitric Oxide (NO), hydrogen sulfide (H2S)

Name 3 classes of hormones

Amino acid derived hormones - catecholamines (ex. epinephrine, norepinephrine) - serotonin - thyroxine and triiodothyronine Protein/peptide hormones - insulin - growth hormone - vasopressin Steroid and lipid derived hormones - androgens (testosterone and DHEA)- (steroid derived) - prostaglandins and leukotrienes (lipid derived)

Drug-induced hyperprolactinemia

An adverse effect of a variety of drugs that are D2 antagonists - Antipsychotics (ex. Haloperidol) - Metoclopramide (D2 antagonist targeted at CTZ and gastric emptying) * Primary clinical symptom of this adverse effect is gynecomastia and/or galactorrhea

Deficiencies in glycogen branching enzyme that generates the alpha (1-6) glycosidic bonds can lead to

Andersen Disease

RBC count is decreased in

Anemia

Angiotensin I is converted to angiotensin II via

Angiotensin converting enzyme (from the lung) ** Angiotensin II does vasocontriction, increases blood pressue, remodeling of the heart especially in heart failure

Name for condition in which red cells are of unequals size. - it is a feature of many anemias and other blood conditions

Anisocytosis

A drug which, when bound to its receptor (or target) fails completely to produce any activation of that receptor AND blocks the effect of an agonist

Antagonist - Competitive: compete with agonist for the agonist binding site, increased agonist concentration can overcome competitive antagonists - Non-competive: either bind to site on the receptor that is separate from agonist binding site and allosterically reduce the effect of the agonists or they bind irreversibly and reduce the effect of agonist; when these bind the agonist concentration does NOT alter the effect of this type of antagonist

The junction between nervous and endocrine systems

Anterior Pituitary 1. Nervous tissue in the hypothalamus releases specific releasing and inhibiting hormones into a hypophyseal portal system 2. Specific cells in the anterior pituitary respond by secreting hormones that are often both tropic and trophic - Tropic: any hormone whose target tissue is another gland. All of the hypothalamic releasing and inhibiting hormones and most of the anterior pituitary hormones are tropic hormones - Trophic: any hormone which stimulates growth and differentiation of its target tissues. In clinical situations where the trophic hormone is not present, the target tissue will often experience apoptosis of its preexisting cells and that tissue will atrophy as those cells are not replaced *** some hormones can be both (ex: TSH has another gland as its target (thyroid, so tropic) and can cause follicular tissue there to grow and differentiate (trophic) ** most of hypothalamic releasing hormones are tropic. Most are also trophic, such that without them most secretory cells in the anterior pituitary DO NOT function 3. Pituitary hromones then affect target organs throughout the body 4. Some of these target organs are glands, too 5. Ultimately body functions are controlled

Dopamine (DA) from the hypothalamus works on the

Anterior pituitary to INHIBIT release of prolactin which usually causes growth and milk production, immune and osmo-regulation ** dopamine inhibits an otherwise constitutive release of prolactin by activation of the dopamine-2 receptor (this release is usually controlled by combination of small stimuli from many hormones)

B- lymphocytes can transform into

Antibody-secreting plasma cells (in tissue) ** have extensice rER and "clockface" nucleus

When T cells develop in the thymus- they have to be educated and selected for. What does this?

Antigen Presentation does this - it gets rid of self reactive T-lymphocytes

Characteristics of Adaptive Immune responses

Antigen-Specific - Cells express a unique antigen receptor Called upon only when necessary Slow response Long-lived: - Second response against pathogen is better, faster, and stronger than first - "Immunological Memory"

It should appear valid that any blood recipient would be able to receive any blood once (this is true for most blood type including Rhesus) BUT this is NOT true because

Any of us carries antibodies against those A, B, or H antigens that we do not encode ourselves and this is probably due to cross reactions with bacterial antigens *** it is very important to note that we also have ABO antigens on other cells- and this is important to note in transplantation

Blind pouch off the cecum of the large intestine

Appendix - lamina propria and submucosa are generally FILLED with lymphocytes and lymphoid follicles - has high endothelial venules (HEVs) to bring in naive T and B cells from the blood *** the appendix is a significant part of MALT ** has a muscularis externa NOTE: peyers patches in the ileum had a muscularis mucosa

Testosterone becomes estradiol with the help of

Aromatase

Describe the blood supply of the pituitary gland

Arterial Supply -Superior hypophyseal artery (from internal carotid) supplies pars tuberalis and infundibulum. Also forms the primary capillary plexus in the median eminence - Inferior hypophyseal artery primarily supplies posterior lobe; with a few branches to the anterior lobe * Note: capillaries are fenestrated so they have many small channels with high vascular permeability which allows a rapid exchange of substances between the hypothalamus and the pituitary Venous Drainage - Hypophyseal portal veins drain primary capillary plexus (formed by superior hypophyseal artery) which delivers its blood into the second capillary plexus

Blood supply of the pancreas

Arterial: branches from the splenic, superior and inferior pancreaticoduodenal arteries Venous: from the body and tail join the splenic vein, and the pancreaticoduodenal veins drain into the superior mesenteric vein or portal vein

Thalassemia is a

Autosomal Recessive Disorder - due to absent/decreased synthesis of alpha-beta globin chains ** quantitative Hb abnormalities - Beta-thalassemia: failure of beta chain synthesis (common in black americans, greeks, italian, india and east asia) - Alpha-thalassemia: failure of alpha chain synthesis (common in south-east asia and in black americans) Fetal Hb: predominant in fetus, trace in adults (HbF- alph2gamma2) Adult Hb: 95-97% adult blood (HbA- alpha2beta2) Adult Hb2: 1-4% adult blood (HbA2- alpha2delta2)

Difference between BCRs and TCRs in the Cognitive Phase of Adaptive Immune Recognition

B cell recptor (BCR, immunoglobin, antibody)- bind antigen DIRECTLY (NO MHC needed, & it recognizes many different kinds of antigen) - Used by B cells to recognize antigens - in response to antigen they secrete antibodies T cell receptor (TCR)- MHC RESTRICTED- recognizes ONLY peptides on MHC - used by T cells to recognize antigen - in response to antigen they help other cells become cytotoxic (with cytokines and cell-surface interactions) - kill infected cells ** BOTH BCR and TCR belong to the IgSuperFamily - when you have an issue with BCR this can affect the TCR

What cells are part of Adaptive Immunity

B cells and T cells - along with their products

If V(D)J recombo events cannot take place due to the absence of RAG1 and RAG2 genes...

B cells and T cells will be affected

Mediators of Humoral Immunity

B lymphocytes ** these respond to extracellular microbes by secreted antibody which blocks infections and eliminates extracellular microbes

Which vitamin is covalently coupled to the acyl carrier protein?

B5 (pantothenic acid) is a constituent of CoA and of the acyl carrier protein- BOTH are required in fatty acid synthasis, BUT the B5 is coupled covalently to the acyl carrier protein

If you have an autoimmune disease due to activation of T cells. What are you going to want to target?

B7 - sequestering this will turn off the T cell if you do not need it

FSH, LH, TSH, and ACTH are

Basophils

The rarest leukocyte, less than 1% of the total leukocyte population

Basophils - have numerous basophilic (blue) granules in the cytoplasm that usually make it difficult to see the nucleus clearly - has an S-shaped nucleus, but you usually cant see it in light micrographs because of the granules ** the specific granules of basophils contain heparin and histamine (like mast cells)

Why are enzymes measured?

Bc the relase of enzymes from cells may indicate: - necrosis or severe damage to cells - increased concentration of enzymes in cells - duct obstruction (ex. in bile duct) - reduced urinary excretion

What are some associated clinical syndromes of Beta Thalassemia

Beta Thalassemia Major (Cooleys Anemia) - Beta+/Beta+ or Beta0/Beta0 or Beta+/Beta0 - severe - transfusion dependent Beta Thalassemia Minor/Trait - Beta+/Beta or Beta0/Beta - Mild anemia ---------------------- **Beta: Normal Beta-globin chain synthesis **Beta+: some beta-globin chain synthesis **Beta0: No Beta-globin chain synthesis --- Defective globin chains results in ineffective erythropoiesis due to precipitation of abnormal Hb's within newly formed RBCs and increased erythrocyte fragility

After birth you have a switch from the embryonic gamma in the liver and spleen to the

Beta ~ 3 months after birth , you also begin to see delta later on in life * NOTE that starting in the embryonic period and at full production at 2 months of life the alpha chain is present throughout a persons life span -- these expression switches involve epigenetics (methylation) of genes no longer needed ((this is NOT changing the DNA sequence BUT it changes access to the DNA and therefore changes the expression pattern of proteins))

Type II Diabetes Mellitus Drugs (have 9 different classes):

Biguanides - Metformin Sulfonylureas - Glimepiride - Glyburide Thiazolidinediones - Rosiglitazone Alpha-glucosidase inhibitors - Acarbose Incretin Mimetics - Exenatide - Liraglutide Gliflozine (SGLT2 inhibitors) - Canagliflozin Meglitinides - Repaglinide Dipeptidyl Peptidase-4 (DPP-4) Inhibitors): - Sitagliptin - Lingalipitin Dopamine-2 Agonist - Bromocriptine

The fraction of administered drug that reaches the general circulation in biologically-active form

Bioavailability - will be unique to each route of administration ** the IV bioavailability of ALL drugs is 100%

Hypoglycemia

Blood glucose <60mg/dL - when extreme is fatal quickly Causes: too little food, too much insulin or diabetes medicine, or extra activity Sxs - Shaking, fast HR, sweating, dizziness, anxious, hunger, impaired vision, weakness/fatigue, headache, irritable. [Euglycemia (normal glucose 70-110mg/dL) is always preferred]

How do epithelial reticular cells aid in forming the blood-thymus barrier

Blood- thymus barrier (formed by 3 structures): 1. Capillary endothelial cells linked by tight junctions 2. Dual basal laminae produced by ERC and endothelial cells 3. ERCs joined by desmosomes - also macrophages hover nearby to "gobble up" any antigens that manage to pass through this barrier ** the blood-thymus barrier regulates exchange of substances between the circulatory system and thymus, providing a sequestered environment for immature T cells to develop - the barrier prevents immature T cells from contacting foreign (non-self) antigens coming from the blood, because contact with "random" antigens at this stage will cause the T cells to die by apoptosis

Absorptive (fed) state

Bodys endocrine/metabolic status at the time when - energy levels in the gut and blood are very high, absorption occurring - typically lasts 2-4hrs after a meal (post-prandial period) - 5-6hrs for a very big meal - insulin promotes anabolism of target tissues - fuels are absorbed into cells and used and/or stored there

Post-absorptive state

Bodys endocrine/metabolis status at the time when - absorption is long over but energy reserves are still high - typically begins by about 4 hrs after a meal (big heavy meals may be about 6hrs) - glucagon is the primary hormone of the post-absorptive state (it may promote catabolism) - fuel is mobilized from storage sites for body-wide usage - eventually transitions into a starvation state over several days

One of the largest organs of the body, which is the main site of hematopoiesis in adults

Bone Marrow ! it is considered a type of connective tissue ** it is found in spongy/trabecular/canvellous bone and in the medullary/bone marrow cavity of the diaphysis

At about the 5th month of gestation the ___ becomes increasingly important hematopoietic tissue

Bone marrow ** remember 5 + 5

What should be administered to patients with severe hypothyroidism (myxedema crisis)

Both liothyronine and levothyroxine - bc the patients illness may suppress the abilitiy of target tissues to produce adequate liothyronine from levothyroxine alone - in addition, liothyronine can initiate more rapid responses than waiting for levothyroxine to be converted

Since Basophils closely resemble Mast cells of connective tissue and their basophilic granules look like those of mast cells; and their granules both also contain histamine and heparin. How are these two differentiated?

By their location! - If it is in blood- it is a basophil - If it is in connective tissue- odds are it is a mast cell because basophils are very rare in CT

The first protein to rise in an acute infection or inflammation, or response to injury

C-reactive protein (CRP) (the acute phase reactant binds extracts of pneumococal cell walls- CRP is usually increase in pneumococal infection/any inflammatory process) ex. in major surgery- wont discharge till CRP back to normal levels

Hereditary Angiodema (HAE) could be caused by a deficiency in

C1 INH deficiency - increase in edema fluid - edema in the skin and mucosa causing abdominal pain, vomiting, diarrhea, and obstruction of airways (potentially life-threatening) ** the contribution of C1 INH deficiency in HAE is really exerted through its effect on the contact system (kinin/kallikrein system); its contribution on the complement system is minor. - the vascular leakage in HAE is mainly due to lack of plasma kallikrein and factor XII inhibition, which leads to increased bradykinin (ex. C1 INH is also an inhibitor of plasma kallikrein and factor XII; its dysfucntion (either through low serum concentration of normal C1 INH (HAE type 1) or normal concentration of defective C1 INH (HAE type II) leads to increased bradykinin, the main vasoactive effector in HAE and, therefore edema

What is the function of C1 INH

C1 INH is a serine protease inhibitor (serpin) that prevents C1r2s2 from becoming proteolytically active by binding to and inactivating the active site of serine proteases (this process also results in the dissociation of the C1r2s2 tetramer from the C1q hexamer ** NOTE that normally C1q binds to antigen-complexed antibodies, resulting in activation of C1r2s2 ** C1 INH is an inhibitor of both the lectin and classical pathways of complement

All 3 complement pathways (Classical, Lectin, and Alternative) all converge at

C3 cleavage into C3a and C3b - which lead to the activation of late stages of complement (TERMINAL PHASE OF COMPLEMENT ACTIVATION (C5-C9) which form the membrane attack complex (MAC)- culminates with a pore in the membrane that lyses the target cell ** soo all 3 pathways lead to C3 convertases and C5 convertases, with the terminal phase (membrane attack complex or MAC) being identical for all 3 pathways

Complement uses

C3a and C5a

C3 convertase termed as C4bC2a is the same thing as

C4bC2b - note that C3a is soluble and C3b is found on surface of pathogen BUT - C2a is on the surface of the microbe, and C2b is the soluble fragment (so for this exam just remember that C3 convertase whether it be C4bC2a or C4bC2b are BOTH virtually the same thing )

Chemokines exert their action through concentration gradients and ligand-receptor interactions. Can you name two structural families of chemokines?

CC-chemokines - signal through CCR (cystiene-cysteine) - includes: MCP-1, MIP-1, RANTES, eotaxin CXC- chemokines - signal through CXCR - includes CXCL8 (aka IL-8)**

Professional Ag presenting cells present Ag to

CD4 T lymphocytes *This leads to REGULATION of the imune system with: - Th cells: inflammatory - Tfh cells: have germinal center and activating B cells - Treg cells: make sure there is NOT too much inflammation- brings back immune system to normal ** MHC-II presentation: exists for purpose of regulating immune response

Th1 cells are presented Ag by macrophages (MHC-II restricted), and in return these Th1 cells provide

CD40L, IFN-gamma, and TNF-alpha among other things to the requesting macrophage to help it increase it microbicidal capcity ( aids in killing intracellular pathogens) ** remember that a macrophage can secrete IL-12 which affects NK cell to release IFN-gamma which can increase the killing capacity of a macrophage Macrophage increases its killing capacity by: - production of ROS, NO, and increased lysosomal enzymes: leads to killing of microbes in phagolysosomes (effector function of macrophages) - secretion of cytokines (TNF, IL-1, IL-12) and chemokines: TNF, IL-1 do leukocyte recruitment (inflammation) and IL-12 does TH1 differentiationa and IFN-gamma production - increased expression of B7 costimulations, MHC molecules- increased T cell activation (amplification of T cell response

What is the marker for NK cell

CD56 * it is NOT found on any other cell but a NK cell

Somatic nucleated cells (including pAPCs) present antigen to

CD8 T lymphocytes - leading to the elimination of INFECTED or TUMOR CELLS- ** MHC-I presentation: it exists for purpose of killing infected or transformed cells

In the case of Tumor cells what may be turned off

CD8 T lymphocytes- which should normally act in their removal ** treatment would be aimed at overturning this turning off of CD8 cells to keep them on to kill tumor cells

Intraepithelial T lymphocytes (IEL) mostly express

CD8 on gamma:delta T cells - these kill off infection in epithelial cells via perforin/granzyme and Fas-dependent pathways * these are recognized via MHC-I but IEL DONT require activation by APC but they also have an activating receptor found in NK cells (IELs are like hybrid of CTLs and NK cells)- they recognize and kill altered cells in the same way - these are activated in MALTs and the skin - they undergo negative selection in thymus, so few self-reactive IELs leave the thymus Type b IEL are the ones that are gamma:deltaTCRs- these DO NOT bind conventional peptide: MHC-I ligands; instead, they bind non-classical MHC-I molecules and other ligands (ex. PAMPs) --- because of this there is little potential for autoimmunity

Cytokines involved in Apoptosis

CD95L/CD95 (FasL/Fas) TNF-alpha/TNFR-1

NonSteroidal Anti-inflammatory drugs (NSAIDS) such as acetylsalicylic acid, ibuprofen, and acetaminophen are over the counter

COX-1 and COX-2 inhibitors that are used for treating many minor (fever and pain) and major conditions (gout, arthritis, etc.) **** COX-2 is a prostaglandin (it is an IL-1Beta responsive gene turns on in inflammation)

What is part of the B cell receptor (BCR) complex that is necessary for B cell activation?

CR2 (CD21)

Cytokines involved in Chemotaxis

CXCL8 (IL-8)

Preferred drug treatment for hyperprolactinemia

Cabergoline (dopamine receptor agonist) - higher affinity and greater selectivity for D2 receptor (just like Bromocriptine) - has greater efficacy and fewer side effects - it is well absorbed with extensive 1st pass metabolism through liver - half life 63-69 hrs (once a day dosing is sufficient) - normalizes prolactin in 80%, decreases tumor size in significant number Adverse effects: - nausea, vomiting, headache, postural hypotension, dizziness - start low and titrate- tolerance over time Other uses: - use in Parkinsons Disease (like Bromocriptine) *** NOTE: Bromocriptine was in addition used to treat uncontrolled Type 2 diabetes, Cabergoline is NOT

When lab values are obtained for "vitamin D", what compound is being measured

Calcidiol ( 25 (OH)D )

Insulin administartion types and factors that affect its absorption

Can be injected with - pre-filled pen - with a synringe - insulin pump Factors that affects its absorption: - Site of injection - Type of insulin - Subcutaneous blood flow - Smoking - Muscle activity at site of injection - Volume and concentration of insulin - Depth of the injection

Adrenal Hyperfunction

Can be primary or secondary just as in other tissues with hypothalmopituitary control - usually presented as hypersecretion of cortisol (CUSHING SYNDROME), so if primary cortisol is up and ACTH is down, and if secondary both cortisol and ACTH are elevated

Gliflozine (SGLT-2 inhibitors) - includes Canagliflozin

Canagliflozin MOA: reduce rate of glucose reclamation in the proximal tubule and lower blood glucose by promoting urinary loss Pharmacokinetics - orally absorbed independent of food - 90% protein bound - Half life ~12 hrs (OK for once daily dosing) NOTES: - risk of bacterial and fungal UTI - Osteoperosis - risk of amputation and reduce CVD (cardiovascular event) - hypoglycemia rare alone; increased when combined with other drugs

Malonyl CoA inhibits

Carnitine Palmitoyl Transferase I (CPT I) to block movement of fatty acids to the mitochondrial matrix

Difference between catecholamines (e.g. epinephrine) and glucagon

Catecholamines have strong effects on both adipose tissue and muscle, while glucagon effects are marginal in adipose tissue, and, for lack of receptors, nonexistent in muscle - so catecholamines can work in adipose tissue and muscle whereas glucagon can barely in adipose, and can not at all in muscle

Infectious Mononucleosis (IM)

Cause: - EBV (herpes virus)- most common cause - CMV: less common: heterophila-ve IM Clinical feature - in adolescents or young adults - aka "kissing disease" - classic triad: fever, pharyngitis (sore throat with gray-white membrane on tonsils), lymphadenopathy (posterior auricular), and sometiems hepato-splenomegaly ------- Peripheral blood smear will show >10% atypical lymphocytes - Downey cell cytoplasm ~ "ballerina skirt" appearance - resemble monocytes (thus called mononucleosis) ---- Pathogenesis: - EBV invades B-lymphocytes via CD21 receptors - CD8 T-lymphocytes respond against B cells to form atypical lymphocytes **** abnormal looking cells are T cells even though the virus is invading the B cells*** ----- Lab diagnosis: Mono-spot test: - Rapid slide test based on Paul-Bunnel reaction - Heterophile antibodies (non-specific IgM) - react with other species i.e. RBCs of sheep, beef and horses - few patients may be negative in 1st week- repeat may be necessary Specific tests - IgM antibodies against EBV viral antigen: most helpful in acute disease --- Potential complication: splenic rupture, this is why patient should avoid contact sports for 6 weeks --- Course: - self-limited - resolves within 4-6 weeks

Acute lymphadenities

Caused by - Bacterial infection: focal involvement- cervical lymphnode draining infected teeth, tonsils, axillary/inguinal lymph node draining infections in extremities - systemic viral infection: generalized lymph node involvement C/F: - enlarged, painful lymphnode with red overlying skin - can form draining sinsues; heal by scarring ---- Lymph node morphology - gross: swollen, gray-red congested - microscopy: prominent reactive germinal centers or necrosis, neutrophils, macrophades with ingested debris

Central vs Nephrogenic Diabetes Insipidus

Central: inadequate vasopressin secretion Causes: - injury, surgery, trauma to head in regio of pituitary or hypothalamus - tumor - cerebral aneurysms - CNS ischemia - brain infection (i.e encephalitis) - familial (autosomal dominant) - idiopathic Treatment: - Desmopression (variety of dosing options, the dose is individualised to response) - fluid restriction Nephrogenic: insufficient renal response to vasopressin (we wont be tested on details of this at the moment) ** to distinguish these from eachother give the pt. Desmopressin (if desmopressin works pt ahas central) Both: - impaired renal water conservation - excrete large volumes (>30ml/kg/day) of dilute (<200mOsm/kg) urine: polydipsia ** you can distinguish Diabetes Insipidus from Primary polydipsia through measuring the plasma osmolality

What are the specific pharmacokinetics to each Second Generation H1 antagonist?

Cetirizine: - High bioavailability (~70%) - No p450 metabolism; minor hepatic glucuronidation and oxidation - 70-85% excreted in urine, remainder in feces Fexofenadine: - shouldnt be taken with fruit juices which may inhibit absorption - is a CYP3A4 substrate, but only ~5% is metabolized - most is excreted unchanged in feces; about 5% in urine Loratadine: - extensively metabolized via CYP2D6 and 3A4 to an active metabolite - excreted about equallly in urine and feces ---------------- All 3 of these Second Generation H1 Antagonists are therapeutically used for: - relief of allergic symptoms due to seasonal allergies - pervention and relief of urticaria (hives)- but oral administration, not topical Possible adverse effects: - nausea and GI symptoms - drowsiness Precautions: - cross the placenta; fexofenadine has been shown to be teratogenic in animals (category C) - cetirizine and loratadine are category B

McCardles syndrome

Characterized by temporary muscle weakness and cramping with exercise (recovers from exercise then gets exhausted quickly again) - due to a congenital deficiency in Glycogen Phosphorylase

What drives the separation in electropheresis?

Charge difference! NOT size ** Ex: Electrophoretic separation between HbA and HbS is possible because the sickle cell mutation (Glu -> Val) removes a negative charge from the Beta chain (remember that a cathode= negative charge entering)

Neutrophil behavior in inflammation

Chemical messengers are released by basophils, mast cells, blood plasma, and damaged tissue. These inflammatory chemicals stimulate leukocyte margination (adhesion to the capillary wall), diapedesis (crawling through the capillary wall), chemotaxis (movement toward that source of the inflammatory chemicals), and phagocytosis (engulfing bacteria or other pathogens)

Synthesis pathway for VitD

Cholecalciferol from the sun --> Calcidiol in the liver --> Calcitriol in the kidney * in the kidney a precursor molecule can be modified two ways- one is the active form of Vit D and other is inactive - what is this precursor molecule? Clacidiol, and the carbon hydroxylation that is specifically stimulated by PTH and inhibited by FGF-23 is on carbon 1

Vitamin D supplements

Cholecalciferol= Vitamin D3 (animal form, potency higher) Ergocalciferol= Vitamin D2 (plant form, used for food fortification, and in US for high dose VitD injection) ** lab values do not discriminate between these two ----- - orally absorbed - sequestered in fat (fat-soluble); obestiy may lead to functional VitD deficiency - very long hald life - hepatic metabolism then renal metabolism Adverse effects: - Vit D toxicity - Hyperphophatemia Drug interactions: - sunscreen may prevent adequate vitD formation ==== Primary use - replacemnet therapy to prevent/treat osteomalacia and rickets (undermineralized bone) - hypoparathyroidism - osteoperosis Other uses: - Psoriasis - Some cancers - Supports innate immunity * for all these uses it is 1,25 (OH)2D (calcitriol) that is the active form of the drug

Steroid hormones are usually derived from

Cholesterol using several enzymes (3beta-HSD, CYP450 and others) it can make: - Progesterone which can become Aldosterone, Cortisol, and Testosterone - Testosterone then goes on to become Estradiol (E2) -------- Congenital Adrenal Hyperplasias (CAH) - deficiency in cytochrome P450 enzymes or - deficiency in 3beta-HSD (does not need cytochrome P450)

Synthesis of Progesterone

Cholesterol is fed to the enzyme desmolase by the StAR (steriodogenic acute regulator) protein (this feeding step is regulatory). Desmolase then convertes the cholesterol to pregnenolone which becomes progesterone

What cells are found in the adrenal medulla

Chromaffin cells (ChC) - polyhedral cells - large with pale-staining cytoplasm - have an extensive vascular network

What cell types can be found in the Anterior Lobe of the Pituitary Gland (adenohypophysis or pars distalis)

Chromophil Cells: they have the affinity for ACID and BASIC dyes (these cells are arranged in irregular CLUSTERS or CORDS): Acidophil Cells (alpha cells): pink with H&E dye - Somatotropes: secrete growth hormone - Mammotropes: secrete prolaction Basophil cells (beta cells): blue with H&E dye - Gonadotropes (FSH and LH), Thyrotropes (TSH), and Corticotropes (ACTH) *** these different hormone producing cells in the anterior lobe (pars distalis) of the pituitary gland are detected with Immunohistochemistry (IHC) Chromophobe cells: low or no affinity to any dyes

A pt comes to your office complaining of recurrent life-threatening bacterial and fungal infections in either his skin, lungs, GI tract, lymph nodes, liver, and spleen. What could be the cause hmmmmm

Chronic Granulomatous Disease (CGD) - an inherited disorder of phagocytic cells - results from an inability of phagocytes to produce bactericidal superoxide anions O2- (caused by a defect in the NADPH oxidase enzyme of phagocytes) ** CGD can lead to these recurrent life-threatening bacterial and fungal infections that occur most commonly in those organs that serve as barriers against the entry of microorganisms from the environment

An absence of NADPH oxidase could lead to

Chronic granulomatous disease

Monocytosis is due to

Chronic infections (ex. tuberculosis), bacterial endocarditis, rickettsiosis, and malaria; autoimmune disorders (ex. systemic lupus erythematosus); inflammatory bowel diseases (ex. ulcerative colitis)

Granulomatous lymphadenitis

Chronic lymphadenitis with granulomatous inflammation with or without caseation necrosis - granuloma: focal accumulation of activated macrophages - caseation necrosis- cheesy appearance of dead tissue occuring within a granulom ex. tuberculosis, fungal infections

Where are blood cells taken out of when you take out blood

Circulating Pool * excercise moves cells from marginating to circulating

GLUT-1,2,3,4 are the

Class I Glucose Transporters - GLUT-4 is the only one thats insulin-dependent (high affinity for glucose) - GLUT-2: important in metabolism on behalf of the beta cell itself- it is co-directional unlike the others- allos release of or absorption of glucose into cells such as hepatocytes (transports galactose and fructose) - GLUT-1 and GLUT-3: are dependent on the conc. of glucose and are mainly expressed in brain and erythrocytes, with some GLUT-3 in other tissues (these also transport galactose, not fructose) -------- GLUT-1: in brain, RBC, endothelial cells, fetal tissues GLUT-2: liver, pancreatic beta cell, SI, kidney GLUT-3: brain, placenta, testes GLUT-4: skeletal and cardiac muscle, adipocytes

GLUT-5 is a

Class II FRUCTOSE transported - important in digestion and absorption of carbohydrates, but also in maintainence of sperm motility, in locations where fructose will not otherwise be used as a food source (spermatozoa, in the uterus and uterine tubes) ** expressed in small intestine and sperm

Which two complement pathways are exactly identical except for their starting point

Classical and Lectin Pathway Classical: activated by antigen-antibody complexes Lectin: activated by plasma lectings binding to microbes ** there is also the alternative pathway (which is the first to kick in) it is activated by microbial surfaces *** ALL 3 pathways of complement activation lead to the formation of a common terminal cell lytic complex that is inserted in cell membranes - Alternative and lectin pathways are innate - Classical pathway is acquired/adaptive

Different cytokines can activate a macrophage to be classically activated or alternatively activated. What is the difference?

Classically activated macrophages (M1): inflammatory vs. Alternatively activated macrophages (M2): can be anti-inflammatory or involved in tissue repair

Agranulocytosis

Clinically significant reduction in neutrophils (<100 neutrophils/microL0 - serious consequence of making individuals susceptible to bacterial and fungal infections Causes: Drug toxicity (most common cause) - alkylating agents, anti-metabolites - predicatble dose related Idiosyncratic reaction to drugs - antibody mediated destruction of mature neutrophils ---- Clinical Features of neutropenia Neutropenia - malaise, chills, fever - marked weakness and fatigability - ulcers and enlarged regional lymph node Agranulocytosis - mouth ulcers with pseudo-membranes laden with infective bacteria and/or fungi - death within a few days

Fibrinogen is involved in

Clot formation

MHC expression is

Co-Dominant - you inherit 3 alleles of MHC I from both paernts - also inherit 3 alleles for MHCII each alpha and beta from both parents * and each are equally expressed (co-dominant) ----- if you inherit 3 alleles from MHCI from 1 parent and 3 diff. alleles from another parent- you will express 6 diff. MHC I molecules If you inherit same alelles from both parents for only ONE of the genes you will express 5 **** review this**** ------- Number of expressed MHC types on cells: MHC-I: minimum of 3 and maximum of 6, avg 6 given high polymorphism MHC-II: minimum of 3 and maximum of 12 (bc 2 chains to consider- so in theory it is 12) ** use theoretical values (but note that the real avg is about 8- this is lower than expected bc 1. even though ppl are heterozygous at most loci, some people may be homozygous, and 2. some alpha:beta pairings are unstable and never get expressed on the cell surface * combined MHC-I and MHC-II: minimum of 6 and maximum of 18 (again, in theory), avg of 14 ** use theoretical values when calculating**

CFU stands for

Colony Forming Unit

What allows antibodies to bind to different epitopes?

Combinatorial Diversity - their genes exsist in segments (V, D, J segments) that give them their variety Light chains: V and J recombinations ** you can have two types of light chains: gamma and K - any given antibody will either have K or gamma- NOT both Heavy chains: have V, D, J recombinations - your heavy chain will posses a Cm of C something at the end (ex. Cm= IgM- this determines the type of heavy chain) *** Gene rearrangement is mediated by RAG-1 and RAG-2 (without these there would be no rearrangement- so cant make antibodies) NOTE: if a heavy chain has two C's at the end (ex. Cm and Cd in the constant region- you pick the C that is closest to the variabl V D J portion - so in this case you would have IgM) NOTE: TCR part of immunoglobin family- they also depend on RAG1 and RAG2 for its construction

Name some subunit compositions of cytkine receptors

Comming Gamma Chain Family - this is mainly for proliferation cytokines

Both the intrinsic and Extrinsic pathway meet at the

Common pathway: - activation of factor X (10) which convers prothrombin --> thrombin thrombin then converts Fibrinogen --> fibrin and activated XIII which then converts Fibrin --> cross-linked fibrin with the help of calcium ( a fibrin monomer closs-links into a fibrin fimer --> which forms a fibrin polymer to form a mesh) *** this cross-linking occurs through Transglutaminase Reaction (from Glutamine ---> Lysine): makes a peptide bond to form the fibrin polymer (remember this step needs Factor XIII to be converted to XIIIa by Thrombin in order for it to occur)

What is present on the surface of erythrocytes, coupled with complement fragments bound to IgG, that are paramount for clearing immune complexes?

Complement Receptor Type I (CR1) * inefficient immune complex clearance (i.e. defficiency in some complement components) can lead to serious, sometimes fatal, disease manifestations: - Systemic lupus erythematosus - Polyarteritis nodosa - Poststreptococcal glomerulonephritis - Serum sickness (clinical and experimental) - Arthus reaction (experimental)

Disorders of the Adrenal Cortex

Congenital Adrenal hyperplasia (CAH) Disorders with increased function (hyperadrenalism) - Hypercortisolism (Cushing Syndrome) - Primary Hyperaldosteronism (increased mineralcorticoids) Disorders with decreased function (hypoadrenalism) - Chronic adrenal insufficiency (Addison disease) - Acute adrenocortical insufficiency (Adrenal crisis): Waterhouse-Friderichsen Syndrome

Vasopressin Antagonists

Conivaptan and Tolvaptan Conivaptan - nonselective V1a/V2 antagonist - intravenous - half-life 5-12h, metabolized in liver, eliminated in kidney Tolvaptan: - selective V2 antagonist - oral - half life 3-12 hrs, 1% excreted by kidney Adverse effects seen in both: - osmotic demyelination syndrom - polyuria, dehydration, hypotension, thirst, dry mouth, GI - In tolvaptan use an adverse effect could be liver damage Therapeutic effects - SIADH (syndrome of inappropriate ADH) - Congestive heart failure - Cirrhosis - Nephrosis - Low or normal arterial blood volume with concomitant hyponatremia (euvolemic hyponatremia and hypovolemic hyponatriemia)

the process of the body returning back to normal after an immune response is referred to as

Contraction (homeostasis) * your cytokines can start a response and also end it

Through what mechanims does thyroid hormone alter the activity of its target cells

Conversion of T4 --> T3 in the cytoplasm, then T3 binding to a nuclear receptor, then stimulation of transcription

Glucocorticoids include

Corticosterone (from ZG) Cortisol (from ZF)

Glucocorticoids

Corticosterone from the ZG and Cortisol (aka hydrocortisone) from the ZF are the two priamry glucocorticoids * cortisol is more prominent and more potent A general circadian rhythm is associated with cortisol secretion and concentraion in the plasma (circadian rhythm plus pulsatile secretion)

With decrease in 21-hydroxylase and 11-hydroxylase, progesterone cannot become

Cortisol nor aldosterone - so instead progesterone is pushed toward the production of testosterone Testosterone using aromatase can become estradiol

Stress response includes increases in

Cortisol, Growth hormone, and Epinephrine - Cortisol: promotes fatty acid release from adipose tissue and synergistically enhances the effects of epinephrine and glucagon - Epinephrine prepasres cells for increased glycogen breakdown and glycolysis and also promotes release of free fatty acids

Which has a longer half-life cortisol or aldosterone

Cortisols half-life is greater than that of aldosterone * cortisol remains in the plasma for a longer time than aldosterone - on avg, cortisol is produced at a secretion rate 100x greater than that of aldosterone and its concentration in the plasma is 2000x greater than that of aldosterone --- cortisol is a glucocorticoid from ZF aldosterone is a mineralcorticoid from ZG ----- Aldosterone lacks a specific binding protein of its own to transport it through the blood, so generally speaking as it is secreted it is bound loosely to albumin, is delivered to its target tissue, and is rapidly metabolized thereafter. In contrast, cortisol binds tightly to a cortisol-binding globulin, so it takes longer for any of its molecules to be released. If one stores a higher number of molecules (ex. Higher concentration), then even the small fraction released at any time is enough for the bodys needs. So the binding protein is what makes the difference

Cortisol is a glucocorticoid, but has also mineralcorticoid activity. What is its inactive product

Cortisone is cortisols inactive product Cortisol --> Cortisone (via 11-hydoxysteroid dehydrogenase) ** licorice inhibits this reaction in the kidneys - causes an increase in cortisol which can lead to an increase in hypertension because it is a mineralcorticoid ** this is why pateints with hypertension should not eat licorice

What conditions is supplementation with iodine (found in salt from stores) intended to prevent

Cretinism and Primary hypothyroidism - cretinism: a condition characterized by physical deformity and learning disabilities that is caused by congenital thyroid deficiency.

A syndrome of glucocorticoid excess

Cushing Syndrome - Many cases are iatrogenic (caused by a doctor overprescribing/pateint taking to much anti-inflammatory steroids) Leads to: - truncal obesity, but fat is lost from extremities - weak connective tissue, striae - insulin-antagonistic effects (from glucocorticoids), can cause secondary diabetes mellitus ------------ Different from Cushing Disease: - ACTH-secreting tumor in anterior pituitary gland. Causes 70% of non-iatrogenic cushing syndrome. Pigmentary changes in addition to Cushing Syndrome (remember alpha-MSH stimulater hyperpigmentation if the person has increased ACTH)

ACTH-secreting tumor in the pituitary gland can lead to

Cushing disease

Integrated response to chronically elevated cortisol could result in

Cushings Syndrome - cortisol effects combine with those of excess insulin to promote excess food intake and nutrient stoage, resulting in obesity and other pathological aspects of cushings syndrome

Oxytocin and Vasopressin (ADH) from the posterior pituitary are

Cyclic nonapeptides that differe by 2 amino acids at the 3 and 8 position (Ile-->Phe and Leu--> Arg) - they need to be parenterally administered for indications requiring careful dosing - can be administered intranasally for less critical conditions

Major enzymes of drug metabolism are

Cytochrome P450 (cyp) enzymes (referred to as a "microsomal enzyme" ) and UDP-glucuronosyltransferase

Dopamine is an agonist at its receptors

D1 and D2 - in the pituitary, activation of D2 receptors by dopamine agonists DECREASES prolactin release

Paroxysmal Nocturnal Hemoglobinuria (PNH) could be due to deficiency in

DAF (CD55) or Protectin (CD59) due to phosphatidylinositol glycan class A (PIGA) mutation - this can lead to pore formation in erythrocytes - causes fatigue, smooth muscle dystonias, venous thrombosis, abd pain, intravascular hemolysis, and hemoglobinuria *** lack of phosphatidylinositol glycan class A (PIGA) results in lack of blood cell glycosylphosphatidylinositol-linked CD55 and CD59 proteins that protect them from the attack by the complement system

Angiotensin II ________ change ACTH levels

DOES NOT - cortisol does change ACTH levels ** on the contrary Angotensin IIs primary effect on increasing aldosterone is DIRECT, not indirect ---- - Angiotensin II can modulate cortisols main negative feedback control over CRH and ACTH secretion - It can also stimulate thirst to increase water ingestion and eventual plasma volume - It stimulates postereior pituitary ADH (AVP) secretion to further increase water retention, but these too are minor functions of Angiotensin II compared to its directly stimulating aldosterone secretion

Lymphopenia

Decreased circulating lymphocytes Causes: Durgs: corticosteroids, cyclophosphamide Autoimmune destruction: SLE Immuno-deficiency syndrome: DiGeorge syndrome (T cell deficiency), AIDS, Severe combine immunodeficiency Endocrine: Cushings Syndrome

Role of the immune system

Defense against infections: - Primary Immunodeficiencies: deficient immunity results in increased susceptibility to infections; ex. AIDS - Vaccination boosts immune defenses and protects against infections (prevention of disease through vaccination) Defense against tumors: - Potential for immunotherapy of cancer (ex. B cell acut lymphoblastic leukemia (ALL)- CAR therapy The immune system can injure cells and induce pathologic inflammation - immune responses are the caused of allergic, autoimmune, and other inflammatory diseases (ex. TNF-alpha mAb for treatment of rheumatoid arthritis) The immune system recognizes and responds to tissue grafts and newly introduced proteins: - immune responses are barriers to transplantation and gene therapy

Describe the clinical uses of Deferasirox and Deferoxamine (**these are iron chelators)

Deferasirox - Given orally only (only chronic) - used in treatment of chonic iron overload - Adverse effects: acute renal failure, hepatic failure, and GI hemorrhage, which may be fatal Deferoxamine - Given IV, IM, and SubQ - used in treatment of acute iron overload and chronic iron overload - Adverese effect: infusion reaction (skin, flushing, urticaria and shock) *** Both of these MOA= binds to Fe3+ (ferric) ions to form a complex which is then excreted in urine (deferoxamine) or feces and bile (deferasirox)

Deficiencies in alternative pathway components can include:

Deficiences in Factor B, D, properdin, MBL, or MASP-2 - these can lead to increased susceptibility to meningococcal (Neisseria Meningitidis) infections (more frequent, or recurrent, disease; greater dissemination, or spread in the body, leading to different type of disease) - thin-walled organisms which tend to be more affected by complement lysis - some Neisseria spp. strains posses polysaccharide capsules that do not activate the innate pathways of complement activation well

Genetic deficiencies in classical pathway components can include

Deficiencies in the following from the lectin and classical pathway: C1q, C1r, C4, C2 or Deficiencies in C3 (which would affect all the pathways) ** C2 deficiency is the most common: individuals can be asymptomatic to increased susceptibility to infections * C3 deficiency is frequent in pyogenic infections, and it is sometimes fatal

Von Gierke Disease (aka Glycogen storage disease I)

Deficiency in glucose-6-phosphatase - results in severe fastin hypoglycemia - there are two types resulting from deficiencies in the phosphatase (Type Ia) or in the translocase T1 (Type Ib)

McArdle Syndrome

Deficiency in glycogen phosphorylase (affects glycogenolysis) - these pts have temporary weakness after exercise and accumulation of glycogen in muscle. It is chronic and relatively benign.

Adrenal androgens include

Dehydroepiandrosterone Androstenedione Dehydroepiandrosterone Sulfate (DHEA-S) ALL made from the ZR

Adrenal androgens

Dehydroepiandrosterone --> DHEA-S and Androstenedione * in ZR

Roles of chylomicrons

Delivers: - dietary fat to adipose tissue - dietary cholesterol to the liver - fatty acids to muscle Activates lipoprotein lipase

What are the major cell types (in addition to lymphocytes) in secondary Lymphatic tissue

Dendritic Cells, Macrophages, Plasma Cells 1. Dendritic Cells - the BEST antigen presenting cell in the body - main fx: to process antigen material and present it on the cell surface to the T cells of the immune system ** these are dericed from monocytes (are a type of macrophage) 2. Macrophages - are phagocytis AND APCs - less efficient APC than dendritic cells - they are excellent "garbage collectors" but not nearly as good antigen-presenting cells as dendritic cells - they do the bulk of filtering lymph in lymph nodes and blood in spleen by phagocytosis * derived from monocytes 3. Plasma cell - a fully differentiated B-lymphocyte that produces a single type of antibody - has an asymmetric "clock-face" nucleus - more cytoplasm than lymphocyte 4. Follicular Dendritic Cells

Signal 3 of Antigen Presentation for T cell Activation

Depends on the particular pathogen (i.e. the cytokines provided by the innate system during Ag presentation) Th1 cells: in presence of IL-12 and IFN-gamma Th2 cells: in presence of IL-4 Th17 cells: in presence of IL-6, IL-23, and TGF-Beta Treg cells: in presence of IL-10, TGF-Beta or both *** NOTE: cytokine signaling is primarily achieved through the Jak/STAT signaling pathway

Therapeutic effect

Desired pharmacological outcome - could be cure: like in the case of antibiotics or cancer chemotherapy or - could be alteration of physiological functions and/or alleviation of symptoms: like most other durgs

Synthetic analog of Vasopressin

Desmopressin (DDAVP - change at AAs 1 and 8 - 3000x antidiuretic/vasopressor ratio compared to vasopressin --- - can be given orally (<1% bioavailability) - intranasally (3-4% bioavailability) - parenterally

A rare congenital disorder involving failure of the thymus to develop properly

DiGeorge Syndrome (AKA Thymic Aplasia) Cause: - Faulty development of 3rd and 4th pharyngeal pouches in early development (caused by a defect on chromosome 22 due to a recombination error during meiosis) * Pt's with this may have poor T-cell production because of a smaller thymus and, as a result, have an increased susceptibility to viral, fungal and bacterial infections

Passage of blood cells (especially white blood cells) through intact capillary walls and into surrounding tissue is known as

Diapedesis

Anisocytosis

Difference in widths of RBCs ** RED CELL DISTRIBUTION WIDTH (RDW): reflects variation in size of RBCs in peripheral blood Nml range: 11.6=14.8% - Increased in many types of Anemia: Iron deficiency, Pernicious (due to lack of intrinsic factor, resulting in lack of VitB12 resulting in Megaloblastic Anemia), or Folate deficiency (caused Megaloblastic Macrocytic Anemia) - Thalassemia - Liver Disease

In Common sites of invasion by pathogens because the lumens of these tracts are open to the external environment (digestive, respiratory, genitourinary)- you can find alot of

Diffuse lymphoid tissue "guarding" these mucosal surfaces, called Diffuse Lymphatic Tissue or MUCOSA-ASSOCIATED LYMPHATIC TISSUE (MALT) * this is NOT surrounded by a connective tissue cpasule (except for tonsils which are partially encapsulated) - consists of lots of lymphocytes clustered together in (usually) lamina propria of certain tissues, can form nodules or follicles MALT is populated by: - T and B lymphocytes - Plasma cells - Macrophages - Dendritic cells - Follicular Dendritic cells ** each of which is well situated to encounter antigens passing through the mucosal epithelium

Folate requires action by the enzyme ____ to be turned into THF

Dihydrofolate reductase (DHFR) ** Methotrexate (aka Amethopterin) is a competitive inhibitor: used to treat lung cancer, breast cancer, leukemia, lymphoma, osteosarcome and also various autoimmune diseases - Aminopterin is another folate analogue used as a chemotherapeutic and immune suppressant Both methotrexate and aminopterin work by inhibiting dihydrofolate reductase (competitive inhibitor)- this prevents THF formation and prevents purine and pyrimidine biosynthesis. *rapidly dividing cells req purines and pyrimidines for DNA replication- therefore these agents target dividing cells more than non-dividing cells in Go. - the severe side effects are because normal cells that undergo division are also targeted- this particularly affects the immune system and erythropoiesis

Which is more potent: testosterone or dihydrotestosterone

Dihydrotestosterone - it is made mainly in the target tissues Testosterone (from the testes, not the adrenal gland) and either become - (6-8%) Dihydrotestosterone via 5-alpha reductase - (0.3%) Estradiol with help of aromatase - inactive products

First generation H1 blockers include

Diphenhydramine

The only antihistamine on the drug list that is administered topically

Diphenhydramine

The prototype drug for the first generation H1 antagonists

Diphenhydramine Mechanism of action: competitive antagonist at histamine H1 receptors - it is also a competitive antagonist at muscarinic cholinergic receptors (this means it is not completely selective for H1 receptors) ---- Diphenhydramine - can be administered via multiple routes: oral, IM, IV, topical - widely distributed in the body, including the CNS (except when used topically) - nearly 100% is metabolized in the liver by cyps: more rapidly in children than adults - potential for clinically-relevant drug interactions and/or effects of decreased liver function (appears to inhibit CYP2D6)

Leptin has a ___ on secretion of thyroid hormone

Direct effect on arcuate and paraventricular neurons, increasing TRH secretion

Growth hormone (AKA Somatotropin) has 2 distinct effects which are

Direct effects (binding its receptor on target cells) - fat cells (adipocytes) growth hormone receptors - growth hormone stimulated them to break down TAG and supresses their ability to take up and accumulate circulating lipids or Indirect effects (mediated primarily by a insulin-like growth factor I (IGF-I)) - secreted from the liver and other tissues in response to GH. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells

Parvicellular hypothalamic-anterior pituitary system

Dopamine (DA) producing neurons in the arcuate nucleus of the hypothalamus- regulation of pituitary prolactin (PRL) secretion from the anterior lobe

Where would an antigen entering the body in subcutaneous injection most likely activate its specific lymphocytes

Draining lymph nodes

Body compartments where the drug becomes located and/or concentrated as it moves through systemic circulation

Drug distribution (ex. a drug concentrated in adipose tissue)

If the transcription factor NF-KBeta is inacctive what is most likely responsible for the lack of activation of this factor

Dysfunction of Toll-like receptor

Why is being referred to by ADH vs Vasopressin

EXACTLY the same hormone! - ADH- typically talking about its renal effects - Vasopression or arginine vasopression- cardiovascular effects for its vessel-squezzing effects ------- 1. Osmoreceptors detect increased osmotic pressure and Baroreceptors (in the aortic arch, carotid sinus) detect decresed blood pressure) 2. These circumstances stimulate the release of ADH from the posterior pituitary- this ADH can either act to - vasoconstrict blood vessels (vasopressin) - increase reabsorption of water in the kidneys (ADH) 3. either way both these lead to increased blood volume and increased blood pressure

Once leaving the periphery, CD4 T cells differentiate from a TH0 cell (mature, naive, resting T lymphocyte into

Effector cells (after re-circulation between secondary lymphoid tissues and if colicited by antigen presentation, activation, proliferation, and differentiation.... they can become:) - Th1 (if exposed to IL-12 and IFN-gamma) - Th2 (if exposed to IL-4, with or without combos of IL-13, IL-5, and IL-10) - Th17 (if exposed to IL-6, IL-23, and TGF-Beta) - Tfh (if exposed to IL-21, IL-12, IL-23, and TGF-beta) - Treg (if exposed to TGF-beta and/or IL-10) ** these can then now in the secondary lymphoid tissue and in the site of infection either carry out their - effector functions in which case they will be short-lived and die quickly after performing their function or - become memory cells (long-lived) which become reactiveate upon Ag presentation ----- On other hand antigen presenation to a CD8 cell in secondary lymphoid tissue leads to CTL differention- these can also become memory cells (long-lived) which are reactivated upon Ag presentation

the largest effect that can be achieved with a particular drug, regardless of dose

Efficacy

Lipid derived/ Arachiodonic Acid derived hormones include the

Eicosanoids - Phospholipids combined with DAG make--> Arachiodonic Acid or eicosatrienoic acid or eicosapentaenoic acid this can either directly become a Leukotriene (LTs) or Prostaglandin H - Prostaglandin H then can become either Prostacylcin, Prostaglandin, Thromboxane

The terminal phase of complement activation, which is common to ALL 3 activation pathways it the

Elaboration of the membrane attack complex or MAC 1. C5 convertase (C3bBb3b of alternative pathway or C4b2a3b of lecting and classical pathwa) results in cleavage of serum C5 into C5b and C5a - C5a is released into fluid-phase where it mediates further inflammatory reactions - C5b binds serum C6 to induce conformation change in C6 that allows the C5b/C6 complex to bind the membrane surface 2. Serum C7 then binds C5b to form a C5bC6C7 complex - membrane-bound C7 is amphiphilic and penetrate the membrane 3. Serum C8 then binds C5b of the C5bC6C7 complex and stably penetrates the membrane to form an unstable pore (0.4-3.0nm in diameter) - large numbers of C5bC6C7C8 unstable pored can result in cellular lysis, BUT the recruitment and polymerization of serum C9 creaters larger stable pores (1.0-11.0nm in internal diameter) that act as channels through which water and ions move freely - the resulting osmotic swelling culminates in cellular rupture of lysis 4. Serum C9 molecules bound to the curface C5bC6C7C8 complex therefore polymerize to create a large stable pore in the plasma membrane to yield an active membrane attack complex (MAC) NOTE: C9 is structurally homologous to the perforin secreted by NK cells and cytotoxic T lymphocytes, and that the pores formed by C9 are similar to the pores that result from the polymerization of perforin

What two forms of secondary lymphoid tissue are possible

Encapsulated and Not Encapsulated 1. Encapsulated: i.e. Surrounded by CT capsule Forms Lymphoid organs: - lymph nodes - spleen - tonsils (partially encapsulated) 2. Not encapsulated: diffuse within lamina propria CT below epithelium - Mucosal-associated lymphoid tissue (MALT)- has multiple locations

The gastrula can differentiate

Endoderm (internal layer) - Lung cell (alveolar cell) - Thyroid cell - Pancreatic cell Mesoderm (middle layer) - Cardiac muscle cells - Skeletal muscle cells - Tubule cell of the kidney - RBCs & WBCs - Smooth muscle (in Gut) Ectoderm (External Layer): - Skin cells of Epidermis - Neuron of Brain - Pigment Cell Germ Cells: - Sperm - Egg

Endogenous Insulin vs. Therapeutic Insulin therapy

Endogenous: circulates unbound, short half-life (~6 minutes) Therapeutic insulin therapy: altered to extend half life - parenteral use (SQ, IV, IM).. pluse inhaled product Insulin is prepared as - an aqueous solution - dosing and concentrations expressed as "units" - standard= 100 units/ml - also preparations that are 200,300, or 500 units/ml Formulations: Alterations to pharmacokinetics - slow absorption from administration site - alter AA sequence or structure to accelerate or prolong absorption (short acting/long acting-insulin)

Glucose-6-phosphate is synthesized in the

Endoplasmic reticulum - it allosterically regulated both glycogen synthase and glycogen phosphorylase

In synthesis of thyroid hormone, what state and through what cellular mechanisms does iodine from the plasma enter the follicular cell

Enters as iodide via facilitated diffusion vis a sodium symporter - it exits the follicular lumen still as iodide via facilitated diffusion via a uniport called Pendrin ----- In secretion of thyroid hormone, iodine from the colliod enters as iodine into the follicular cells via endocytosis of iodine-containing proteins

An increase in the number of eosinophils in the blood is referred to as

Eosinophilia * associated with parasitic infections and allergic reactions

On EM which WBC can be recognized because of the dark stripe on its specific granules

Eosinophils ** this line is the Major Basic Protein

Thyroid has permissive action on ___, increasing it in cardiac muscle - bc its proteins were result of thyroid hormone action

Epinephrine

3 patterns of hormone secretion

Episodic Release - A specific stimulus arrives and the hormone is released. If only paracrine/autocrine substance are released, this can be called a "localized burst" - Insulin is an ex. of hormone released when glucose levels rise in the bloodstream Pulsatile Release ***most common*** - hormone is released in a series of regularly timed short bursts, typically with time between the bursts devoted to hormone action and metabolism - Growth hormone is an ex. of hormone released in short bursts when stimulated to do so by hypothalamic hormones Circadian and other larger-timed rhythms: - A modulation of pulsatile release. Significantly more hormone is released at certain times of the day (circadian), month or yr than at other points in the respective time cycle - ex. Melatonin

Secretion of insulin is an

Episodic secretion - When blood glucose levels rise, insulin is secreted until blood glucose levels fall again to a normal range *NOTE: there is a transport maximum

Describe the difference between Erythropoietin Drugs: Epoetin alfa and Darbepoetin Alfa

Epoetin alpha - a recombinant human EPO Darbepoetin alpha - a modified form of EPO with a greater half-life *** both given IV and SubQ *** both MOA= induction of erythropoiesis by interacting with EPO receptors on RBC progenitors and stimulating differentiation and proliferation. Induces the release of reticulocytes from the bone marrow to the bloodstream. This results in an increase in hematocrit and hemoglobin levels Both are clinically used in: Anemia - due to chronic kidney disease (EPO is made in the kidney) - due to chemotherapy in patients with cancer - due to zidovudine in HIV-infected patients also in Patients scheduled to undergo elective, noncardiac, nonvascular surgery- reduces the need for allogenic RBC transfusion ---- Adverse effects: BLACK BOX WARNING: erythropoeisis- stimulating agents (ESAs) increased the risk of serious cardiovascular events, MI, stroke, venous thromboembolism, vascular access thrombosis, and mortality in clinical studes when administered to target hemoglobin levels >11g/dL - contraindication in patients who are mildly anemic or nonanemic - hypertension

PGI2

Epoprostenol (chemically same as native PGI2)

How are all the nuclei that are released by erythroblast degraded

Erythrocyte clones develop in the bone marrow on the surface of a macrophage nurse cell, which phagocytoses and digests the nuclei discarded by the erythroblasts before their conversion to reticulocytes

What does the presence of reticulocytes in a peripheral blood smear indicate?

Erythropoiesis - reticulocytes are newly released RBCs from bone marrow * they are identified with supra-vital stains what is seen is thread-like RNA filaments in the cytoplasm ** in 24 hrs these develop into mature erythrocytes

CFU-E leads to

Erythropoiesis- development of erythrocytes - cells get smaller - nucleus condenses, eventually it is extruded - gradually loses ribosomes, mRNA, and organelles - gradually gains hemoglobin Steps: 1. Hematopoietic Stem Cell - CFU-GEMM and CFU-E are intermediates-- 2. Proerythroblast (20hr) 3. Basophilic erythroblast (20hr) 4. Polychromatophilic erythroblast (25hr) 5. Orthochromatic erythroblast (30hr) 6. Reticulocyte (2-3days) - No nuecleus (nucleus condenses becomes pyknotic and eventually gets extruded) 7. Erythrocyte (120 days) ** from first recognizable (proerythroblast) to release into bloodstream takes 7 days

Bromocriptine (a dopamine-2 receptor agonist)

Exact mechanism in DM is unknown but improves insulin resistance and reduces glucose production - oral absorption * Used in Parkinson's disease and hyperprolactinemia (a pituitary disorder) Side effects: nausea, dizziness, headache

Leukemoid reaction

Exaggerated benign leukocyt response - high leukocyte count >30,000 (often >50,000/microliter) with immature myeloid granulocytes in blood stimulating leukemia (chronic myeloid leukemia) - composed largely of mature neutrophils with low portion of bans and myelocytes Causes: - severe infections: sepsis, perforated acute appendicitis, whooping cough, infectious mono; severe hemorrhage *** present with fever and shift to the left

Factor H deficiency can lead to

Excess activation of the alternative pathway which leads to excessive consumption of C3 - can lead to glomerulonephritis and atypical haemolytic uremic syndrome resulting from reduced clearance of immune complexes

The pancreas is an accessory gland of the digestive system with both exocrine and endocrine function can you describe both

Exocrine: production of digestive enzymes that are carried via the pancreatic duct to the duodenum Endocrine: release of hormones that regulate carbohydrate metabolism, the endocrine portion is referred to as the islets of langerhans (l), and are scattered among the exocrine portion (secretory acini) * its flimsy connective tissue capsule forms septa, which subdivide the gland into lobules

A PT test could show abnormalities in

Extrinsic and Common pathway & deficiency/inhibition of VII, X, V, II, I ** this is commonly caused by liver disease, warfarin therapy, and DIC

T or F: fatty acid degradation supports gluconeogenesis

FALSE it does not , niether does Acetyl-CoA * neither fatty acids nor acetyl-CoA acts as a gluconeogenic precursor * this is a major principle of metabolism and dictates much of the metabolic logic in starvation and diabetes

T or F: fatty acids can be used as carbon source for gluconeogenesis

FALSE! - Fatty acids are NOT gluconeogenic precursors - Lactate and glycerol are however

T or F: prostaglandins and their analogs are highly specific

FALSE! - they lack selectivity and this explains their many adverse effects and why a drug may target very diverse actions

T or F: oxtytocin causes the breast to make milk

FALSE! prolactin does

T or F: so many glucocorticoids and mineracorticoids are produced in the ZR

FALSE! synthesis of these are gone in the ZR - in its place are enzyme to move the products from cholesterol into one of the 3 adrenal androgens: dehydroepiandrosterone (DHEA), androstenedione, and DHEA-sulfate (DHEA-S)

T or F: RBCS have a HUGEEEE Nucleus

FALSE! they have absolutely NO nucleus or organelles ** they had one in their development in the bone marrow but then they released it NOTE: RBC (aka erythrocytes) primary function is the transport of O2 and CO2 - RBCs are basically just bags of hemoglobin - RBCS make up 99% of ALL blood cells

T or F: whole blood is always used for blood transfusions

FALSE! this happens next to never! - butt if it did you would have to have a donor and a recipient with the same blood type

T or F: Platelets are cells that are formed from other cells

FALSE!!! Blood platelets (aka thrombocytes) are NOT cells, they are pieces of a cell - derived in the bone marrow from a giant precursor cell: megakaryocyte * platelets life spain is about 10 days ** their primary function is to prevent excessive internal or external bleeding after and injury by helping to form blood clots NOTE: in a blood smear, platelets are often found as aggregates

T or F: you only need the Extrinsic pathway to clot properly

FALSE!!! you need both the extrinsic and intrinsic pathways - they are intertwined in such a way that if youre missing something on either the extrinsic or intrinsic side you will NOT be able to clot properly (form fibrin) - you need factors VIII and IX to use the intrinsic pathway

T or F: the spleen filters lymph

FALSE!!!!! the spleen ONLY filters BLOOD!!! ---lymph nodes filter lymph--

T or F: the bone marrow is the greatest storage site for erythrocytes

FALSE!!!!!! bone marrow is NOT a storage site for erythrocytes

Both PTH and Calcitriol increase production of

FGF23 - which in turn decreases the production of both PTH and VitD

GnRH from hypothalamus stimulates release of

FSH and LH from the anterior pituitary - Works on gonads to cause ovulation, estrogen, progesterone - In males does spermatogenesis and testosterone ** trophic effects

Von Willebrand factor carries

Factor 8 (VIII) ** it is NOT a clotting factor it just carries

Hemophilia B is caused by lack of

Factor IX (9)

Hemophilia A is caused by lack of

Factor VIII (8)

Vitamin-K dependent coagulation components

Factors X, IX, VII, II proteins C, S (mnemonic: 1972- [10,9,7,2]

Binding of ___ to ___ induces cell death in fas-expressing cells

FasL to Fas - the cell that kills expresses FasL - the cell that is to be killed expresses Fas ex. NK cell expresses FasL ** binding of FasL and Fas turns on the death domain which will turn on caspase-8 and lead to apoptosis

Hyperglycemia

Fasting blood glucose levels >125mg/dL Causes: too much food, too little insulin or diabetes pills, or stress - often starts slow, may lead to medical emergency if not treated Sxs: - Extreme thirst, need to urinate often, dry skin, hungry, blurry vision, drowsy, slow-healing wounds ------- Hyperglycemia is - normal after a large meal- that is why insulin is secreted..but when hyperglycemia persists, there can be problems - this leads to a large number of possible sxs, both acute and chronic- if chronic and sustained, diagnosed as Diabetes Mellitus - If hyperglycemia is extreme, it can lead to ketoacidosis, coma, and death

Fasting vs Starving

Fasting: VOLUNTARY abstention from eating, while hunger cues last (24-48hrs since the persons last meal) Starving: INVOLUNTARY lack of food consumpton despite hunger cues * body's response, to maintain energy availability to brain and other fuel-sensitive tissues, will be the same, though more means may be employed than during a normal post-absorptive state ------ The fasting state (chronic starvation) is a "survival mode" variant of a typical (early) post-absorptive state - cortisol is typically a hormone of the fasting state, but not of the early post-absorptive state - epinephrine and GH also support glucagons continued maintenance of blood glucose * by a few days after ones last meal, this fasting state for metabolic purposes should be fully established

Stress results in the rapid mobilization of which circulating energy carriers

Fatty acids and glucose **** involved in both stress and exercise

Fc receptors allow recognition of the

Fc portion of antibodies ex: the Fcgamma receptor (CD16) on NK cell binds to the Fc portion of an antibody ** this is what can result in ADCC

DMT1 (divalent metal transporter) absorbs non-heme iron as

Fe2+

Oral Iron preparations are with

Fe2+ - Ferrous Sulfate - Ferrous Gluconate (these work to increase iron, replace iron found in Hb, myoglobin, and enzymes) (works for prevention and treatment of iron-deficiency anemia- hypochromic, microcytic anemia) ** oral and Fe2+ (ferrous) iron are perferably used --- Adverse effect: - acute iron toxicity (overdose): GI bleeding, vomiting, abd pain and bloody diarrhea- seen most commonly in young children who accidentally ingest iron tablets

Dietary iron is generally liberated as the Fe3+ form (ferric), this is then converted into

Fe2+ Form (ferrous) for transport through the dmt-1 divalent metal transporter ** it is stored in enterocytes in ferritin (Fe3+) and released as needed and converted to Fe2+ (this Fe2+ exits through ferroportin) - is converted back to Fe3+ by hephaestin or by ceruloplasmin and bound to transferrin (Tf) ** excess dietary iron in ferritin lost as enterocytes are sloughed off (~1mg/day)

Ferroportin brings

Fe2+ across basolateral membrane

What state does iron have to be in to bind oxygen

Fe2+ state

Parenteral Iron is usually

Fe3+ - Iron Dextran (given intramuscularly and IV) - Ferric Gluconate (given via IV) MOA: - increase iron, replaces iron found in Hb, myoglobin and enzymes Used to treat: - iron-deficiency in pts with chronic anemia who cannot be maintained with oral iron (ex. chronic kidney disease undergoing hemodialysis in conjunction with supplemental erythropoietin therapy) - treatment of iron-deficiency in pts who are unable to tolerate or absord oral iron Adverse effects - not so bad: injection site reactions, headache, light-headedness, muscle cramps, nausea and diarrhea

Transferrin (Tf) binds

Fe3+ in the blood * it carries 2 Fe3+ ** it is the main iron carrier in circulation - It is rarely occupied- normally around 30% of sites have iron (normal range is 20-55%) Transferrin concentration is measured as Total Iron Binding Capacity (or TIBC): how much iron can be bound by transferrin Serum Iron/Total Binding Capacity= Transferrin Saturation ** these numbers are useful in screening chronic iron overloas or deficiency

Ferritin and Hemosiderin (a partially denatured form of ferritin, that is abundant when iron stores are high) store

Fe3+ in the cell ** Ferritin is the major storage form or iron in cells, it is regulated to maintian iron levels appropriately and measured clinically for anemia and hemochromatosis - Ferritin can oxidize iron to Fe3+ and stored it in a mineral form (ferric hydroxyphosphate FeO(OH) with some FeO(H2PO4)- this is enclosed by 24 subunits in a shell around the mineral core- makes a repeating unit of iron storage (many of thses are inside the shell) - release of iron from ferritin occurs by transport of ferritin to lysosomes (along with DMT1 transporters), where it is degraded and the iron reduced and exported Nml values: - Men: 18-270 ng/mL - Women: 18-160 ng/mL - Children (6 months-15yrs): 7-140ng/mL - Infants (1-5 months): 50-200ng/mL - Neonates: 25-200 ng/mL >1000ng/ml- indicates hemochromatosis * ng/mL= nanograms per milliliter * ng/mL- mcg/L

Iron is stored as cells as

Ferric Iron (Fe3+) in ferritin and hemosiderin ** NOTE: iron is also transported in the blood as ferric iron bound to transferrin

Transport of iron across the membranes requires it to be in the

Ferrous State (Fe2+)- divalent cation transporters ** redox enzymes called ferroxidases cooperate with membrane transporters to change the oxidation state

Thrombin also activates Plasmin which leads to

Fibrinolysis Fibrin polymer (with help of Plasmin that becomes activated by Thrombin) is lysed into Fibrin fragments ** this clot dissolution occurs as soon as the injury is healed - to restor the normal flow of blood ** Plasminogen is converted to the active form PLasmin by 2 distinct Plasminogen Activators (PAs): - tissue plasminogen activator (t-PA) from injured endothelial cells - urokinase from kidney endothelial cells and plasma

What hormone is responsible for reducing plasma phosphate alone

Fibroblast Growth Factor 23 (FGF23) - secreted by osteocytes and to a lesser extent, osteoblasts - primary stimulus for secretion is increased serum phosphate or increase phosphorus - other stimuli= PTH and calcitriol - it is a peptide hormone, water soluble, short half life Direct effects 1. impairs sodium-dependent phosphate transport in both intestinal and renal brush border membrane vesicles 2. inhibits production of calcitriol and stimulates breakdown of calcitriol 3. inhibits production/secretion of parathyroid hromone * it DOES NOT directly interact with calcium

Mineralcorticoid drugs

Fludrocortisone (a corticosteroid agonist)

Differences between the Folic Acid Preparations: Folic acid and Leucovorin (folinic acid)

Folic Acid - given oral (preferred), IM, IV, and SubQ - MOA: supplementation of folic acid required for enzymatic reactions necessary for nucleic acid synthesis - used as supplementaton to prevent neural tube defects in developing fetus Leucovorin - oral, IM and IV - MOA: is a reduced form of folic acid- provides folic acid required for nucleic acid synthesis. Bypasses the dihydrofolate reductase catalyzed reaction that synthesizes tetrahydrofolate, which is blocked by the chemotherapy drug methotrexate - used as rescue agent after high dose methotrexate (cancer chemotherapy drug) treatment - cancer chemotherapy; increase the toxicity of the cancer chemotherapy drug 5-fluorouracil ** BOTH used in treatment of megaloblastic anemia due to folate deficiency

In the cortex of the lymph node this is where

Follicles with B cells are found - in paracortex T cells are found

What can be found in a secondary follicle that is required for the creation of more specific antibodies

Follicular Dendritic Cells (FDCs) - found in the germinal center of secondary follicles - have Fc receptors; can bind antigen antibody complexes - have many cytoplasmic processes that can TRAP antigen; FDCs are NOT APCs, they dont phagocytose and process antigen ** they are require for creation of more specific antibodies - B lymphocytes that can make more specific antibodies bind tighter to antigen coating FDC - Soak up growth factors produced by FDC and stay alive - the lower affinity ab-producing cells die by apoptosis because they DONT get growth factors

Growth hormone has important direct effects on protein, lipid, and carbohydrate metabolism

For carbs and lipids: - generally works in the OPPOSITE direction as insulin, it causese INCREASES in plasma glucose and TAGs For AA and overall growth - it acts in the same direction as insulin, uptake of AA, increased protein synthesis and growth, and decreased protein catabolism ---- so Insulin and GH workin in opp directions (insluin gets glucose out of the blood, GH gets it into blood) BUT once in the tissues they work similarly- both work to increase protein synthesis

Hormones that can increase blood glucose in the presence of hypoglycemia include

For the postabsorptive state: the most important is glucagon, but others (ex. cortisol, EPI, GH, and thyroid hormone) also play major roles ***In contrast, ONLY INSULIN is available to directly deal with a hyperglycemic state (most typical is the transient period known as the absorptive state) and bring it back towards normal blood glucose level - Insulin has no back up hormone in case it fails

Free (unbound or unchelated) iron is

Free iron (Fe3+ and Fe2+) is dangerous due to catalyzing free radical formation * Role of iron in Haber- Weiss reaction: Free iron can catalyze formation of hydroxyl radical, the hyper-reactive ROS species NOTE: Fe3+ is safer- but almost all iron in the body is tightly bound to proteins

What small molecule inhibits fructose 1,6-bisphosphatase (one of the 3 unique enzymes in gluconeogenesis)

Fructose 2,6-bisphosphate - this small reg. molecule directly inhibits fructose 1,6 bisphosphatase, competitively - this is part of the insulin/glucagon regulation of the PFK-1/F16BPase regulatory bubble

Fructose 1,6-bisphosphate is regulated by

Fructose-2,6-bis-phosphate concentration

Both monocytes and neutrophils share ___ as their progenitor

GFU-GM

GHRH from the hypothalamus stimulates the release of

GH (aka somatotropin) from the anterior pituitary which works on the - liver and other cells to secrete IGFs (aka somatomedins) - and other organs and tissues to increase protein synthesis metabolism of carbohydrates and lipids *** GHIH (aka somatostatin, SST, SS, SRIH) from the hypothalamus has an inhibitory effect of GH in the anterior pitutary and inhibits these functions

Hypothalamo-pituitary-liver axis for GH and IGF

GH: exerts short-loop feedback being a pituitary hromone IGF-1: exerts long loop feedback being a peripheral gland hormone * both are negative feedback bc end result is restriction of GH secretion from the pituitary somatotropes - by restricting hypothalamic GHRH you limit GH secretion - by stimulating hypothalmic release of the inhibitory somatostatin you also inhibit GH secretion from pituitary gland - if you directly inhibit somatotropes you limit GH secretion too - hypothalmic NYP-secreting neuron also increases somatostatin secretion and is an access point for other forms of modulation

The different GLUT transporters and their Kms

GLUT1 is the default transporter in most tissues, including skeletal muscle (it is NOT in the liver, kidney, intestines or beta-cells) - has medium Km GLUT2 has a HIGH Km wrt the physiological blood glucose concentration- the higher the glucose the faster it enters into cells, good for organs that need glucose to import to increase upon feeding (liver, kidney, intestine). Thus, transport is responsive to changes in glucose concentration - in these tissues, the glucose entry is NOT rate limiting, rather glucokinase activity is the rate limiting step in committing glucose to the cell GLUT3 has a LOW Km - higher or lower glucose will NOT have a large effect on how much glucose enters the cells. The brain which relies on glucose, then maintains a reasonable supply even at lower randes of blood because the GLUT3 transporter is low Km GLUT4 transport has a medium Km (like GLUT1)- this is the INSULIN SENSITIVE transporter, works in adipose tissue and muscle - this is the principal means of hormone regulated glucose utilization ** in tissues with GLUT1/GLUT4, typically glucose entry is the rate limiting step in glucose metabolism

CaSR (calcium-sensing receptor) is a

GPCR that functions to adjust rate of secretion of PTH in response to the level of circulating calcium * calcitriol may affect PTH production and secretion in hyperparathyroid secreting states by altering the synthesis of both the CaSR and PTH

Hemochromatosis

Genetic Iron Overload 10-40g of iron (2.5g is typical in a male) * more prevalent in older men from northern europe *** exacerbated by mutations in HFE gene (homozygosity for the C282Y mutation) , which senses iron in the liver: this reduces hepcidin secretion, more iron absorption through ferroportin - this affects the liver, heart, and endocrine glands, anterior pituitary malfunction, darkening of the skin - it increases risk for liver cirrhosis, diabetes, cardiomyopathy, and arthritis Treatment= repeated phlebotomy ** only 5% of homozygotes develop symptoms - "Bantu hemosiderosis" in South Africa is caused by a mutation in ferroportin gene

The protein part of hemoglobin is

Globin * fromed in cytoplasm and joined in the cytoplasm to the heme that was fromed in the mitochondria - Hemoglobin- erythrocyte - Myoglobin- muscle (if in blood indicated muscle damage- called rhabdomyolysis, or toxicity to the kidney: protoxin as myoglobin, ferrihemate is the toxin (it dissociates from myoglobin in acidic environment) - Neuroglobin- nervous system (used as oxygen store during ischemia and hypoxia)

Zone fasciculata (ZF) of the adrenal (suprarenal) gland secretes

Glucocorticoids- cortisol

Glucokinase vs. Hexokinase

Glucokinase- in liver, pancreas (high Km- simialar to Km of GLUT2 ) Its regulation: - induced by insulin (higher expression levels) - cooperative response to glucose (sharper transition point with changes in concentration) - mobilized from nuclear sequestration by glucose (sequestered in nucleus during fasting state) Hexokinase- in muscle and most other tissues (low Km) * regulated step- strongly favorable -- Hexokinase commits glucose to the cell in many tissues, however: 1. In liver, G6P can be reversed to glucose by glucose-6-phosphatase to export glucose, or G6P can be diverted to glycogen storage 2. In skeletal muscle, G6P can be diverted to glycogen storage, for entry into glycolysis at a later time 3. Most other tissues neither export glucose, nor store much glycogen (most store a little), so hexokinase largely determines entry into glycolysis

Von Gierke Glycogen storage disorder is due to deficiency of

Glucose-6-phosphatase

Oxytocin is mature when the ___ removed leaving the amino group

Glycine ---Prepro-oxytocin has the amino portion cutt off, removal of the glycine from this portion yields oxytocin- The other portion of prepro-oxytocin that was left behind gave Neurophysin I, also the COOH portion yields Hid - Neurophysin I is the transport protein for oxytocin (it is a monomer and carries 1 oxytocin)

Deficiency in Glycogen Synthase leads to

Glycogen Storage Disorder 0 - characterized by fasting hypoglycemia and postprandial hyperglycemia and gluoseuria

A key liver enzyme that responds to high extracellular insulin is

Glycogen Synthase Kinase (GSK) - Insulin acts on Akt protein (protein kinase B) which in turn modifies and inhibits basal acitivity of GSK. Therefore, when insulin is present the net effect is less conversion of glycogen synthase "a" into glycogen synthase "b', and more of the available glucose is stored as glycogen

Regulation of glycogen metabolism in muscle

Glycogen phosphorylase is - Inhibited by G6P and ATP - Activated by Ca2+ and AMP (important in muscles bc there may be more immediate needs for glycogen reserves during muscle contraction) *Particularly important for muscle: AMP allosteric activator and Ca2+ through effects on calmodulin-dependent phosphorylase kinase- via neuronal stimulation of muscle activity Glycogen synthase is activated by G6P

Glycogenesis

Glycogen storage that occurs in - Mostly liver and muscle - smaller amounts in other tissues (like RBCs) Liver glycogen: for maintaining circulating glucose Muscle glycogen: for energy during exercise ------ Main points: 1. Protein called Glycogenin (which is part of glycogen) - it carries out the initial two glucose additions 2. Glycogen synthase does elongation of the glucose chain with alpha 1,4-linkages 3. Branching enzyme adds branch points as needed using alpha 1,6 linkages Steps: - G6P converted to G1P by phosphoglucomutase - G1P converted to Uridine-Diphosphate-Glucose (UDP-glucose) - Glycogenin catalyzes addition of 2 glucoses to itself on a tyrosine, using UDP-glucose as the substrate - Glycogen synthase catalyzes chain lengthening of alpha (1-4) glycosidic linkages using UDP-glucose as a substrate - Branching enzyme moves a chain to make alpha (1-6) glycosidic linkages and generates a branch point

GEMM stands for

Granulocyte Erythrocyte Monocyte Megakaryocyte & Mast cell

Most common cause of Hyperthyroidism

Graves Disease

The immunoglobin isotype is determined by the

H chain constant region

Collagen Type I is stained with

H&E

Antihistamine drugs are

H1 receptor antagonists

The Three MHC-I genes (alpha-chain) are

HLA-A, HLA-B, HLA-C * HLA stands for Human Leukocyte Antigen ** these are on ALL somatic, nucleated cells (hence erythrocytes and gametes do not normally express HLAs)

t1/2

Half-life: the time required for half of the drug in the body to be removed - after 1 half-life: 50% of the original amount of drug in blood remains - 2 half-lifes: 25% of the original amount - 3 half-lives: 12.5% - 4 half-lives: 6.25%

What is an Idiotype difference in and antibody

Has to do with the Fab region (antigen binding site) * determined by the variability of the domains of the heavy and light chains *** sooo has to do with variations in variable region, particularly the hypervariable region ** this defines the specificity (which antigen it will bind) ----- Different from isotype*** which deremined the class of Ig

Why do RBCs sickle?

HbS molecules aggregate and polymerize in deoxygenated state into long needle-like fibers (RBCs assume a sickle/boat-like shapr) * predominantly extravascular hemolysis of sickle cells - cytoplasm is transformed into a rigid filamentous gel and leads to less deformable sickled red cells NOTE: HbS must be >60% in order for RBCs to sickle this is why you rarely see sickling in Sickle Cell Trait bc HbS is too low in HbAS to produce sickling in peripheral blood ** sickling may occur at high altitudes or increased atmospheric pressure (scuba diving) Increased deoxyHb causes increase risk sickling - Acidosis (causes O2 release from RBCs) - Dehydration: increase deoxyHb in RBCs - Hypoxemia: decrease O2 saturation of Hb

Blood collected in the presence of an anticoagulant (heparin or sodium citrate) and centrifuged will form what at the bottom

Hematocrit - this is the percentage of red blood cells (42-47%) above this there will be the Buffy coat (leukocytes and platelets, 1%) - and above this at the top is the Plasma which contain albumin, fibrinogen, immunoglobulins, lipids (lipoproteins), hormones, vitamins, and salts as predominant components

The percentage by volume of packed red blood cells in a given sample of blood after centrifugation is referred to as

Hematocrit In males= 40-50% Females= 35-45% ** note that males have more erythrocytes per unit volume than females do males= 4.7-6.1 x10^6/ mm^3 females= 4.2-5.4 x 10^6/mm^3 ** Females have a lower hematocrit because they menstruate every month- women with heavier flows can at times become anemic- this is not much concern for a doctor- they will just prescribe/recommend that the women take iron. However, for a male this is much more alarming it may signify a problem such as colon cancer where a pt may be losing significant amounts of blood through their stool

Porphyrin- iron complex is

Heme - Fe2+ is added to the porphyrin in the bone marrow - iron on transferrin is picked up from the blood by immature erythroblasts in the marrow - Heme is assembled in the mitochondria of immautre erythroblasts

which is absorbed more efficiently: Heme or Non-heme iron

Heme iron

In the body- the most mg of Iron can be found in

Hemoglobin - with men having more than women

Best indicator of oxygen-carrying capacity of blood

Hemoglobin (Hb) * it is accurate and preferable to hematocrit for diagnosis of Anemia

Examples of Anticoagulants

Heparin Citrate Oxalate EDTA Ex: Blood + Anticoagulant ( like Citrate/EDTA - binds to Ca++ and Mg ++ ) centrifuge gives you plasma as the supinatant (plasma is 60% albumin, as well as other plasma proteins- and it does have fibrinogen)

What increases the activity of ATIII and aPTT in vitro

Heparin (drug) - is purifed from animals

Decreased levels of plasma cholinesterase (BuChE) could be indicative of

Hepatic disease: decreased synthesis of the enzyme or an Inherited abnormal variant of plasma cholinesterase with low biological activity - Ingestion of organophosphates (OP's) or absorption via skin interferes with the activity of both plasma and acetyl cholinesterases. OP's are irreversible inhibitors of acetylcholinesterase ** clinical symptoms of this arise from the buildup of ACh Treatment: Atropine Sulfate (competitive antagonist of ACh receptors- it inhibits the action of ACh on all the muscarinic receptors)

Increased GGT (Gamma-Glutamyltransferase) is increased in

Hepatocellular damage

Hepcidin acts to

Hepcidin is released when iron is high It works to limit iron absorption by inhibiting the iron exporter ferroportin in: - intestinal enterocytes - macrophages (which phagocytose sensecent RBCs and release the iron from the cells to the circulation) - liver stores * its net effect is to LOWER circulating iron and dietary absorption and it effectively acts as FEEDBACK INHIBITION NOTE: - iron increases hepcidin - some pathological conditions (cancer or inflammation) also increase hepcidin - hepcidin is regulated transcriptionally (increased hepcidin mRNA levels with higher iron levels) ** Iron can be rate-limiting for growth of bacteria in blood. Hepcidin restricts iron supply in infections and cancers and lead to Anemia of Chronic Disease because Iron is trapped in macrophages

A Macro-ovalocyte of a RBC could be seen in

Hereditary Spherocytosis

A patients RBCs are found to be round and convex this could be do to

Hereditary Spherocytosis (HS) - a somatic dominant trait * defective spectrin or ankyrin, which binds spectrin to plasma membrane ** the RBCs do not form their normal biconcave shape but rather they are found to be round and convex --- this makes them abnormally fragile and prone to rapidly break down- they also transport less O2 ** Morphology of HS: RBCs are more spherical, lack the central area of pallor on a stained blood film

Lymphocytes enter secondary lymphatic tissue by diapedesis through specialized blood vessels called

High Endothelial Venules (HEVs) - the endothelial cells lining there are cuboidal/coulmnar (rather than squamous like other blood vessels) * they are located in the paracortex of the lymph node

The purpose of insulin is to regulate blood glucose (sugar) in the normal range, it is secreted in response to

High blood glucose Action: stimulates many cells of the body to absorb and use glucose thereby decresing blood sugar levels * C-peptide (connecting peptide) from the original proinsulin molecule is co-secreted with insulin - its secretion is inhibited by low blood glucose- ** An example of product-mediated negative feedback (different, than say, levels of GH in the blood) ------ Insulin is a peptide hormone so it requires - hnRNA transcription - mRNA processing - translation - post-translational processing - its secretion is via exocytosis, like every other peptide hormone

Innate Effector Functions include

Humoral Response - acute phase proteins (ex. CRP) - complement Cellular Response - phagocytes - intra epithelial lymphocytes - natural killer cells ** cellular responses use receptors such as Toll-like receptor, cytokine receptor, and complement receptor- which can release cytokines, phagocyte oxidase, nitric oxide, and enhace phagocytosis respectively- leading to inflammation (enhanced adaptive immunity), or the killing of the microbe

Most high risk adverse effect of calcitriol administration

Hypercalcemia ----- Calcitriol is most likely required in the treatment of renal failure - calcitriol can help to promote intestinal calcium absorption

Bone marrow in neutropenic pateints

Hypercellular: - compensatory increase with peripheral neutrophil destruction - ineffective production (megaloblastic anemia, MDS) Hypocellualr: - agents that suppress or destroy granulocytic precursors - aplastic anemia

Major clinical manisfestation of Primary Hyperaldosteronism

Hypertension (retention of Na+) - hypokalemia in severe cases --> muscle weakness and cardiac arrhythmias Classification by cause: - Bilateral idiopathic hyperaldosteronism due to bilateral nodular adrenocortical hyperplasia (in 66% of cases- most common cause*) - Solitary aldosterone-producing adrenocortical adenoma (Conn syndrome -33% of cases) Rare causes: - Adrenocortical carcinoma - Glucocorticoid- remediable due to mutations in zona glomerulosa cells make them responsive to ACTH

Biggest risk of "tight control" of Type I Diabetes is

Hypoglycemia

The true "master gland" of the body- for endocrine purposes

Hypothalamus - it is a site of production of many "releasing" and "inhibiting" hormones that affect anterior pituitary gland function - site of production of oxytocin and vasopressin/ADH, which will eventually be secreted in posterior pituitary - controlled through feedback systems with modulation from neural and hormonal factors

Secondary Endocrine Glands (have priamry functions associated with other organs)

Hypothalamus Pineal gland Heart (right atrium) - atrial natriuretic peptide (ANP) Liver Stomach Kidney Adipose tissue - Leptin Small intestine

How is EPO concentration regulated by oxygen levels?

Hypoxia-inducible factors (HIFs) are constitutively synthesized transcription factors for EPO ** in the presence of HIGH levels of oxygen, HIFs are hydroxylated and proteosomally degraded, transcription of EPO falls

The hypothalamus has 2 morphological and functional classes of neurons (I and II) that fall into 3 functional categories

I. Magnocellular (big neurons) 1. These neurons (functional category) contain VASOPRESSIN and OXY. they project axons into the posterior pituitary (neural lobe) for hormone release II. Parvicellular (small neurons) 2. A subset of neuron, the neuroendocrine-related functional group- they project into the median eminence (ME)- they secrete RELEASING and INHIBITING hormones into the hypohphyseal portal blood stream (long portal vessels) for control of anterior pituitary hormone secretion 3. A subset of parvicellular neurons of the PVN. They are involved in central autonomic control and are thus outside the normal scope of this module

Expresssion of IgG2a is induced by

IFN-gamma Inhibited by IL-4

Cytokines inolved in antiviral activity

IFN-gamma TNF- alpha

The expression of IgG3 is induced by

IFN-gamma and Inhibited by: IL-4 and TGF-Beta

GH acts first on the liver, muscle, and adipose- then the

IGFs bind to receptors on its target tissues throughout the body to regulate growth and maintenance ** IGF1 is apprx only 1/10th to 1/12th effective as insulin in lowering serum glucose, so most of actual glucose uptake required for skeletal muscle growth is probably being mediated by insulin directly, not IGF-1

Cytokines involved in TH1

IL-12 (released from macrophages- stimulates the secretion of IFN-gamma by NK cells, which in turn activates macrophages to increase their microbicidal activity) IFN-gamma TNF-alpha ** these target macrophages and activates them so that they can protect against intracellular pathogens

Th17 cells migrate to the tissues where they release

IL-17 and IL-22 (to get rid of extracellular bacteria and fungi) - In the BM: IL-17 triggers BM cells to secrete IL-6, G-CSF, and GM-CSF to increase monocyte and neutrophil (especially) production- this explains the neutrophilia associated in bacterial infections - In epithelia: IL-17 and IL-22 stimulate the production of more proinflammatory cytokines (IL-1, IL-6, and TNF-alpha) as well as chemokine (CXCL8 and CXCL2) to recruit newly produced neutrophils to the infection site, and the production of antimicrobial peptides such as defensins; IL-22 also contributes to greater barrier integrite of epithelia

Cytokines involved in proliferation

IL-1Beta IL-2 IL-6 IL-7 IL-21 M-CSF G-CSF GM-CSF

Many available drugs aimed at reducing inflammation act on

IL-1Beta signaling or the gene products it activates

Cytokines involved in hematopoiesis/ development

IL-3 IL-5 IL-6 IL-7 M- CSF G- CSF GM- CSF

Cytokines involved in TH2

IL-4 IL-5 IL-13 IL-10 ** these activate eosinophils and mast cells; and alternative macrophage activation against Helminths

IgG1 expression is induced by

IL-4 inhibited by IFN-gamma

IgE expression is induced by

IL-4 and inhibited by IFN-gamma

The expression of IgM is inhibited by

IL-4, IFN-gamma, and TGF-beta

In order to deal with a large extracellular pathogen (worms), what cytokines will be produced

IL-4, IL-5, (IL-10) and (IL-13) ** mast cells and eosinophils release this IL-4 - these will produce a TH2 cell NOTE: aberrant TH2 activation is involved also in asthma and allergies (TH2 signals eosinophila to attack parasites (helminth) - can play a role in allergy)

Which cytokine stimulates hepatocytes to produce actue phase proteins that function as early indicators of inflammation

IL-6

Cytokines involved in TH17

IL-6 TGF-Beta IL-17 IL-22

In order to deal with extracellular microorganisms, what cytokines will be produced

IL-6 and TGF-beta (secreted by dendritic cells) these make an inflammatory Th17 cells - which goes on to secrete IL-17 and 22 ** Some types of TH17 responses are also involved in the development of autoimmune disease hence TH17 are divided into inflammatory (i.e protective) and pathologic (i.e. autoimmune) - these TH17 work via neutrophils to attack extracellular pathogens- and they may play a role in autoimmunity

Cortisol, which helps to facilitate protein breakdown in skeletal mucles, actually

INCREASES protein synthesis in the liver - Same with GH * glucagon, cortisol, GH all promote gluconeogenesis

A PTT test would show abnormalities in

INTRINSIC and Common pathway deficieny/inhibition of XII, IX, VIII, X. V, II, I ** this is commone in heparin therapy

A secretory component is ONLY found in

IgA

IL-5 augments the production of

IgA - TGF-beta induces the production of IgA

Late antibody

IgD (higher affinity than IgM)

Which two isotypes are expressed on the surface of naive B cells

IgD and IgM

Expression of IgG2b is induced by

IgG2b

first antibody

IgM (low affinity and short half life- this is why it needs to switch from IgM to IgD= Somatic Hypermutation)

BCR is classified as an immunoglobulin. What two immunoglobulins can it be

IgM and IgD ** remember as the B cell develops it must engage RAG1/ RAG2 to mediate gene rearrangements (this allows for adpative diversity)

What is involved in the humoral immune response to T- INDEPENDENT antigen

IgM production

What molcules are required in B cell signaling

Igalpha and IgBeta are required for the signaling of a BCR ** remember CD3 was required for the signaling of a TCR

Antigens that provoke an immune response are termed

Immunogens - ALL immunogens are antigens - but, NOT all antigens are immunogens ** sooo not all antigens are able to provoke an immune response

Glycogenolysis

In fasting state: (insulin dropping, glucagon rising) - maintains circulating glucose concentrations and prevents hypoglycemia during short to intermedia-term fasting (2-4hr plus) - it releases glucose for export to the circulation - insulin is low, glucagon is high. Cortisol, epinephrine and norepinephrine may also be high ------ Glycogen phosphorylase: cleaves the 1,4-glycosidic bond of the linear portions of the glycogen chain from the non-reducing ends yielding glucose-1-phosphate Glycogen debranching enzyme: processes the branch points through a seires of transfers of glycosidic bonds between shortened branches- the branch point itself (1-6) is hydrolyzed to glucose rather than glucose-1-phosphate by the debranching enzyme

How is iron regulated intracellularly

In iron deficiency, cells make more transferrin receptor and less apoferritin - this is done by Iron Regulatory Proteins (IRPs)- that bind to iron response elements in the mRNAs when iron is scarce- these are forms of TRANSLATIONAL regulation * at same time a decrease in Ferritin means you will release more Fe from iron store

Gluconeogenesis

In the fasting state Purpose: to maintain circulating glucose conc. and prevent hypoglycemia during extended fasting (>4hr) occurs in: liver and kidney - synthesizes glucose for export to the circulation - hormone status: insulin is low, glucagon is high. Cortisol, epinephrine, and norepinephrine may also be high --- During extended fasting (early starvation), insulin drops to low levels and glucagon continues to increase. Glucagon stimulated glycogen breakdown to supply circulating glucose, and with extended fasting, will then also induce gluconeogenesis- the synthesis of glucose from precursors -- Pyruvate is considered start point in this process, it cant be directly revered to PEP so it goes through 2 other reactions: - conversion to oxaloacetate --> phosphoenolpyruvate (OAA is a TCA cycle intermediate and allows TCA cycle to feed into gluconeogenesis) - from PEP glycolysis is revered till Fructose 1,6-bisphosphatem where a separate enzyme is required to convert it to F6P - the reversal results in G-6P. Another gluconeogenic enzyme, glucose phosphatase is req. to convert G6-phosphate to glucose

In what compartment does the acutal production step of T3 and T4 synthesis take place

In the lumen of the thyroid follicle

The greatest concentration of T lymphocytes is found in which part of the lymph node

In the paracortical zone

Define an antigen

In the past: An antigen is a substance that induces the formation of antibodies because it is recognized by the immune system as foreign to the body Presently it is defined as: - a molecule that is recognized by the immune system - a substance that can induce an immune response, usually foreign * NOTE: the immune response is not limited to antibody production; may be humoral or cellular, innate or adpative * when an antigen actually produces a response it is referred to as an immunogen (sometimes an antigen is unable to produce a response)

What occurs once senescent erythrocytes are taken up by macrophages

In these macrophages heme is converted to bilirubin which then travels on albumin to the liver - the liver conjugates bilirubin and sends diglucuronide to bile and intestines - bilirubin is deconjugated in intestine and converted to urobilinogen (whihc is mostly converted by bacteria to brown stercobilin and excreted- some is re-absorbed, oxidized in the kidney and excreted there as urobilin (yellow) unconjugated= indirect bilirubin conjugated= direct bilirubin

Thalassemia:

Inability to make hemoglobin alpha or beta chains

Pathogenesis of Neutropenia

Inadequate/ ineffecitive production: - aplastic anemia (bone marrow failure) - space-occupying lesions - solid cancers - granuloma - hematologic malignancies that suppress granulopoiesis DNA problems - megaloblastic anemia - cancer chemotherapy, radiation sickness Increased destruction/splenic sequestration - immune mediated injury- idipathic, SLE, drugs - splenomegaly Increased peripheral utilization: - overwhelming bacterial, fungal, rickettsial infections Drugs - anti-cancer drugs-alkylating agents/anti-metabolits - idosyncratic reaction: aminopyrine, cholramphenicol, suldonamides, chlorpromazine, thiouracil, phenylbutazone

Primary affect of calcitriol

Increase intestinal absorption of calcium and phosphate ions (increases calcium levels) MOA: increase in production of proteins in intestinal epithelial cells that facilitate the absorption process - this occurs when calcitriol binds to Vitamin D receptor and increases the transcription of these proteins * this assumes adequate Ca2+ is being taken in in the diet ----- Secondary effect - increases calcium and phosphate reabsorption Tertiary effect (only in emergencies) - until calcium and phosphate levels are restores ---- Calcitriol DIRECTLY: inhibits PTH mRNA transcription INDIRECTLY: decreases PTH secretion- by increasing plasma Ca++

Factors stimulating insulin secretion

Increased - blood glucose - blood FFAs - blood AA's - GI hormones (gastrin, CCK, secreting, glucose-dependent insulinotropic peptide) - GH - Parasympathetic stimulation: ACh - Insulin resistance; obesity - Certain drugs ------- **** glucose-dependent insulinotropic peptide (gastric inhibitory peptise) and ACh, increase intracellular Ca2+ through other signaling pathways and enhance the effect on glucose- but do NOT have major effects on insulin secretion in the absence of glucose

What would one expect to find in a hematological assessment of a patient with Polycythemia

Increased Rbc, Hb, and Hct can have - Polycythemia Vera - Secondary Polycythemia from high altitude, smoking, obesity, COPD etc

Transferrin saturation (normally 20-55%) and serum ferritin (normally 1.2-30mcg/dL) are

Increased in iron overload - Hematocrit (41-49%) and hemoglobin (12-18%) remain normal ** Serum Ferriten is an indicator of tissue iron stores (it is used to confirm iron deficiency) - it leaks out of dying cells in liver and elsewhere who release ferritin, and can be measured in with a radioimmunoassay (this value is much lower than serum iron- which is mostly on transferrin In iron overload: the Serum Ferriten is >50-100mcg/dL

Complications of Hemolytic Anemia

Increased ineffective erythropoiesis - destruction of RBC precursors - erythroid hyperplasia in BM - BM expansion results in bony deformities Progressive Splenomegaly - mature RBC hemolysis Extra-medullary Hematopoiesis (causes hepatosplenomegaly and formation of soft tissue masses) - Excess Fe absorption and progressive tissue deposition ** increased O2 affinity of HbF as well as the underlying anemia impair oxygen delivery and lead to increased EPO - EPO excess causes marrow erythroid hyperplase - the marrow apace is expanded causing facial and cranial bone deformities ** excess erythropoiesis causes increased iron absorption; which along with repeated blood transfusions, creates iron overload

Mechanisms and causes of leukocytosis

Increased production in the marrow - chronic infection or inflammation (growth-factor-dependent), paraneoplastic (ex. Hodgkin Lymphoma; growth factor-dependent), myeloproliferative disorders (ex. chronic myeloid leukemia; growth factor-independent) Increased release from Marrow store (like in thalassemia: - Endotoxemia - Infection - Hypoxia Decreased Margination: - Excercise - Catecholamines Decreased Extravasation into tissues: - Glucocorticoids

The rise in insulin after parenteral administration of a given dose of glucose is 2-3 times LOWER than that for the same quantity of glucose from the oral route. The difference is attributed to

Incretins (a class of GI-secreted hormones, among whose targets are beta cells- they modulate the sensititvity of insulin secretion) - Primarily glucose-dependent insulinotropic poylpeptise (aka gastric inhibitory peptide [GIP]) and - Glucagon-like peptide 1 [GLP-1] -------- The fact that GI-secreted hormone can boost insulin secretion supports a feed-forward effect in which presence of glucose in the tract causes the hormones to prime the beta cells for glucoses arrival following absorption * incretins do their function by binding to receptors on pancreatic beta cells, and increasing cAMP within the cell- the more cAMP- the more secretory proteins in the ready state- so that when the Ca2+ does arrive from somewhere else (ex: ECF secondary to high plasma glucose)- motor proteins are as charged up as possible

Causes of lymphocytosis (increase in lymphocytes)

Infections - viral: infectious mono, CMV, mumps, measles - bacteral: whooping cough, TB, brucellosis - parasitic: toxoplasmosis Autoimmune disease- SLE Endocrine- grave's disease Malignancy: chronic lymphoid leukemia

First response to infection or trauma

Inflammation - chang in vascular permeability: Mast cells aid in this: note that the immune cells are inside of the blood vessel and they have to get out to reach the site of infectionDe- Cardinal Signs: - Redness (rubor): increased blood flow-erythema - Warmth (calor): increased blood flow- pyrogens - Swelling (tumor): leakage of plasma- local edema - Pain (dolor): pressure on nerve ending, bradykinin, histamine - loss of function ** long before any of this occurs the CRP (C-reactive protein) increases (which is an acute phase protein)- this is an indicator of inflammation

Differences between receptors of the Innate Immunity vs Adaptive Immunity

Innate Immunity - Specificity inherited in the genome - Expressed by all cells of a particular type (ex. macrophages) - triggers immediate response - recognizes broad classes of pathogens - interacts with a range of molecular structures of a given type Adaptive Immunity - encoded in multiple gene segments - requires gene rearrangement - clonal distribution - able to discriminate between even closely related molecular structures

Complement can be both

Innate and Adaptive It can be activated in 3 ways: 1. Alternative Pathway 2. Clasical Pathway 3. Lectin Pathway **** classical pathway is the only one that is adpative because it involves antibodies, the other two are innate Some key players of Complement: - C3a: inflammation - C3b: opsonization and phagocytosis - C5a: inflammation - C6-9: lysis of microbe *** note ALL pathways end in lysis

What process takes place during the lag period between antigen contact and detection of adaptive immunity

Innate immune effectors are eliminating antigen

Regulation of glycogenesis by hormones

Insulin activates Phosphatase-1 (reverses phosphorylation by glucagon/cAMP/PKA pathway) - reversal/dephosphorylation of these pathways leads to: - inactivation of phosphorylase kinase and glycogen phosphorylase - ACTIVATION of glycogen synthase (is activated via dephosphorylation) --- Insulin counteracts glucagon or epinephrine beta-adrenergic signaling by increasing cAMP degradation -therby blocking PKA and the following effects --- Glucagon phosphorylates via cAMP/PKA - this activates phosphorylase kinase - inactivates glycogen synthase --- Epinephrine aslo phosphorylates via beta-adrenergic/cAMP/PKA effects - can induce Ca2+ release in the liver which also activates phosphorylase kinase

GHs indirect effects are mediated primarily by

Insulin like growth factor- I (IGF-I) - it is secreted from the liver in response to GH - a majority of growth promoting effects of GH are actually due to IGF-1 ** like GH, IGF-1 has a dedicated transport protein (IGFBP-3) that extends its half-life to match that of GH ---- so IGFs also Increase: - Synthesis of protein, RNA, DNA, and cell size and number and organ size and organ function in the kidneys, prancreas, intestine, islets, parathyroids, skin, CT, bone, heart, lung and also Increase: - AA uptake, protein, RNA, and DNA synthesis, collagen, chondroitin sulfate, cell size and number, and linear growth in chondrocytes ** unlike most other peptide hormones, almost all of the effects of IGF-1 are due to its ability to induce gene transcripiton and translation of gene products into working molecules in target cells, much as steroid would do - many of the effects of IGF-1 tend to be "long-range" such as incresed cell size and number, increased collagen mass, etc

IGF-1 has receptors that are much like

Insulins receptors - many of its growth promoting effects also resemble insulin BUT - unlike insulin, IGF-1 does NOT significantly promote glucose uptake by muslce, adipose cells- at physiological levels * another form of IGF, IGF-2 has less physiological activity in adults than does IGF-1 (but it appears to be more important than IGF-1 in fetal life) * IGF-1 can bind to the insulin receptor but at 100 times less affinity than insulin, so it is functionally inactive through that receptors ----- IGF Type 1 receptor: - ACTIVE second messenger signaling - receptor signaling: TYRK (tyrosine-kinase) phosphorylation, multiple pathways: - SH2 (Src) pathway - PI3K/PIP2 pathway - SH2 pathway

Epistasis/ Modifier gene

Interaction between non-allelic gene (interaction between one gene and a diff. one, not allowing the other gene to express itself- so basically one gene is a modifier gene of the other gene) ex. An hh person has blood type O (subtype Oh) even if she has genotype AB in the ABO system- because she has a mutation in glucose transferase ** Epistasis might be the underlying reason for reduced penetrance in some diseases ** Modifier genes is another term for epistatis interactions

Microcytic Anemia secondary to

Iron Deficiency (low Hb, low Hct, low MCV)

Methemoglobin, MetHb

Iron is in the Ferric state, Fe3+ : it cannot bind/transport oxygen- the color is deep bluish, chocolate brown (dark maroon) ** used as a treatment for cyanide poisoning - it binds cyanide at a very high affinity; poorly reversible and prevents the cyanide binding to cytochrome c oxidase, have to induce formation of Methemoglobin Note: nitrates induce methhemoglobenemia * blood stains turning brown is a result of the spontaneous formation of methemoglobin when exposed to air (hemoglobin is converted to methemoglobin spontaneously: Methemoglobin reductase --> MetHb --> Hb) ** if you have greater than 70% metHb- could result in death

Antianemia Drugs

Iron preparations: Oral: - Ferrous sulfate - Ferrous gluconate Parenteral: - Iron dextran - Ferric gluconate Iron Antidotes: - Deferoxamine - Deferasirox Vitamin B12 Preparations - Cyanocobalamin Folic Acid Preparations - Folic Acid - Leucovorin

Alkaline phosphatase (ALP)

Is used to detect bone disease (in an electropheresis you would see high levels in bone and liver) Physiological changes in ALP levels seen in: - normal pregnancy - infancy and childhood - high fat meals - diseases that affect the bile duct * - bone dieases * ------ there is also a leukocyte alkaline phosphatase (LAP) score - if its high= leukemoid reaction - if its low= chronic myelogenous leukemia

What is the function of Factor H?

It decays Bb from C3b and is a cofactor for degradation of C3b to iC3b by the serine protease FI (it works in conjunction with Factor I) * this dismantles the C3 convertase ** it is more for the alternative pathway

What would one expect to see in a hematological assessment of a pt with Anemia

It depends on the type of Anemia Blood Loss Anemia & Hemolytic Anemia: - Decreased RBC, Hb, Hematocrit; but increased Reticulocytes Inadequate production Anemia: - Decreaased RBC, Hb, Hct AND DECREASED reticulocytes

Importance of Dihydrotestosterone (DHT)

It is a more potent androgen than testosterone itself. In utero it helps males develop normal external genitalia ** remember that 5-alpha reductase is needed to convert testosteron into dihydrotestosterone * a deficiency in 5-alpha reductase inhibits this process- testosterone is therefor pushed to make estradiol instead with the help of aromatase (this increase of estradiol is what accounts for the ambiguous genitalia seen in 5alpha-reductase deficiency) ** remember testosterone can also become inactive products- along with dihydrotestosterone and estradiol

Describe the structure of the pineal gland

It is covered by pia mater, which sends CT septa into the organ, dividing it into lobules Two cell types: 1. Pinealocytes (95% of the cells) - large, round cells with pale nuclei organized into cord-like clusters - they are secretory cells and produce SEROTONIN and MELATONIN - sympathetic nerve fibers form synapses on the pinealocytes (stimulate melatonin secretion during darkness) 2. Interstitial cells (less common) - Modified astrocytes - elongated cells with elongated nuclei - supportive in function

What is the purpose of the "tight-fit" of a RBC moving through a capillary

It maximizes membrane-membrane contact to facilitate gas exchange ** RBCs pass easily through the smallest blood vessels by folding on themselves and can thus pass through even the narrowest capillaries

Type I and Type II cytokine receptors only differ slightly in structure, but they respond similarly and generally activate a

JaK/STAT signaling pathways 1. Cytokine receptor sitting on plasma membrane with JAK attached 2. Attachment of cytokine leads to cytokine-mediated receptor dimerization; JAK-mediated phosphorylation of receptor chains 3. Recruitment of STATs to cytokine receptor 4. JAK-mediated phosphorylation and dimerization of STATs 5. Translocation of STATs to nucleus 5. transcription

Cortisol is a steroid hormone

Just like any other steroid, the specific proteins produced vary by target tissue - like aldosterone, cortisol acts by entering cells, binding to a receptor in the cytoplasm, and the hormone-receptor complex acts in the nucleus to alter transcription for the mRNAs of many protein that will carry out the cellular function for those target cells * UNLIKE aldosterone, cortisol has MANY target cells with MANY different functions * NOTE: these effects do not go away till the proteins are degraded

Drug that is an inhibitor of Steroidogenesis

Ketoconazole Antifungal agent - Dose related inhibition of CYP17 and CYP11A1 involved in steroid biosynthesis - In addition to glucocorticoid synthesis, it also inhibits androgen synthesis; can cause gynecomastia as a side-effect in male patients - typical dose 2-4x dose as antifungal --- -Bioavailability decreases as gastric pH increases (why it is recommended patients take on empty stomach) -Hepatic metabolism: half life ~8 hrs Drawbacks - hepatic dysfunction, possible severe injury, death - has MANY drug interactions

Drugs that inhibit Steroidogenesis

Ketoconazole ( a corticoisteroid synthesis inhibitor)

PGF2alpha drugs

Latanprost Bimatoprost- additionally used to increase eyelash growth Tafluprost Travoprost *** these above are used in eye to treat open angle gluacoma Carboprost- effects on uterus

Which is theoretically the second complement pathway to be activated?

Lectin Pathway * this is because the lectins (Ex: Mannose-binding lectin (MBL)) that trigger this pathway are part of the so-called Acute-Phase proteins which are generated as a result of inflammation (IL-6 action in the liver) 1. MBL associates with the mannose-associated seriene proteases 1 to 3 (MASP1, MASP2, and MASP3) these are AKA mannan-binding lectin serine proteases 2. MASPs cleave plasma C4 into C4b and C4a, resulting in the deposition of C4b on cell surface and release of C4a in the fluid phase - then plasma C2 is cleaved by MASPs to yield C2a cell surface deposition and release of C2b in fluid phase in fluid phase 3. Surface bound C4bC2a= the C3 convertase which catalyzes cleavage of C3 into C3b and C3a to yield 1) microrganism opsonization and release of inflammatory soluble C3a (in analogy to the alternative pathway, this is an amplification step of the lectin pathway) and 2) C3b binding to C4bC2a to yield C5 convertase (C4bC2aC3b) 4. C5 convertase catalizes cleavage of numerous C5 molecules into C5b and C5a ** the actions of the lectin pathway C3 convertase and C5 convertase result in the same effects as those described for the alternative pathway, namely stimulation of inflammation, opsonization for phagocytosis, and pore formation as a result of MHC

C4BP prevents the formation and accelerates the decay of the C3 convertase of what two pathways

Lectin and Classical pathways of complement activation - it does so by cleaving C4b into C4c and C4d ** also remember that C4BP is also a cofactor for Factor I that leads to C3b and C4b inactivation (inhibits C3 convertase)

The lectin and classical pathways of complement activation are identical except for the opsonins that trigger their activation- what are the differences

Lectins and folicins of the lectin pathway are like C1q (the first complement component of the classical pathway of complement activation) - also MASPs from lectin pathway are homologous to the serine proteases C1r and C1s of the classical pathway of complement activation * C1q is a hexamer of 6 collagen-like arms that each posses a globular head, the head being the part that binds the Fc portion of antibodies

Neoplastic WBC disorders include

Leukemia Lymphoma

How can you tell apart the leukemoid reaction vs leukemia

Leukemoid reaction has high LAP score Chronic myelogenous leukemia has low LAP score ** soo LAP score is increased when it is just reaction, not cancer LAP= leukocyte alkaline phosphatase (LAP)

Deficiency in complement receptors could lead to

Leukocyte adhesion deficiency - deficiency in CR3 or CR4 (mutation in beta chain of CR3 and CR4; the beta chain (CD18) of CR3 & CR4 is shared by the CD11/CD18 family of integrins) - leads to defects in leukocyte adhesion and therefore, recruitment of neutrophils (leukocyte adhesion deficiency) - leads to recurrent pyogenic infections

An increase in the total number of white cells per liter of blood exceeds the higher limit of normal in peripheral blood due to any cause

Leukocytosis> 11,000/cmm * normal range of white cell count: 5,000-11,000cmm Causes: Physiological - newborn, pregnancy Pathological - early reaction to many diseases - type of WBC affected varies with cause - neoplastic/non-neoplastic conditions Ex: can be a combination of any of the following: - neutrophilia - lymphocytosis - monocytosis - eosinophilia - basophilia

Inhibition of COX-1 and COX-2 will increase production of

Leukotrienes - can lead to asthmatic symptoms

Most appropriate single agent to perscribe to pt with hypothyroid

Levothyroxine (T4)- primary drug used for thyroid hromone replacement therapy - while liothyronine may sometimes be indicated as a second drug- it is rarely indicated for single use

Acute adrenal insufficiency

Life threatening Sxs: Nausea, vomiting, abd pain, dehydration, hypnatremia, hyperkalemia, weakness, lethargy, hypotension Causes: - Adrenal gland disorder - Structural/functional lesions of anterior pituitary or hypothalamus - Abrupt withdrawal of glucocorticoid therapy Treatment - IV Hydrocortisone or Dexamethasone - IV fluids - Therapy for any precipitating cause (treat underlying cause)

In the 5th week of gestation __ and __ are temporary hematopoietic tissues

Liver and spleen ** mostly liver ** remember 5 + 5

Hypothalamo-pituitary adrenal axis

Long loop negative feedback - Cortisol from the peripheral gland (adrenal cortex) dominates the feedback process (stops its own production) - in the gonads, it would primarily be testosterone and estrogen, the sex steroids, that would feed back upon their own production ** similarly the thyroid gland would secrete thyroid hormone, which would feed back upon the hypothalamus' action in a long loop

The thyroid gland is covered by

Loose CT capsule that sends septa into substance of the gland (parenchyma) forming a supporting framework - The parenchyma is composed of thyroid follicles that consist of a simple epithelium that surrounds colloid * Note also the presence of parafollicular cells that manufacture the hormone calcitonin

People with strict vegetarian diets may have

Low iron status * because vegetable iron (NON-heme iron) is more poorly absorbed

Antigen presentation for the purpose of T lymphocyte acitvation (response to infection) occurs in the

Lymph nodes, spleen (secondary lymphoid organs) ** this requires co-stimulatory signals (CD80/CD86)

Which Agranulocyte consititutes 20-25% of the total circulating leukocyte population

Lymphocytes - round cells, slightly indented - dense (heterochromatic) round nucleus (apprx. 8 microns) that occupies most of the cell - thin rim of cytoplasm stains light blue and contains a few azurophilic granules, BUT NO SPECIFIC GRANULES - they vary in life span (some live only a few days and others survive in the circulating blood for many years) ** the 3 groups of lymphocytes (B, T, and NK cells) ALL look the same by histological staining

Describe Lymphocyte recirculation

Lymphocytes circulate twise 1. they circulate to find antigen and become activated (inductive site) 2. they re-circulate to find and destroy pathogens (effector site)

Hematopoietic Stem Cell ((old) PPSC- pluripotential stem cell) splits into

Lympoid Stem cell (CFU-L) and a Myeloid Stem Cell (CFU-GEMM) Lymphoid Stem Cell (CFU-L): - Some migrate to THYMUS where they become T Lymphocytes, then they migrate to populate specific regions of peripheral lymphoid organs - Some differentiate into B lymphocytes within the Bone Marrow and then migrate to peripheral lymphoid organs ** actually, B cells do not completely develop until after they leave bone marrow

Eosinophil specific granules contain

MAJOR BASIC PROTEIN (50% of total granule protein) - the highly basic nature of the protein contributes to its toxicity by causing it to "gum up" and denature proteins on the plasma membrane of other eukaryotes ** it causes eosinophilia (acidophilia) of specific granules- gives eosinophils their name! NOTE: eosinophils contain diff "weapons" than neutrophils because they are hunting different "prey" (not bacteria)

T cells recognize antigens as peptides presented in

MHC (i.e. are MHC-restricted) * B cells directly interact with free antigen * MHC restriction means that the TCR must interact favorably with BOTH the antigenic peptide AND the MHC molecule (i.e. the antigenic pepitide AND the alpha1 and alpha2 domains of the MHC-I molecule, or the antigenic peptide AND the alpha1 and Beta1 domains of the MHC-II molecules ** SO recognition ONLY occurs when BOTH the antigenic peptide AND the MHC molecule are a good fit

A NK cell WILL kill a cell if

MHC class 1 is downregulated/lacking - KAR (Killer Activation Receptor) is bound - leads to release of perforin and granzymes to kill the cell

What ligand do KIRs (killer inhibitory receptors) on natural killer cells recognizae

MHC class I molecules

CD8 T lymphocytes respond to antigen presented on

MHC-I

The endogenouc MHC is

MHC-I restricted Antigen Presentation (allows for detection of injuries within the cell- like viruses) Steps include: 1. Production of proteins in the cytosol - antigenic peptides loaded onto MHC class I molecules are mostly generated by the proteasome(proteolitc degradation of proteins), peptides produced in te cytosol must first be transported into the lumen of the ER via the transporters associated with antigen presentation TAP1 and TAP2 2. newly synthesized MHC class I molecules remain inside the ER until they are loaded with antigenic peptides- this is achieved via accessory and chaperon proteins - Calnexin: keeps MHC class I alpha chain inactive and partially folded inside the ER - ERp57: does proper folding of MHC class I alpha chain through isomerization of disulfide bons present on the heavy chain - Tapasin functions like the invarient chain and/or HLA-DM chain in MHC-II (Tapaisn brides TAP1 with the MHC-II molecule) ** this occurs after the binding of Beta2-m 3. The loaded MHC class I molecule can then be transported to the cell surface, via the golgi complex and secretory vesicles, where antigen presentation occurs following the fusion of the secretory vesicles with the plasma membrane ** it can now bind with a CD8+ cytotoxic T lymphocyte

Natural killer cells (NK) cells respond to

MHC-I-like proteins or foreign proteins expressed at the surface of a cell to be eliminated These MHC-I-like molecules (or altered-self) ligands are: - MICA - MICB - (HLA-E) ** these can be induced by cellular stress to signal cytotoxiv cells that stressed cells need to be eliminated (provided that stressed cells express little or no MHC-I) NOTE: NK cells can also be activated with Pathogen-derived ligands: - viral proteins (in plasma membrane) - heparan sulfate - proteoglycans NOTE: - if the NK cells inhibitory receptor is engaged- NK cell is NOT activated; no cell killing - if the NK cells inhibitory receptor is NOT engaged- NK cell is activated; killing of infected cell

CD4 T lymphocytes respond to antigen presented on

MHC-II

There is greater variation int he length of peptides presented by

MHC-II, as compared to those presented by MHC-I - As for MHC-I, diff class II MHC alleles bind peptides with different anchor residue preferences (but these anchor residues are located more centrally as compared to MHC-I anchor residues), but a single MHC-II allele can also bind peptides with anchor residues that are related. - this agian explains the variability of peptides that can be presented by only a limited set of MHC-II molecules * the source of these peptides is mainly endosomal (phagocytic/endocytic vacuoles)

Exogenous Pathway of antigen presentation

MHC-II-restricted Ag presentation - these are produced in acidified endocytic vesicles like endosomes and phagolysosomes steps include 1. Uptake of extracellular protesin intor vesicular compartments of APC (like a dendritic cell) 2. Processing of internalized proteins in endosomal/lyososomal vesicles -- - in the mean time on the membrane of the ER there is an unstable alpha beta chain of the class II MHC- it is so unstable that it may fall apart so it is involved iwth an invariant chain (this is a place holder for the peptide- this structure goes to the golgi where it acquires sugar moieties bc it is glycoprotein 3. Is this above biosynthesis of class II MHC molecules and their transport into endosomes - at this location there are HLA-DM proteins which allow for replacement of the place holder CLIP peptide with the antigenic peptides (this is the association of processed peptides with class II MHC molecules in vesicles) 4. then at last you have expression of peptide-MHC II complexes on the cell surface which can engage a CD4+ Helper T cell

Incretin Mimetics (includes exenatide and liraglutide)

MOA: activation of GLP-1 receptor resulting in increased biosynthesis of excretion of insulin in a glucose dependent manner - CNS GLP-1 activation affects appetite and gastric emptying Pharmacokinetics - administration by SQ injection - products vary in half life, metabolic and elimination pathways - dose frequency varies from twice daily to weekly administration NOTES: - primary side effects: nausea, vomiting, delayed gastric emptying - pancreatitis - low risk of hypoglycemia when used alone - CVD benefit: liraglutid, semaglutide, dulaglutide **** Thyroid C Cell tumore- BLACK BOX WARNING ***

Sulfonylurea (includes Glimepiride and Glyburide)

MOA: bind to and inactivate the SUR1 (sulfonylurea receptor) subunit of the ATP-sensitive K+ channel on beta cells, analogous to response in the fed state, leading to release of insulin - will increase insulin release regardless of glucose levels - risk of hypolycemia Pharmakokinetics: - orally absorbed, best on empty stomach - highly protein bound - half life 2-4 hrs but effects 12-24 hrs - hepatic metabolism and renal elimination NOTES: - 50-80% initially respond. Many will cease to respond with prolonged course Conrtaindications: Type 1 pregnancy, lactations, severe renal or liver dysfunction **** SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY ---- Complications of hyperinsulinemia In Type 2 Diabetes - elevated serum insulin levels in most patients - giving medications that further increase may reduce blood sugar by may potentiate worsening in other body systems *** wont increase heart disease in combination with other products, so you should get diabetics on - low dose aspirin - lipid lowering with "statin" - ACE inhibitors (when indicated)

Alpha-glucosidase inhibitors (include acarbose)

MOA: inhibits breakdonwn of starch and oligosaccharides to monosaccharides by inhibiting alpha-glucosidase - slows absorption of carbs - blunts postprandial rise in plasma glucose Pharmacokinatics - minimal absorption (local effects) - renal elimination NOTES: - dose prior to meals and snaks - GI side effects: intensity related to food choices - May affect absorption of other medications - Used in combo therapy- not monotherapy

DPP-4 Inhibitors (include Sitagliptin and Linagliptin)

MOA: lower the activity of DPP-4 by >90% causing a two fold increase in concentrations of GLP-1 and GIP leading to increased insulin secretion and reduced glucagon levels Pharmacokinetics: all available drugs in class are orally absorbed; most given once daily, are NOT bound to plasma proteins and have renal excretions NOTES: - No consistent adverse effects noted - Possible severe joint pain

Thiazolidinediones (includes Rosiglitazone)

MOA: selective agonist of PPARy - activation of insulin-responsive genes that reg. carb and lipid metabolism - primary site of action is fat, but also muscle and liver - increases glucose utilization and decreases glucose production Pharmacokinetics: - oral absorption - hepatic metabolism - slow onset: 1-3 months for full therapeutic effect NOTES: - Monotherapy or combination therapy (req. endogenous or exogenous insulin) - weight gain and edmea - osteoperosis

Medlitinides (includes Repaglinide)

MOA: similar to sulfonylureads, bind to KATP channels in pancreatic beta cells to stimulate insulin release Pharmacokinetics - oral absorption - short halfe life (~1hr) - high protein binding - hepatic metabolism NOTES: - not for monotherapy - control of postprandial blood sugars - risk of hypoglycemia - drug interactions via protein binding or hepatic mechanismes

Folate (vitamin B9) and B12 deficiency refers to ____ anemia

Macrocytic

If a large academic center involves many divisions, specialties, and support services, linking microsystems and mesosystems to care for patients in a large geographic community it is referred to as a

Macrosystem

Complement has both innate and adaptive functions. What are they

Main function of complement is lysis of extracellular organisms - adaptive functions are activated by antibodies * the term complement was coined following initial observations that these serum proteins assisted, or complemented, microbial lysis mediated by antibodies - complement is a set of serum and cell surface proteins that interact with one another and with other molecules of the immune system to generate important effectors of innate and adaptive immune responses

Treatment goal in DM

Maintain appropriate glucose levels as continuously as possible 1. use long-acting insulin to maintain baseline insulin to support ongoing metabolic needs 2. administer short-acting insulin prior to meals to guard against postprandial hyperglycemia 3. Balance the above to prevent hypoglycemic episodes between meals and overnight

What can be found in large quantities lining the walls of the subcapsular sinus and what is its function

Many macrophages and dendritic cells line the walls of the subcapsular sinus to phagocytose any antigen, and then present it to naive T cells to begin an immune response

Basophil function is very similar to the function of

Mast cells BUT they are different cell types! On the good side of basophils: - they leave the blood and accumulate at the site of infection or other inflammation- there they release a variety of mediators such as histamine, serotonin, prostaglandins and leukotrienes which increase the blood flow to the area and in other ways add to the inflammatory process On the bad side of basophils: - they have immunoglobulin E (IgE) receptors (like mast cells) and the mediators released by basophils play an important part in some allergic responses such as hay fever and in anaphylactic response to insect stings

Average Hb concentration in a given volume of packed RBCs

Mean Corpuscular Hb Concentration: MCHC MCHC= Hb/PCV [Nml= 31-36 g/dL] *** this is what give the color or chromia of RBCs** - Hypochromic (decreased): can be due to Fe deficiency - Normochomic RBC - Hyperchromic (increased staining): can be due to hereditary spherocytosis, sicle cell disease, homozygous hemoglobin C NOTE: hyperchromic is NOT a term used clinically to describe Anemia

Average mass of Hb in an individual RBC

Mean Corpuscular Hemoglobin (MCH) MCH= Hb/RBC count [Nml= 25.4-34.6 pg] * MCH increases or decreases in parallel with MCV- therefor once you have MCV, MCH does not provide much additional diagnostic information

Most important blood INDEX for classifying Anemias

Mean Corpuscular Volume (MCV) * it is the avg volume of RBCs MCV= PCV (packed cell volume or hematocrit)/RBC count [Nml= 80-100micrometers^3 or fl] BASED ON MCV VALUE ERYTHROCYTES CAN BE CATEGORIZED AS: - Microcytic (<80micrometers ^3): Low MCV - Normocytic (80-100): Nml MCV - Macrocytic (aka Megaloblastic) (>100): High MCV ** cells are paler than normal and larger

In the medulla of a lymph node, what is the difference between the medullary cords and the medullary sinuses

Medullary cords: are sites of high antibody production containing - plasma cells - macrophages - B cells Medullary Sinuses (or sinusoids): are vessel-like spaces separating the medullary cords * lymph flows into the medullary sinuses from cortical sinuses and then into the EFFERENT lymphatic vessels

Macrocytic (MCV >96fL) wwould be found in

Megaloblastic Marrow and it could occur with Vitamin B12 or folate deficiency

Who has more erythrocytes per unit volume? People living at lower or higher altitudes

Members of both sexes who live at higher altitudes will have more erythrocytes! ** the number of RBCs in the circulation is regulated to meet O2 carrying needs and this is done via the hormone Erythropoietin (which is secreted mainly by kidneys in adults and by the liver in the fetus, it adjusts RBC production to match O2 demand)

A cardiac care program which consists of multiple services aimed at the treatment of patients with cardiac issues is reffered to as a

Mesosystem - multiple microsystems linked together to care for patients with a specific type of problem - linked microsystems working together for management of specific type of problem/problems ex: cardiac care organization - CCU and cardiac step-down units (inpatient): nursing, clerical, cardiologist - cardiac catheterization lab - cardiac rehabilitation (outpatient) ex. Emergency department - nursing, medical staff, laboratory & radiology, clerical, social services ex. Neonatal ICU care (family, physicians, nurses, respiratory therapy, biomedical technology, admissions, discharge planners, laboratory)

First line of therapy for type II Diabetes

Metformine (a Biguanide) - Monotherapy or combination * UKPDS trial showed that the use of Metformine was associated with lower microvascular complications AND lower macrovascular complications Side effects: -GI (if you start low does and titrate- tolerance develops); B12 deficiency, peripheral neuropathy - Most concerning: Lactic acidosis ** whats recommended to not get lactic acidosis: - baseline renal function and periodic monitoring - renal dose adjustments and contraindication points - suspend therapy for real or possible renal insults

Decreased iron refers to ___ anemia

Microcytic

Two types of anemia include

Microcytic and Macrocytic Microcytic: - small or immature erythrocytes - lack of: iron, heme, or hemoglobin - can be do to lead poisoning Macrocytic: (growth of RBC without division) - Megaloblastic Anemia (folate) ** enlarged cells and nuclei- do to a failure to make sufficient number of normal erythrocytes because cells do not divide normally - Pernicious Anemia (B12)

What Special cell is located in the gut-associated lymphoid tissue (GALT/MALT) of the Peyers patches and other parts of the GI tract

Microfold (M) cells - these transfer antigens from the lumen (by phagocytosis and pinocytosis) and present them to dendritic cells and macrophages & helper T and B cells lying in deep invaginations of their basal cell surfaces - then the appropraite immune response is generated in the underlying lamina propria ** the antigen is transported by the M cell to the organized lymphoid follicle containing B cells. The activated B cells mature into plasma cells, which produce secretory IgA and release it into the lumen where it reacts with antigen that caused its production

What are some abnormal shapes (poikilocytosis) that there can be of RBCs

Microspherocyte - In hereditary spherocytosis and immune hemolytic anemia Sickle cell - homozygous sickle cell disease Tear-drop cell - Myelofibrosis and Marrow infiltration ** reflects marked fragmentation Schistocyte - Microangiopathic hemolytic anemia

A small group ambulatory care clinic with multiple services such as local small lab and xray would be referred to as a

Microsystem - a small group of people who work together on a regular basis to provide care to a discrete subpopulation of patients (ex. private physician office) includes: - small group of doctors, nurses, others - some administrative support - some information technology - a small population of patients ** interdependent for a common aim, purpose

Glucocorticoid Receptor Antagonist drug

Mifepristone (RU486)

Zona glomerulosa (ZG) of the Adrenal (suprarenal) gland secretes

Mineralcorticoids- aldosterone

Spironolactone and Eplerenone are both

Mineralocorticoid (aldosterone receptor) Antagonists - Potassium sparing diuretic used in CHF, liver disease used in the treatment of primary hyperaldosteronism - Spironolactone is sometimes used as an antiandrogen - Relatively slow onset of action (several days to become fully effective) and long duration of action. Hepatic metabolism Side effects: - Hyperkalemia, Hypertriglyceridemia, Dizziness, fatigue, gynecomastia (from spironolactone) - Caution: K level >/= 5.5mEq/L at initiation, CrCl </= 30ml/min, concurrent use of strong CYP 3A4 inhibitors

Ketone bodies are synthesized in what cellular locale

Mitochondria

The largest of the circulating blood cells (range in size from 12-20 microns) are

Monocytes - an Agranulocyte- - they are ~2-3 times the diameter of RBCs - constitute 3-8% of the leukocyte population - have large, acentric, indented or kidney-shaped nucleus - the chromatin network is coarse by not overly dense - their cytoplasm is bluish gray and has numerous azurophilic ganules, (lysosomes) BUTTTTT it has NO SPECIFIC GRANULES

Marker of chonic inflammation

Monocytosis found in - Chronic infections: tuberculosis, bacterial endocarditis - Chronic inflammation in ulcerative colitis, collagen vascular diseases (SLE- systemic lupus erythematous)

Steroid hydrozylations are

Monooxygenase reactions - molecular oxygen is a substrate, and only one oxygen atom from the oxygen molecule enters the steroid - cytochrome P-450 is a heme-containing subunit of the enzyme - it activates O2 for the reaction ** this requires NADPH

A hematopoetic stem cell is

Multipotent ** they give rise to "transient" cells of connective tissue

Glycogen mobilization in the liver vs muscle

Muscle: glycogen for internal use only (exercise) ** remember muscle lacks the enzyme glucose-6-phosphatase so it can not supply any other organ Liver: glycogen is converted to circulating glucose ---- In initial fasting: liver will break down glycogen to supply circulating glucose Signaling for the breakdown of glycogen: - Liver: glucagon in the liver; epinephrine can also signal- BOTH go through cAMP/PKA - Muscle: Epinephrine signals glycogen breakdown. Also exercise via calcium or low ATP will signal glycogen breakdown * glucose is NOT sent to circulation in muscls, but used directly by muscle

at what stage of granulocytopoiesis can the cells be told apart

Myelocyte ** first stage in which specific granules appear

What kills more bacteria: NETs or by neutrophil phagocytosis

NETs!!! * these are both good and bad On good side: - delivering the granule proteins into NETS may keep potentially injurious proteins like proteases from diffusing away and inducing damage in tissue adjacent to the site of inflammation (i.e. prevent "collateral damage") On the bad side: - NETs may also later cause autoimmune disease by stimulating formation of antibodies against DNA. Exaggerated NETosis or diminished NET clearance likely increases risk of autoreactivity to NET components

which signaling pathway is at the root of the initiation of inflammatory response

NF-KBeta Signaling Pathway "canonical pathway" - can be activated with TNF family receptor, TLR, or Antigen receptor which ever it is they all lead to activation of NEMO which phosphorylates IKBetaalpha leading to protesomal degradation of it --> this realeases and translocates NF-kBeta transcription factor to the nucleus where it bind NF-kBeta responsive elements (ex. cytokine gene as cytokine receptor gene promoters among others)

Macrophage-released IL-12 following microbe internalization stimulates

NK cells to secrete IFN-gama - IFN-gamma secretion by NK cells in turn enhances macrophage microbicidal activity - this increases the macrophages killing capacity (M1= classically-activated macrophage) *** this release of IL-12 from the macrophage is targeted to treat Psoriasis, Chrons disease, and ulcerative colitis with Ustekinumad

Regulation of glycogen metabolism in the liver

NO AMP regulation unlike in muscle Glycogen phosphorylase: - inhibited by G6P, ATP and glucose - activated by Ca2+ ** liver phosphorylase is also Ca2+ activated for "fight or flight" by epinephrine/ alpha-adrenergic mediated Ca2+ release by activating phosphorylase kinase Glycogen synthase: - activated by G6P

Do chylomicrons activate hormone sensitive lipase?

NO!

Would deficiency of TBG in plasma cause any symptoms

NO!

Does Fe3+ function as an oxygen carrier

NO! only Fe2+ (ferrous iron) can bind to oxygen

Do mast cells come from basophils

NO! - Mast cells also come from CFU-GEMM, but by a different lineage than basophils

Are red bloods cells fed by fatty acids in the fasted state?

NO! - RBCs do not have a mitochondria so they cannot utilize fatty acids as an energy source

Is tissue factor just floating around in the body

NO! - it appears when you need to form a clot * tissue factor and VIIa (which does happen to be floating around in the blood) convert factor X --> Xa (which then convertes prothrombin --> thrombin, which converts fibrinogen --> fibrin) ** so clotting initially begins in the extrinsic pathway !! - As soon as we make a little Xa, that Xa along with the tissue factor pathway inhibitor turns off the extrinsic pathway! - NOTE: a little thrombin is formed before the pathway is shut off and that thrombin is actually what kicks off the intrinsic pathway! (with factors VIII and IX) - Fibrin formation then proceeds along this pathway until it is no longer needed

Are neurons and erythrocytes target tissues for insulin?

NO! Most neurons are NOT target tissues, nor are erythrocytes - Though they use glucose, their glucose transporters (GLUT-1 or GLUT-3), are INSULIN-INDEPENDENT (neither glial cells, neurons, nor RBCs are insulin-dependent) * Regulation of plasma glucose levels are therefore necessary to prevent neurons from losing their proper level of activity. Too much can be as bad as too little, but there's a wider rand into "too much" than into "too little" - A severe hypoglycemia will cause neurons to run out of ATP, since their ability to produce ATP anaerobically is minimal. This will also produce neuronal damage and could lead to death (neurons have a relatively higher metabolic rate than RBCs, so imbalances in BG more likely to affect them- disorientation, coma, etc.

Are granulocytes dividing cells

NO! they are ALL NONDIVIDING terminal cells- with a life span of only a few days after they are released from bone marrow, if they dont "die in battle" first ** withdrawal of growth factors when granulocytes leave the bone marrow is what triggers their apoptosis in the CT after a few days Lifespans: - Neutrophils: live a few hours in blood, a few days in tissues - Eosinophils and Basophils: only live a few days

Once in the blood stream do granulocytes divide again

NO! they never divide again In contrast, - monocytes/macrophages and lymphocytes all have the potential for further division

Is iron overload caused by anemia treated with phlebotomy

NOO Only Hemochromatosis- Genetic Iron Overload (due to homozygosity for the C282Y mutation in HFE gene) is treated by phlebotomy

Thyroid hormones increased production of sex-hormone-binding-globulin is

NOT directly related to metabolism

Lymphocytes are able to respond to an antigen when they see one (unlike stem cells) BUT what are they called if they have YET to be exposed to an antigen

Naive

In the case of IgG, how many antibodies do you need to activate the classicy pathway of complement activation?

Need atleast 2 Antibodies to activate in case of IgG becuase you must crosslink the Two Fc portions in order for it to work *** on the contrary the IgM antibody and 5 Fc portions so there is only one antibody needed in the case of IgM *** this is why IgM is much better at initiating complement than IgG

Glucagon release from alpha cells in the pancreas is regulated by

Negative feedback in response to the level of blood sugar Inhibited by: elevated blood glucose Activated by: a fall in blood glucose below normal, AAs (substrates for gluconeogenesis)

Increased alpha2-globulins could lead to

Nephrotic syndrome

What are the most numerous of the white blood cells

Neutrophils (aka Polymorphonuclear leukocytes) - they constitute 60-70% of the total leukocyte population Description: * the lobes of their multilobed nucleus (3-5lobes) are connected to each other by slender chromatin threads * neutrophils are motile cells: they leave the circulation and migrate to their site of action in the connective tissues (they are the best at diapedisis bc their lobes allow them to get really skinny- and slip through endothelial cells) ** neutrophils (and all WBCs) are INACTIVE and spherical while circulating in the blood stream but show an ACTIVE ameboid movement upon adhering to a solid substrate (like in the tissues)

Which cells are responsible for the major changes in WBC count

Neutrophils and lymphocytes

Describe the structure of a lymph node

Nodes are covered by a capsule (dense irregular CT) and have capsular extensions, the trabeculae, which provide support for blood vessels entering into the nodes * the concave surface contains the hilum: where arteries, veins, and EFFERENT lymph vessels enter and exit the node 3 main regions of a lymph node include: 1. Cortex: mostly B cells- contains lymphatic follicles/nodules 2. Paracortex: mostly T cells 3. Medulla: mostly plasma cells- made of medullary cords and sinuses

Chronic Lymphadenitis

Non-tender lymph node enlargement Types - Follicular hyperplasea - Para-cortical lymphoid hyperplasia - Sinus (reticular) hyperplasia - Necrotizing lymphadenitis - Granulomatous lymphadenitis

___ single type of hematopoeitic stem cell in the bone marrow gives rise to ALL the formed elements of the blood

ONE! (Multipotential hematopoietic stem cell) ** differentiates into two lines - Lymphoid Line: gives rise to ALL the lymphocytes (B cells, T cells which mature in the Thymus, and NK cells) - Myeloid line "relating to bone marrow": gives rise to everything BUT lymphocytes (erythrocytes, platelets, neutrophils, eosinophils, basophils, monocytes; also mast cells)

Which GLUT receptor is insulin dependent

ONLY GLUT-4 - it is found in the tissues that make up much of the gross mass of the body (skeletal muscle + fat) and cardiac muscle, too - it is NOT found in hepatocytes (these only have GLUT-2)

Maintenance of Iron Homeostasis

On a dialy basis as much iron is lost as is absorbed (net intesting absorption and excretion is near zero in adults) - ~1mg out of 10-20mg daily req. of iron is absorbed and a similar amt is lost to excretion along with excess dietary iron ** Iron from worn-out RBCs is recycled from macrophages in spleen, liver, and elsewhere to the bone marrow - bone marrow uses ~20mg/day for making fresh erythrocytes- this is delivered via transferrin from liver and spleen macrophages * A similar amt of iron (~20 mg total) is delivered to spleen and liver from senescent erythrocyte taken up by macrophages

Palatine Tonsils

On the L and R area of the oral cavity - dense lymphoid tissue that forms a band of lymphatic nodules that lie just below a non-keratinized, stratified squamous epithelium lining the oral cavity in this region - Overlying epithelium forms invaginations called crypts that penetrate into the band of nodules - the cryptes are labyrinth tubules that are entered by things such as bacteria and other small particles in the mouth - movement of particles down the crypts allows contact with the tonsil immune system cells - there is an incomplete CT capsule surrounding the tonsil - there are EFFERENT lymphatic vessels coming out of the tonsils, but NO afferent ones ** any antigen comes in from the mouth cavity

Opsonin vs. Opsonization

Opsonin: - molecule that becomes attached to surface of microbe and can be recognized by surface receptors of neutrophils and macrophages and that increases the efficiency of phagocytosis of the microbe - opsonins include: IgG antibodies, which are recognized by the Fcgamma receptor on phagocytes, and fragments of complement proteins, which are recognized by CR1 (CD35) and by leukocyte integrin Mac-1 (CD11b/CD18) - these are basically molecule that binds a cellular surface to trigger phagocytosis ex. antibodies, or complement components Opsonization: process of attaching opsonins, such as IgG or complement fragments, to microbial surfaces to target the microbes for phagocytosis (so this is the process of molecule binding to a cellular surface for the purpose of triggering phagocytosis)

Name the stage in erythropoiesis: Nucleus continues to condense, lose evident basophilic (but not quite all polyribosomes) resulting in uniform acidophilia

Orthochromatophilic erythroblast

which bone cell is the primary target of teriparatide in treatment of osteoperosis

Osteoblast - Teriparatide mimics PTH which works to stimulate osteoblastic bone formation --- exposure to higher levels of PTH can begin to recruit osteoclasts into bone resorption- changing net balance of bone turnover to net resorption

Primary target of calcitonin in the treatment of osteoperosis

Osteoclast - calcitonin inhibits osteoclast activity- decreases bone resorption in the short term - it is NOT an effective overall monotherapy for osteoporosis

What does PDSA stand for

P: background and aim D: intervene/do S: measure/study A: change and next steps/act ** the PDSA cycle is a model for improvement similar to a treatment plan for a patient- simple to complex with as many iterations as warranted

What ligand do KAR (killer activating receptors) on natural killer cells recognize

PAMP on microorganisms

Which step of glycolysis is bypassed by fructose-1-phosphate

PFK-1

Misoprostol

PGE1 analog used with mifepristone for termination of early pregnancy

Alprostadil

PGE1 drug used to maintian patency of the ductus arteriosus

Dinoprostone

PGE2 used for cervical ripening in induced labor

What would you use to measure the function of the EXTRINSIC PATHWAY and the COMMON PATHWAY. Extended by Warfarin

PT (prothrombin time)

Direct vs indirect affects of increases paraythroid hormone secretion and plasma concentration as a result of trying to correct low plasma calcium concentration

PTH DIRECTLY - increases bone resorption to increase release of calcium into plasma - increases renal tubular reabsorption of calcium and decreases urinary excretion of calcium - increases Calcitriol production by the kidneys, increases its plasma concentration PTH INDIRECTLY - increases intestinal absorption of calcium VIA VITD production! - Calcitrol can also decreases urinary excretion of calcium **** All these thins restore plasma clacium concentration toward normal ***

Vitamin D receptor activators

Paricalcitol and Doxercalciferol Paricalcitol - Synthetic calcitriol derivative with vitD2 (not D3) side chain - reduces PTH without causing hypercalcemia or altering phosphate - administered oral or IV - treat secondary hyperparathyroid in patients with CKD (chronic kidney disease) Doxercalciferol - Prodrug that is metabolized to active form of VitD2 in liver (DOES NOT need kidney for activation - Precaution: hypercalemia, hyperphosphatemi, over suppresion of PTH - Oral or IV administration - Treat secondary hypeparathyroid in patients with CKD

Anterior lobe of Pituitary Gland

Pars Distalis (adenohypophysis) - much larger than posterior lobe-

Posterior lobe of Pituitary Gland

Pars Nervosa (neurohypophysis) - smaller than anterior lobe-

Where is Melanocyte-stimulating hormone (MSH) thought the be released from

Pars intermedia of the pituitary gland

The two classes of neurons of the hypothalamus that most DIRECTLY affect the endocrine system are

Parvicellular (paraventricular and medial basal) and Magnicellular (paraventricular and supraoptic) hypothalamic neurosecretory cells Parvicellular: - deliver their endocrine products to capillaries that drain into a portal system, one that runs specifically from hypothalamis capillary beds to anterior pituitary capillary beds - then the pituitary cells respond to those hormones by secreting THEIR hormones into those capillaries which then go out through venous drainage to the rest of the body Magnicellular: - cell bodies are located within the hypothalamus but they DONT deliver their products to hypothalamic capillaries. Instead their axons proceed to the posterior pituitary where a different capillary bed is located. Into that different capillary bed the axon terminals of these secretory neurons will deliver their products, again to go out to the rest of the body ---- Parvicelluar: paraventricular n. , preoptic n., arcuate n. Magnicellular: paraventricular n. and supraoptic n.

Drugs that inhibit ACTH secretion

Pasireotide

Drug that is an inhibitor of ACTH secretion

Pasireotide: A Somatostatin Analog that inhibits growth hormone secretion, ACTH secretion and reduces cortisol levels - subcutaneous dosing - highly protein bound, half life ~12 hrs, renal and hepatic elimination Side effects: - Bradycardia, QT prolongation, peripheral edema, hyperglycemia, GI distress, headache, fatigue, hepatic enzyme elevation

PAMPs

Pathogen- Associated Molecular Patterns that bind with PRRs these are: - not shared with the host - common to many pathogens - invariant (preferably, ex: flu is variable always changing- not good for us) ** A Type 3 PRR: TLRs (toll-like recptors)- can be found on the plasma membrane and they recognize extracellular material ex. - TLR-2: binds Bacterial peptidoglycan (a component of the bacterial cell wall) - TLR-4: Most frequently seen* binds to lipopolysaccharide on gram negative bacteria - TLR-5: binds to flagella ** Some TLRs can also be found on the inside of the cell in an endosome and these are known to bind to viruses- specifically the nucleic acids of ingested microbes

If only the patient and the physician are invovled in a medical care scenario it is referred to as a

Patient-provider system - individual caregiver and patietn system-

The metabolic pathway which produces 5-carbon monosaccharides is the

Pentose Phosphate Pathway - the rate-limiting enzyme and comitted step for this is the Glucose-6-Phosphate dehydrogenase enzyme - this enzyme is product inhibited by NADPH, the other sig. product of the pathway ** 5 carbon sugars could still be produced by bypassing this enzyme using the glycoclytic intermediates as start points

Somatostatin (SS, SST, SRIF, GHIH) is a

Peptide hormone secreted by pancreatic delta cells and the GI tract, and the hypothalamus - stimulus for pancreatic delta cell release is increase blood glucose (lower than that needed to stimulate insulin secretion) - delta cells SST inhibits both insulin secretion and glucagon secretion * It can alter PLC/PKC, reduce cAMP, and alter Ca2+ flux to counter other hormones stimulatory effects on target tissue ------ In pancreatic islets, somatostatin is a paracrine agent, secreted from cells in the endocrine pancreas' delta cells to prevent oversecretion of both glucagon and insulin - therefore prevents "burnout" of either alpha cells or beta cells in the pancreatic islet

Long Loop negative feedback is from a

Peripheral gland hormone Ex: The hypothalamo-pituitary-adrenal axis * Cortisol released from adrenal cortex provides negative long-loop feedback (inhibits release of ACTH from pituitary and inhibits CRH release from hypothalamus)

The gene expression-production of more enzymes so that eventually there will be greater chages in the response of the cell to a given hormone is an example of a

Permissive effect - so is stoppage of production so that as existing proteins wear out eventually there will be smaller changes in cellular responsiveness to that hormone

Name a component of MALT (GALT: gut-associated lymphoid tissue)

Peyer's Patches - aggregates of lymphoid nodules found in the ileum ~30 in humans - involved in the development of immunity to antigens present there ** they are diffuse lymphatic tissues with secondary nodules ** Peyers patches are located in the Lamina Propria

Type 2 PRRs in Innate immunity are

Phagocytosis PRRs/ Scavenger Receptors * when these bind the result is phagocytosis - High affinity for mannos residues - bind to bacteria and facilitate phagocytosis - pathogen-derived proteins are presented to T cells (antigen processing and presentation)

The science of how chemicals interact with living systems

Pharmacology

What are the phenotypes and genotypes of the ABO blood groups

Phenotypes: A, B, AB, O Genotypes: AA/AO (for Type A), BB/BO (for Type B), AB (for Type AB), and OO (for Type O) - alleles A and B are codominant (presence of both alleles at the same time) - allele O is recessive Definitions: antibody is produced by the immune system; antigen is whatever the antibody will bind therefore A and B are antigens

After glycogen phosphorylase adds the phosphate to the 1-position of glucose (where cleavage occurs)- this phosphate has to be moved to the 6-position to continue glycolysis. What enzyme carries out this reaction

Phosphoglucose Mutase * we recover a high energy phosphate bond that was lost during glycogen synthesis- this is why addition of glucose only costs 1 ATP equivalent -- Phosphoglucomutase converts G1P to G6P- G6P is hydrolyzed to glucose Glc in liver by glucose-6-phosphatase (not in muscle, only gluconeogenic organs have G6Pase- liver and kidney ) -- Glucose 6-phosphatase is located in the ER (it is transported to the ER and glucose is transported back out)- it is principally reg. by its Km for G6P (higher than the typical G6P conc. in the fed state - during gluconeogenesis and glycogenolysis, G6P conc. rise and then enzyme can function on the higher conc. of substrate - expression is increase moderately by cAMP and also by cortisol - starvation increases expression

Glycogen Synthase Kinase

Phosphorylates glycogen synthase and inactivates it to glycogen synthase b - GSK is inactivated by insulin via Akt (Protein Kinase B)- thus, insulin prevents glycogen synthase phosphorylation by GSK and renders glycogen synthase active

Where can Corpora Aranaceum (AKA brain sand) be found

Pineal Gland! - These are extracellular mineral deposits (calcium and magnesium salts) - These calcareous concretions begin to form in childhood and increase with age - Function unknown and the "brain sand" does NOT have an effect on pineal gland function

"the leader of the endocrine orchestra"

Pituitary Gland - controls secretions of other endocrine glands - found sitting in the sella turcica of the sphenoid bone - has a connection with the base of the brain by a stalk (aka infundibulum)

Primary Endocrine Glands (purpose is the production and release of chemical messengers that travel throughout the body)

Pituitary gland Thyroid gland Parathyroid glands Thymus gland Adrenal gland Pancreas Ovaries Testes

Transient Endocrine gland or Endocrine structure (present for only a short duration)

Placenta Corpus Luteum

Receptors can be divided into two basic classes based on their structure and mechanism of action. What are these?

Plasma Membrane Receptors (Ion channels, GPCR, or catalytic) and Nuclear Receptors (which bine to regulatory sequences in DNA and increase or decrease gene transcription) ** review Dr. Pederson Cell Signaling Lecture

Main difference between Plasma vs Serum

Plasma contain all the proteins!!! * remember plasma starts with a P ** plasma has the protein fibrinogen- while serum does not

Skeletal muscles of well-trained individuals utliize more ___ than untrained during moderate to severe excercise

Plasma fatty acids - exercise promotes release of free fatty acids and this is the preferred substrate

Platelet (PLT) count

Platelets are anucleate masses derived from cytolpasmis budding of megakaryocytes * normal: 150,000-400,000 mm^3 - counted on automated cell counters - rough estimate on peripheral smear examination Major Causes of Thrombocytopenia: - Decreased platelet production - Decreased platelet survival - Sequestration (hypersplenism) - Dilution (transfusions)- platelets have a short half life so they are lost in transfusions

If your RBCs appear larger with more than one color (bluish gray) this may indicate

Polychromasia - In a case like this one would see persistance of RNA and an increased number of reticulocytes *** remember that is RBC polychromasia is present an addition correction is needed for the reticulocyte count: you must divide the corrected reticulocyte count by 2

Name the stage in erythropoiesis: polyribosomes decrease, and areas of cytoplasm begin to be filled with Hb which is acidophilic. Thus, this stage cell stains both colors (basophilic and acidophilic)

Polychromatophilic Erythroblast

The pathway that converts glucose --> sorbitol --> fructose is referred to as the

Polyol Pathway

Epitopes (AKA antigenic determinants)

Portion of antigen that binds the antigen recognition molecule * number of epitopes= valence of the antigen ** this is the part of the antigen recognized by antibody - peptide recognized by the T cell receptor

Hypothalamo-pituitary-ovarian axis

Positive Feedback loop variant * designed to drive a particular event- it is very RARE in physiology ex. The positive feedback loop with estradiol that drives ovulation at one point in the womans ovarian cycle- some consequences of this process will eventually restore a more typical negative feedback - rapidly increasing LH and FSH and estrogen levels - until some target cells in ovary begin to secrete progesterone, which separately restores negative feedback to this axis * four of the 8 hypothalamo-pituitray gland loops involve the gonads- first three involve the ovaries, fourth involves the testes (no one human has all 4 of these axes present- no one human has both ovaries and testes)

Pharmacotherapy for hyperthyroidism that results in decreased thyroid hormone secretion within a short time (days or less)

Potassium Iodide - PTU (Propylthiouracil) requires much longer to make an effective changes - bc it has little or no effect on release of preformed thyroid hormone

The amount of drug required to produce a specified effect

Potency - this is directly related to affinity - the higher the affinity, the greater the potency

Describe the maturation of insulin

Pre-proinsulin goes to the Endoplasmic reticulum where its peptide portion is cleaved to yield --> Proinsulin which then goes to the golgi where it is further cleaved into Insulin and the C-peptide ** C-peptide can be used as a marker for insulin levels ** NOTE: if you give a Type I Diabetic insulin- you will not see C-peptide, this is because these individuals are five insulin by itself

In the body iron can be found

Present in many proteins either bound to Cys side chains (FeS proteins) or as part of hemes: - Hemoglobin: binds O2 in RBCs - Myoglobin: binds O2 in muscle - Respiratory cytochromes: electron carriers in respiratory chain - Cytochrome P450: enzyme of drug metabolism and steroid synthesis Iron-sulfur clusters: redox centers in electron transport; active sites of various proteins - they are often cubic or rhomboid forms of iron and sulfur (Fe4S4 or Fe2S2)

What conditions can cause Thyrotoxicosis, a condition characterized by heat intolerance

Primary Hyperthyroidism and Secondary hyperthyroidism

Control of Aldosterone Secretion

Primary control - a low sodium level, either directly or indirectly secondary to low plasma volume - low sodium level detected by the kidneys juxtaglomerular cells - they secrete Renin which activates angiotensin I - angiotensin II is then made in the lungs - it then signal the ZG to synthesize and secrete aldosterone Secondary control: is form excess potassium, which directly signals aldosterone secretion Other modulators include ACTH, which is controlled by cortisol feedback but which also increases aldosterone secretion

What form of thyroid dysfuction is characteristic of Hashimoto disease

Primary hypothyroidism

What is the first recognizable cell to know a cell is differentiating into an erythrocyte

Proerythroblast ** it is a large cell, basophilic cytoplasm, visible nucleoli (comes from CFU-E which is NOT morphologically distinguishable) ** basophilia is caused by the large number of polyribosomes invovled in synthesis of Hb

MHC-II are found on

Professional Ag Presenting Cells (pAPCs) like: - Dendritic Cells (**best one) - Macrophages - B lymphocytes (present antigens to CD4 T cells when they need help) - Thymic stromal cells ** NOTE: pAPCs express BOTH MHC-I and MHC-II (leukocytes are indeed somatic nucleated cells) ** also antigen presentation is required during T lymphocyte development and therefore thymic stromal epithelial cells are also pAPCs, but ONLY during the process of T cell development

In the testis cholesterol can be converted to

Progestrine and androgens ** in the ovaries you have this plus estrogens ** and then in the adrenal cortex you can have cholesterol --> progestins which splits into androgens, glucocorticoids, or mineralcorticoids

ACTH, MSH, and Beta-endorphin are all made from

Proopiomelanocortin (POMC) * ACTH can be split into alpha-MSH and CLIP ** an increase in ACTH, MSH, Beta-endorphin means there is an increase in propiomelanocortin

Drugs that can be used to treat hyperthyroidism

Propanolol , propylthiouracil

The conversion of propinoyl CoA to succinyl CoA requires two enzymes which are

Propionyl CoA Carboxylase (w/ Biotin) and Methymalonyl CoA mutase (w/ Vitamin B12)

What is used in the routine identification of Hb

Protein electropheresis under two different conditions together identifies most common variants: - Cellulose acetate at pH 8.6 - Citrate-agar at acidic pH OR iso-electric foscuing can do the same in one gel * more advanced problems are sent to specialty labs ** LOOK at document on protein electropheresis on canvas**

Dominant pattern of secretion for hypothalamic and pituitary regions is

Pulsatile secretion - a hormone with a short half-life is secreted, delivered, and metabolized on a time and quantity regulated fashion ex. GnRH stimulates LH and FSH secretion which in turn stimulates gonadal sterioid secretion and gametogenesis *** can be modified by an addition circadian release pattern for some of these hormones (ex. Cortisol secretion is pulsatile but maximum peak size is usually in the morning) - modulation of existing pulsatile patterns make peaks "bigger" or "smaller" that are reflected in stronger or weaker effects at target cells - in special circumstances, episodic release of hormones can also occur (ex. CRH secretion with severe acute stress) * clearance of water-soluble hormones is typically quick (within a few minutes) and is accomplished by the hormones target cells

The difference between what we should be doing and what we are presently doing

Quality Gap - it is often defined by "best practices" based on clinical guidelines that are "evidence based"; that is, based upon aggregated research that has been systematically reviewed for quality and reliability

Non-neoplastic (reactive/inflammatory WBC disorders) can be seperated into

Quantitative WBC disorders and Qualitative WBC disorders - Quantitative is further divided into Leukopenia and Leukocytosis

Combinatorial Diversity in Antibodies is mediated by

RAG1 and RAG2

What is more abundant in the blood: RBCs of WBCs

RBCS!!! (WBCs or lueukocytes are much less abundant ~600 times less abundant: their total number in peripheral blood is 6500-10,000ul)

The splenic cords contain

RBCs, Neutrophils, Macrophages, and blood platelets ** A reticular cell framework supports the cord. The sinus is bounded by the epithelial cells that form the basket-like structure of the sinus

Causes of Basophilia (increase in basophils)

Rare - >5% basophils: indicative of myelo-proliferative disease (ex. chronic myeloid leukemia)

White blood cell disorders can be classified as

Reactive/inflammatory or Neoplastic Reactive/Inflammatory ones could be either Quantitative or Qualitative - Quantitative could mean leukocytosis or leukopenia - Qualitative is about leukocyte defects (ex. Pelger-Huet and Chediak-Higashi) Neoplasitc: are Leukemias and Lymphomas

Insulin is secreted by beta cells- the arterial and venous blood are on opposite sides of the beta cells- what are in each of these that aid insulin in its secretion?

Receptors are concentrated on the arterial-facing membrane: sense how much glucose there is present Insulin is secreted into the venous blood, enroute to the liver (to portal circulation- directly or indirectly) *technically each cell operates relatively independently, but they combine for a powerful collective effect on secretion *arterial-facing membranes are better for determine the state of glucose levels and hormone levels in the general circulation than are venous-facing membranes

2 central principles upon which the immune system is predicated

Recognition and Self-Discrimination Recognition - The body must have the capacity to "recognize" the invading material and this is achieved through cell surface receptors that bind ligands on invaders Self-discrimination - An immune response must implicitly be directed at a "foreign' substance to defend self from harm - the generation of nonself immune cells occurs by the process of elimination of self-reactive precursors

2 types of bone marrow that exsist are

Red Bone Marrow - color is produced by the presence of blood and blood-forming cells Yellow Bone Marrow - collor is produced by the presence of a great number of adipose cells ** In a new-born all marrow is red. As the child grows, most of the bone marrow changes gradually into the yellow variety ** 25 yr old: red marrow is confined to cancellous bone: the proximal quarters of the long bones (femora, humeri), skull bones, ribs, sternum, scapulae, clavicle, vertebrae, pelvis and upper half of sacrum ** BUTTT in response to severe blood loss, yellow bone marrow can become red bone marrow any time in life Yellow bone marrow is "seeded" by blood-borne hematopoetic cells

what is the difference between Red and White Pulp of the spleen

Red Pulp: - Where blood is filtered (~75% of the spleen) - Consists of: sinusoids and splenic cords (of Bilroth) White Pulp: - production site of lymphocytes that react against the antigen/any foreign antigens that are filtered from the blood in the red pulp and makes antibodies against them ** when stained with H&E, "white" pulp appears blue/purple because of lymphocytes

A Whole Blood Donation is seperated into

Red blood cells - used to increase the amount of RBCs after trauma or surgery or to treat severe anemia (can be stored 42 days in fridge and 10yrs in freezer)- can be used in cases of Beta-thalassemia, car accident, or surgery. Fresh Frozen Plasma - to correct a deficiency in coagulation factors or to treat shock due to plasma loss from burns or massive bleeding (can be stored 1 yr in the freezer) Concentrate of Platelets - to treat or revent bleeding due to lowplatelet levels. To correct functional platelet problems (can be stored 5 days at room temp) Cyroprecipitate - to treat fibrinogen deficiences (can be kept 1 yr in the freezer) ***** Whole blood is never used in a transfusion- it is separated into different blood components which are used

Term used to describe two or more cytokines that have the same effect on the cells that they bond

Redundancy

Short-Acting Insulins

Regular Insulin: - molecules associate as hexamers in solution at neutral pH (slow absorption, take 30-45 min before meals) - - can be administeres SQ, IV, or IM Products - Standard= 100unit/ml - 500unit/ml: altered PK, acts closer to NPH **** Inhaled insulin= preparation of regular insulin attached to a crystallized carrier- single use device - slightly more rapid than the injected lispro- cough is the main adverse side effect, contraindicated in smokers and patients with chronic lung disease, asthma, etc Insulin analog (lispro) ** works fastest - absorbed more rapidly than regular (0-15min before meals) - administered SQ Products - 100 unitl/ml - 3 types available: lispro, aspart, glulisine - this has better outcomes than regular insulin (lower HbA1c, fewer hypoglycemia) - higher cost

Most important route for drug elimination

Renal excretion - drugs or their metabolites are passed out of the body in the urine ** in renal failure the excretion of many drugs is greatly reduced and this must be taken into consideration for prescribing and/or dosing decisions

Angiotensinogen is conveted to Angiotensin I via

Renin (from the kidney)

What forms the framework that holds the lymphocytes in place in ALL lymphoid tissue/organs EXCEPT thymus (bc in thymus the ERCs form the framework)

Reticular CT * cells crawl in and out of this fixed framework - Made of reticular fibers (type III collagen) secreted by reticular cells (specialized fibroblasts) - the fibers are argyrophilic ("silver-loving") ** reticular fibers can be found in the subcapsular sinue where they "churn up" the lymph as it moves through, and any "bits" can get phagocytosed by macrophages and dendritic cells (APCs) lining the walls of the sinuses. ** this is the reticular framework found inside lymph sinuses, but NOT blood sinuses

What type of fibers are found around many small blood vessels (along with nerves and muscles)

Reticular fibers- Collagen Type III

After an orthochromatophilic erythroblast expels its nucleus it becomes a

Reticulocyte (an immature erythrocyte) - still has a few polyribosomes that aggregate (when treated with dye cresyl blue) to form a stained "reticular" network

Marker of effective erythropoiesis

Reticulocyte Count Nml: <3% * this percent count is FALSELY increase in anemia so a correction is required - the initial % must be correct for degree of anemia Corrected reticulocyte count= Actual Hct/45(the avg nml hematocrit) x reticulocyte count Ex: if you Hct=15% and Retic count= 18% your corrected reticulocyte count is 6% *** an addition correction is also required if RBC polychromasia is present: what you would do is divide intial corrected reticulocyte count (for degree of anemia) by 2

Nearly ALL erythrocytes are released into the circulation as

Reticulocytes as soon as they are formed * Reticulocytes are about 1-2% of RBCs in blood stream, % can increase after blood loss

In small blood vessels, RBCs often stack up in aggregates called

Rouleaux

Beta-Thalassemia: Confirming diagnosis and Treatment

Rx= Blood Tx and Fe chealtors: deferoxamine with Vitamin C Hb Electrophoresis: HbF is markedly increased and HbA2 is normal/increased/decreased - In Beta0, most of the Hb is HbF, increased HbA2 (5-8%) is also seen - In Beta+, some HbA is also present Treatment: - Blood transfusions: Fe overload --> Fe deposits --> damages heart, liver & endocrine system

Vitamin D deficiency

Seconary to chronic renal failure, or: - lack of sunlight plus lack of dietary supplementation - Genetic diseases (pseudovitamin D deficiency) * effects: lack of calcium absorption capacity, and sever hypocalcemia, rickets in children, and osteomalacia in adults

Cell Surface hormone receptors require

Second messengers - Membrane-bound receptors are highly variable and hormone specific - Biomolecules binding to membrane-bound receptors INDIRECTLY regulate transcription through second messenger signaling pathways

Secondary Hyperparathyroidism

Secondary because results from either chronic kidney disease (CKD) or dietary VitD deficiency combined with low UV exposure - nephrons that are nonfunctional do not secrete calcitriol - without dietary VitD, it must be produced with req. UV light (w/o adequate light- VitD3 (cholecalciferol) cant be produced de novo so kidneys lack precursors for calcitriol production When this hormone is no longer made nor ingested - calcitriols direct inhibition of PTH production disappears - without this, plasma clacium leveles decreases - PTH levels then rise to deal with low calcium levels, uninhibited by calcitriol

A very important structure found in ALL secondary lymphatic tissue when it is mounting an antigenic response

Secondary lymphatic follicle/nodule - this is a follicle containing lymphocytes that have been ACTIVATED by antigen - ring of B cells that surround lighter-staining GERMINAL CENTER that contains proliferating B cells, plasma cells, and T helper cells - The germinal center develops when a lymphocyte that has recognized an antigen returns to a primary nodule and undergoes proliferaton *** NOTE: in secondary lymphoid nodules the light region is light because the lymphocytes are ACTIVATED and have larger light staining cytoplasm and more euchromatin in nucleus, NOT fewer cells where as in the Thymus, the light regions in medulla are light because there are FEWER lymphocytes present in this region

Type I PRRs in Innate Immunity are

Secreted PRRs: - circulate in blood and lymph - MANNAN BINDING LECTIN (MBL), a collecting- binds to CHO on bacteria to initiate complement activation (this MBL is a protein produced by the liver in serum--> activates complement when bound- this is called the Lectin Pathway) NOTE: formation of MBL is Induced by IL-6 * other C-type lectin receptors and C-reactive proteins function similarly

P, E Selectins

Selectin is on endothelial cells, Carbohydrate ligand is on leukocytes ** used to attract leukocytes like neutrophils to sites of inflammation ** remember- "athletic" process= PE (bc Neutrophils move with diapedesis)

Ability to discriminate between different types of receptors

Selectivity - related to the affinity in that the drug will be relatively selective for receptors for which it has the highest affinity * you may be able to selectively block physiological actions by: receptor selectivity (specificity) and dose (affinity)-- note that these are not completely independent

If a patient is looking up their own treatment online without the help of a physician this is referred to as a

Self-care system - not involving a physician or alternative care provider or any structured system of health care provision The patient plus whatever resources he or she uses that are not part of the health care system like: - advice from family and friends - patients own research - prior experience - assumptions, beliefs (also religious) etc.

Diabetes Mellitus Drugs (short-acting and long-acting insulins)

Short-acting insulins: (very rapid v. regular) - Insulin lispro - Insulin regular Long-acting insulins: (longer duration v. NPH) - insulin NPH - insulin glargine NOTE: all insulin preparations are either native insulin or very similar analogs that have nearly identical actions at insulin receptors

HbS

Sickle Cell Anemia - Due to a change in AA from Glu --> Val to give BetaS ** switch from charged to uncharged AA - All carriers of this anemia have exactly the same mutation * the mutation happenede independently at least twice HbS: tetramer of alpha2Beta^S2 - HbSS is often used to designate a homozygot for Sickle Cell Q) you have a switch from gamma --> beta Hb production happening just before birth, at what age should symptoms of sickle cell become noticeable? - should be 3-6 month of age this is when you have BetaHb becomes predominant - still takes while after this to see the sx's of the disease so pt's usually not diagnosed till 6-12 months of age- some symptoms in previous quarter ** NOTE that at birth the predominant Hb is Alpha2-gamma2

Most common hemoglobinopathy in Black African Descendants

Sickle Cell Anemia An autosomal recessive disorder due to a point mutation in codon 6 (single nucleotide change in a codon): glutamic acid is replaced by valine - Heterozygotes [ Sickle cell trait, HbAS- (HbS-40% HbA- 60%)] *** Note heterozygotes DO NOT develop red cell sickling because their HbA prevents HbS polymerization - No anemia: 8-10% of Black Americans - Homozygous (HbSS)- alpha2beta2- produces anemia

Difference between sickle cell anemia and chronic hemolytic anemia

Sickle cell anemia: point mutation in HbB --> HbS (Glu --> Val at amino acid 6) Chronic hemolytic anemia: HbB point mutation --> Hb C or Hb E

What Laboratory tests could be done for sickle cell anemia

Sickling Test - done if you suspect sickle cell anemia or trait - In vitro sickling after adding reducing agent (Na meta-bisulfit) or Hb electrophoresis - HbS predominant (80-95%) - HbF present - HbA2 normal ** HbA is absent

Type 3 PRRs in Innate Immunity are

Signaling Receptors ** binding of these results in signaling with up-regulation of genes in the nucleus Type include: TLRs (Toll-like receptors): - homologous to toll receptors - on macrophages, dendritic cells, and epithelial cells (cell membrane and on endosomes) - binding to pathogens results in activation of signal transduction and expression of cytokine genes NLRs (Nod-like receptors): - Nucleotide oligomerization domain-like receptors (cytosolic) RLRs (RIG-like receptors): - Retinoic acid-inducible gene-like receptors (cytoplasmic)

When stimulated the thyroid follicle changes from cuboidal to

Simple columnar epithelium surrounding a single follicular lumen

Antigen presentation for the purpose of effector responses (B lymphocyte help, macrophage activation, etc.) as well as Antigen presentation for the purpose of reactivation of memory T lymphocytes occurs at the

Site of infection and Seconday follicles (in the affected tissue)

Explain how you would do a bone marrow (BM) biopsy

Sites: sternum, anterior iliac crest, posterior iliac crest** (safest, favored site) Position: prone or on contralateral side to biopsy site Surface anatomical landmark: Iliac crest identified by palpation. Biopsy sit marked with indelible ink Preparation: Informed, written, signed, conset. Aspectic Technique and Local Anesthesia *** BM could be - Hypoplastic - Normal - Granuloma - Hyperblastic with blasts

Main physical barrier of the innate immune system

Skin - it is oily with antimicrobial secretions (fatty acids, defensins in sweat; sebaceous gland secretions) - chemotactic secretions: TNF-alpha, IL-8, etc. - antigen presentation by dendritic cells - TIGHT junctions at ALL locations *** if these tight junctions break- there is NO defense, these MUST be maintained

Somatostatin Analogs

Somatostatin was named for its effect of inhibiting secretion of GH from the pituitary gland - 5 stomatostatin receptors have been identified and characterized. Each of the receptors activates distinct signaling mechanisms within cells - In addition to the hypothalamus, somatostatin is also produced by D cells of the pancreatic islets, the GI mucosa, and the C cells of the thyroid - In addition to its potent inhibitory effect on GH secretion, somatostatin also has important inhibitory influences on many other hormones, including: - insulin - glucagon - gastrin - secretin - VIP - TSH - Pro- and adverse- effects may occur via interaction with somatostatin receptors at these sites Therapeutic Uses: - GH over-activity - Symptomatic treatment of metastatic carcinoid tumors - Adenomas secreting vasoactive intestinal peptide (VIP) - Thyrotrope adenomas that over secrete TSH - bleeding esophageal varices (exact mechanism is unclear) - perioperative prophylaxis in pancreatic surgery - modified forms radiolabeled for diagnostic uses or targeted destruction of tumors Adverse Effects - GI (50%), Gallstones (25%) - Bradycardia, QT prolongation - Hypothyroid, Hypoglycemia, Hyperglcyemia

Sources of Vitamin B9 (Folate) and its deficiency

Sources: green leafy vegetables, yeast, liver, some fruits (heat labile) - deficiency: pregnant women, alcoholics * most common vitamin deficiency in the US - mild or borderline deficiency is commin it can be caused by: - loss (pregnancy) - poor dietary habits - poor absorption (alcoholism, intestinal pathology). - or inhibition by methotrexate Sxs: Megaloblastic Anemia - megaloblasts= oversized RBC precursors in the bone marrow - macrocytes= oversized RBCs in the blood * these cells are formed when DNA replication cannot keep pace with cell growth, while RBC production slows down * megaloblastic changes are also seen in other tissues with rapidly dividing cells, for ex; Intestinal epithelium sxs: - Loss of appetite - weight loss - weakness - glossitis (sore tongue)* - irritability

Natural Killer Cells (a cell of the innaate immune system) are

Special type of T cell- CD2+/ CD3 negative ** CD2+ is on all of these cells it is an adhesion molecule - it is 5-10% PBL; large Granular lymphocyte ** this is abnormal bc lymphocytes are usually always agranular but this one is granular - they express CD56, but NOT TCR - The express: KAR (killer activation receptor) which enabled NK cell to kill and KIR (killer inhibition recepto) which blocks killing of normal cells with MHC1 NK cells are activated by: - IL-12, IFN-alpha, TNF-alpha, IL-15 etc. They posses Fc receptors, FcgammaRIII (CD16; ADCC) - they have inducible expression of FasL (cell cytotoxicity) - Release perforin (makes a whole in the target)/ granzyme (cell cytotoxicity- goes in and destroys target)- these use KAR - also it releases IFN-gamma in response to IL-12 stimulation

What do Folate Supplements help to prevent

Spina Bifida (incomplete closure of the lumbar spine) and anencephaly(absence of the brain), two common neural tube defects - current recommendation is that all women who might become pregnant should consume at least 400micrograms of folic acid/day * Neural Tube defects are among the most serious birth defects (1:400 births)

Mineralcorticoid Antagonist drug

Spironolactone Eplerenone

In the Red Pulp of Spleen what is the name for the unusually elongated endothelial cells that are oriented in parallel with the sinusoids blood flow

Stave Cells - these are sparsely wrapped in Reticular Fibers (type III collagen)- much like the hoops surrounding a wooden keg *they have incomplete basal lamina (so cells can cross) - When RBCs reach the end of their lifespan, they are no longer flexible enough to fit through the slits- many macrophages sit here and wait to phagocytose the RBCs that cannot make it - also, at the end of lifespan, SCRAMBLASE is activated that flips phosphatidylsering to outside of RBC membrane, "Eat me" signal for macrophages ** after splenectomy- RBCs are phagocytosed by macrophages in other parts of the body (liver, bone marrow; dont have slits) because of this "eat me" signal

IGF-1 effects on muscle

Stimulates - protein synthesis - AA uptake

In the muscle GH

Stimulates - protein synthesis - AA uptake Inhibits: - glucose uptake

IGF-1 effects in chondrocytes

Stimulates: - AA uptake - protein synthesis - RNA synthesis - DNA synthesis - Collagen production - Chondroitin sulfate - Hyperplasia (increase cells) - Hypertrophy (increase size)

Diabetes control and complications trial (DCCT)

Study measuring intensive vs standard blood sugar control in Type I Diabetics with insulin - Showed that ppl with intensive treatment lowered their risk of diabetic eye, kidney, and nerve disease * was not shown to lower risk of heart disease, since only a few had heart disease in the study - participant with intensive treatment had an avg A1C of 7%, while those with conventional treatment- A1C of 9% Risk: Hypoglycemia

Blood supply to the thyroid gland

Superior thyroid aa from the external carotid and Inferior thyroid aa from the subclavian

HbS/Beta-Thalassemia compound heterozygotes

Symptoms will be Sickle Cell disease, not Beta-thalassemia - sickle cell anemia for SBeta0 (or slightly milder due to lower concentrations of Hb) - milder for SBeta+

What are some tools to diagnose Sickle Cell Trait

Symptoms: - generally none - rare renal problems - high altitude splenic infarction - possible hemolytic crisis Lab: - Normal PBS, CBC, and Reticulocyte # Hb electrophoresis shows: - HbA (alpha2-beta2) 60% - HbS 40% - Normal HbA2 (alpha2-delta2) and HbF (alpha2-gamma2) ** HbA prevents HbS polymerization. Normally RBCs do not sickle ** Under extreme conditions (flight at high altitude in unpressurized aircraft, deep sea diving), red cells may sickle

One of the functions of Glucocortiocoids anti-inflammatory effects is the

Synthesis and Function of Annexin 1- which supressed phospholipase A2 (blocks eicosanoid production) - inhibits main products of inflammation, prostaglandins, and leukotrienes * they inhibit prostaglandin synthesis at level of phospholipase A2 as well as at the level of cycloocygenase/PGE isomerase (like COX-2), the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect ** inhibition of arachidonic acid becoming prostaglandin which is then released into cytosol or from cell to cause inflammation --- glucocorticoids can also reduce lymphocyte counts acutely redistributing lymphocytes from the intravascular compartment to the spleen, lymph nodes, and BM also can inhibit monocyte differentiation into macrophages, and macrophage phagocytosis and cytotoxic activity

Cyanocobalamin

Synthetic form of VitB12 Route of administration: - IM and SubQ (IV is not recommended) - Oral: not recommeded due to poor absorption. May be used if parenteral therapy is refused or poorly tolerated MOA: - supplement VitB12 (cobalamin); coenzyme for various enzymatic reactions necessary for the synthesis of nucleic acids and proteins Clinically used for: Treatment of vitB12 deficiency due to: - pernicious anemia (due to decreased intrinsic factor) - deficiency due to dietary deficiency or malabsorption, inadequate secretion of intrinsic factor and inadequate utilization of vitB12 during neoplastic (cancer) treatment - increased requirement due to pregnancy, hemorrhage, thyrotoxicosis, malignancy and liver or kidney disease Adverse effects: - patients with Leber disease who recieve vitB12 treatment may suffer from optic atrophy (severe rapid) - VitB12 deficiency masks polycythemia vera (a blood cancer- cant grow bc doesnt have vitB12 to grow). Resolution of VitB12 deficiency may unmask polychythemia vera

Adverse side effects of Diphenhydramine

Systemic adminisitration - sedation (additive with alcohol) - thickening of bronchial secretions - less freq. dry mouth (xerostomia), blurred vision, hypotension, tachycardia, urinary retention Topical administration: - uncommon: photosensitiviy, rash, hives (urticaria) -------- Precautions when taking this drug (no real contraindications) Systemic: - In people with asthma due to thickening of bronchiole secretions -due to possible muscarinic effects - not recommended for daytime use in children - pregnancy (crosses placenta) - lactation (enters breast milk) Topical administration: - neonates, premature infants, breast-feeding, young children

Immune complex-mediated disease includes

Systemic vasculitis and glomerulonephritis - deposition of immune complexes in the walls of blood vessels and the kidney glomeruli - acute microinflammation resulting in destruction of blood vessel walls and glomeruli leading to thrombosis, ischemia, and scarring

The route of administration is known to affect absorption of the drug. Describe two modes of administration

Systemic: drug is transported throughout body by general circulation, thus reaching all (or most) body compartments - enteral administration (oral)- via GI - parenteral administration (subcutaneous, intramuscular, intravenous, transdermal)- avoiding the GI (includes buccal and sublingual) NOTE: difference between "transdermal" and "topical": when drugs are formulated to be administered to the skin for systemic effects, its referred to as "transdermal" - there are factors affecting absorption from various routes including polarity (water vs lipid solubility), molecular size, site of metabolism, and other parametes - the rate at which drugs will be absorbed from these various routs is directly proportional to blood flow at site of absorption Local: deliver drug primarily to therapeautic target site (but some drug will almost always end up in the circulation) - topical on skiin, eye, nose - rectal or vaginal (which can also be a route for systemic circulation)

Natural Killer T lymphocytes (NKT cells)

T cell receptors of these cells interact with CD1 (an MHC-I like molecule) - CD1 is important in glycolipid antigen presentation (which are present in fungi and microbes) to NKT cells - CD1 reacts by releasing cytokines (ex. IL-4 or IFN-gamma) or being cytotoxic * these are important in innate control of some infections and help direct adaptive immune responses; ex: recognition of mycobacteria NKT cells are: - different from NK cells and T lymphocytes - generally considered innate

Engagement of PD-L1 by PD-L1+ cells induces

T cells apoptosis, anergy, functional exhaustion, or IL-10 production ** some drugs target this as well as the expression of CTLA-4 - used to treat metastatic melanoma and lung cancer

The essential feature of the adaptive immune response is its reliance on

T lymphocytes

Mediators of Cell-mediated immunity

T lymphocytes (can have Helper T or Cytotoxic T lymphocytes) - Helper T lymphocytes respond to phagocytosed microbes that can live within macrophages through activation of a macrophage- this leads to elimination of phagocytosed microbed - Cytotoxic T lymphocytes respond to intracellular microbes (ex. viruses) replicating within infected cell by killing the infected cell and eliminated reservoirs of infection

CD3 is a marker for

T lymphocytes * it is used to count the number of T lymphocytes

2,3 BPG keeps Hb in the

T state - Hb offloads oxygen

Two states of Hb

T state: "tense"- deoxygenated R state: "relaxed"- oxygenated (just imagine yourself breathing in air) ** oxygenation rotaes the alpha1beta1 dimer in relation to alpha2beta2 dimber about 15 degrees - each pair of alpha and beta subunits stay relatively in the same position to each other under both oxygenated and deoxygenated states - deoxy: alpha and beta subunit pairs twist relative to other pair - oxy: alpha and beta subunits twist back to reform salf bridges

what type of T cell is the specialized life-long companion of the B cell

TFH (follicular helper T lymphocytes) - they go into the primary follicle and build the secondary follicle or germinal center NOTE: generation of high-affinity antibodies is done in the germinal center ** also the likelihood of the B and T cell interaction is increased by the convergence of helper T lymphocyte and B lymphocytes to the edge of the primary follicle

Cytokines involved in Treg

TGF-Beta IL-10

Antigen presentaion of naive T cells in presence of IL-12 (from dendritic cell) and IFN-gamma (from NK cell) leads to production of

TH1 cell - good at dealing with intracellular microorganisms ** targets macrophages to deal with intracellular microorganisms- this plays a role in autoimmunity; chronic inflammation

T or F: synthetic prostaglandins are NOT effective after oral administration

TRUE they have a very short half-life- so they are unsuitable for oral administration * some have been created that have a longer biological half life- these are administered orally

T or F: blood is considered to be a specialized connective tissue

TRUE!

True or False: Glucagon and Insulin are normally kept in balance such that blood glucose stays within the normal range by negative feedback on both hormones' production

TRUE!

T or F: the white pulp of the spleen contains both B and T cells

TRUE! But mostly T cells surround central artery- forms PALS (periarterial lymphoid sheaths) - if reacting against antigen- also see a secondary follicle or nodule that is mostly B cells *** In a histological slide of White Pulp - the sinuses can be seen at the periphery between white and red pulp - The marginal zone on the outside of the germinal center is an important area for the interaction of APCs carrying antigens from the red pulp with lymphocytes of the white pulp ** When a large nodule with a germinal center forms in the PALS (periarterolar lymphatic sheath), the central arteriole is deplaced to the nodules periphery

True or F: cytokines are involved in isotype switch

TRUE! * they can help in determining which isotype an antibody will be: IgM, IgG, IgE, IgA

T or F: Mature, naive, resting T lymphocytes are longer-lived than B cells and, in the absence of antigen stimulation, may live for years

TRUE! NOTE: in the presence of antigen, they may become activated and release cytokines that mediate effector functions (these cells have a dramatically shorten lifespan-- days to weeks), or become memory cells responsible for long-term immunity (with a lifespan of months to years)

TRH from the hypothalamus causes release of

TSH (aka thyrotropin) from the anterior pituitary - works on the thyroid to secrete thyroxine (T4) and triiodothyroxine (T3) ** trophic effect

Target cell vs Target tissue

Target cell: any cell that can change its activity in some way, due to its reaction to the presence of a given hormone - target cells contain hormone receptors which may be on the cell surface (if hormone cant cross membrane because it is too big or polar) or intracellular: when a hormone binds the hormone-receptor complex initiates some activity change Target tissue: a group of cells that collectively respond to the presence of a given hormone at each individual cell * for most hormones, mass release of hormone molecules allow target tissues to be affected, often within a single organ

Junctional Diversity is mediated by

TdT - the formation of the junction between gene segments involves DNA cleavage and the addition or deletion of nucleotides to create a joint (this further enhances diversity of antibody by point mutation that can be induced) * this random addition by the enzyme terminal deoxynuceotidyl transferase TdT, or random deletion by exonuclease, results in a further level of variability or junctional diversity

The only drug currently available that stimulates new bone formation?

Teriparatide - stimulates osteoblasts to increase new bone formation ---- Calcitonin works to prevent bone resorption- directly inhibits osteoclast activity

Disease with diminished expression of Hb

Thalassemia also written as Thalassaemia (can be beta or alpha)

Which is the last complement pathway to be activated

The Classical Pathway - because antibody (immunoglobulin) production usually takes atleast a couple of days (on avg 1-2 weeks) 1. C1q cross-linking of Fc portions of antibodies bound to multivalent Ag triggers the cleavage of C1s by C1r 2. Activated C1s then cleaves C4 into C4b and C4a - C4b covalently binds the pathogens surface - C4a is released in the fluid phase where it mediates the inflammatory process 2. Then plasma C2 is cleaved by C1s to yield C2a cell surface deposition and association with C4b and release of C2b in fluid phase 3. Resulting C4bC2a complex = C3 convertase (like in the lectin pathway) - catalizes cleavage of C3 into C3b and C3a to yield 1) microorganism opsinization and release of inflammatory soluble C3a (like alternative and lectin pathways- this is an amplifications tep) 2) C3b binding to C4bC2a to yield C5 convertase (C4bC2aC3b) 5. C5 convertase catalizes cleavage of numerous C5 into C5b and C5a *** the actions of the classical pathway C3 convertase and C5 convertase result in the same effects as those described for the alternative and lectin pathways, namely stimulation of inflammation, opsonization for phagocytosis, and pore formation as result of MAC ** NOTE: C1 (C1qr2s2) is a large multimeric protein complex composed of C1q, C1r, and C1s subunites; C1q is a hexamer that binds the Fc portion of immunoglobin molecules, C1r (dimer) is a serine protease which cleaves C1s to activate it, and C1s (dimer) is the actual serine protease that cleaves C4 and C2

Aplastic Crisis in Sickle Cell Anemia

The bone marrow becomes exhausted- Complete blood count (CBC) shows Pancytopenia (decrease in all RBCs, WBCs, and PLTSs)

What is blood?

The fluid consisting of plasma, blood cells, and platelets that is circulated by the heart, carrying oxygen and nutrients TO and waste materials AWAY from all body tissues

Upregulation vs. Downregulation

The goal is an appropriate response when the hormone is present - Up-regulation: increases receptor number, leaving cells able to respond to even low levels of hormone - Down-regulation: prevents overstimulation in excess of hormone (adaptation or desensitization)

Leukocytes are classified based on

The presence or absence of specific granules (granulocytes or agranulocytes) 1. Granulocytes - Neutrophils (most abundant), eosinophils, basophils: all have specific granules (secondary granules) - and can be differentiated according to their color of staining with Wright stain ** each granulocyte has different set of enzymes/weapons- to fight diff. enemies 2. Agranulocytes - Lymphocytes, monocytes- DONT have specific granules, however ALL WBCs possess small, nonspecific azurophilic granules (secondary granules- lysosomes)

Hematopoiesis (AKA Hemopoiesis)

The process of blood cell formation from established blood cell precursors - mature blood cells have a relatively short life-spain, must be continuously replace by the progeny of stem cells - after birth, production of new blood cells occurs in the BONE MARROW - under normal conditions, the production of blood cells can adjust rapidly to the need of the body, increasing several-fold in a short time - In a healthy adult person, apprx. 10^11- 10^12 (10^12= one trillion) new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation ** increased altitude= increased RBC ** bacterial infection= increased neutrophil

How many blood groups are there

There are about 20 other systems other than the ABO and Rh - transfusion could happen with most of them at least once because: there are no pre-forms antibodies OR preformed antibodies are only reactive at low temperaturs and using blood preheated to 37 degrees celsius alleviates the problem - standard practic is to lab test for compatability between the actual recipient and the expected donor ** most of these (but not all) have protein as their antigens

In nephrotic syndrome (seen in advanced diabetes)

There is a decrease in Albumin as it is lost in the urine, and increase in alpha2 and a decreased in gamma ** BOTH Beta2-microglobulin (subunit of HLA) and alpha2-macroglobulin (a protease inhibitor) are used in the detection of nephrotic syndrome [ both of these are acute phase proteins ]

Long-acting insulin preparations

These decrease rate of release from SQ depots, permitting a single injection to supply longer-lasting "background coverage" (basal insulin) NPH insulin: - combo of crystalline zinc insulin and protamine - after SQ injection, protamine is enzymatically digested to release insulin that is then absorbed in the circulation Insulin glargine: * has the longest duration of action - Soluble at pH4 (as its packaged) due to sequence modifications - and then its aggregated when injected at neutral pH - thus leading to slow release into the circualtion - provides a depndably sustained release from depot injections

Describe platelets

They are nonnucleated, disklike cell fragments 2-4 microns in diameter containing: - lysosomes - mitochondria - some ER - some Golgi - three types of granules - extensive cytoskeleton In a cutaway diagream of a platelet you see: 1. Peripheral MT bundle (maintains the shape) 2. Actin and myosin (clost contraction) 3. Organelles facilitate clotting - Mitochondria for ATP production - Granules contain clotting factors - Dense tubular system sequestering Ca2+ for signaling (similar to SR in skeletal muscle) - Open Canalicular system facilitates signaling and secretion

Since parasites are often too large to be phagocytosed, how do eosinophils kill them?

They attach to their surface and extrude the contents of their granules (both specific and non-specific) into the extracellular space *** IMPORTANT: Eosinophils are often first attracted to surface of parasite by BOUND ANTIBODIES, they then release their granules

What does it mean that the Subendothelium (beneath the endothelium) is thrombogenic in nature

They express Von Willebrand Factor (vWF), collagen, and tissue factor to kick off the coagulation cascade

What does it mean that endothelial cells (which line the vessels) are thromboresistant in nature

They express thrombomodulin and heparin sulfate to keep inappropriate thrombi from forming - they also release tissue plasminogen activator and urokinase in the presence of thrombin shut off the coagulation cascade in the presence of IIa (thombin)

Describe Eosinophils

They have a sausage-shaped, bilobed nucleus - the two lobes are connected by a thin chromatin strand and nuclear envelope - are round cells (in the blood), - have large, salmon pink colored specific granules *** MAJOR BASIC PROTEIN causes eosinophilic/acidophilic staining of specific granules * eosinophils also contain azurophilic non-specific granules (lysosomes)

What is an isotypic difference in antibodies

This denotes the antibody calsses (IgM, IgD, IgG, IgE, IgA) * determined by the heavy chain ** this defines the functioon (how the antibody contributes to the immune response)

Immunosenescence

This has to do with thymic involution (thymus is fully developed before birth then begins to degenerate steadily throughout life one year after birth and is replaced by fat) ** this reduced production of new T lymphocytes DOES NOT impair T cell immunity (neither does a thymectomy in adults) - this is because by adulthood, individuals posses memory T lymphocytes to the most common potentially life-threatening pathogens - soo as one ages theire Memory T cells increase where has their Naive T cells decrease in number ** note memory T cells also decrease wayyyyy later in age- and immunity wanes with time (this is not of importance in this course rlly)

Give an example of pituitary hormones regulating the release of the hypothalamic releasing hormone

This is Short loop negative feedback ex. High levels of GH feeback on the hypothalamus to reduce the secretion of GHRH

The elimination of self-reactive clones (Tolerance Induction) of B cells involves

This is the process of Negative Selection (Tolerance Induction): - heavy and light chain rearrangements are random this means you may have some self-reactive BCRs are often generated - These self-reactive BCRs (recognize ubiquitous self-antigen) are deleted or functionally inactivated NOTE: Unlike T cells who die right away if they are self-reactive, B cells have the ability to undergo "Receptor Editing": - Immature B cells with self-reactive BCRs can attempt to rearrange light chain - Some B cells exhaust their attempts to make a BCR that is NOT self-reactive (i.e. they are still self-reactive) and get signaled to die by apoptosis (clonal deletion) - if the new receptor is no longer, self-reactive, the immature B cell migrates to the periphery and matures

What would Nucleated RBCs indicated on a peripheral blood smear (PBS)

This would be a reflection of erythropoietic response to massive hemorrhage or hemolysis

An injury to a blood vessel may result in thromboplastin release- what are the stops after its release that lead up to coagulation

Thromboplastin, platelet factor 3, and calcium ion interact to form prothrombin activator - prothrombin activator convertes prothrombin --> thrombin - thrombin converts fibrinogen (soluble proteins) into long, insoluble proteins called fibrin * fibrin forms a mesh that traps erythrocytes and platelets, pulls the edges of the broken vessel together and forms a clot

thrombus vs embolus

Thrombus- a blood clot that forms in an unbroken vessel (ex. sitting on a flight for a long time)- a large thrombus may block blood flow, causing tissue death where as an Embolus: is a blood clot that forms then breaks away and floats freely in the blood vessels. An embolus may then lodge in a capillary and block blood flow

All other lymphoid organs except the ___ originate EXCLUSIVELY from mesenchyme (mesoderm)

Thymus ** thymus has DUAL embryonic origin 1. Its lymphocytes are from bone marrow (mesenchymal/mesoderm origin) 2. BUT is Epithelial Reticular Cells (ERCs) are from the endoderm (like some other epithelial cells)

Bilateral organ located in the mediastinum

Thymus - A primary lymphoid organ- * CFU-L cells from the bond marrow develop here into immunocompetent T cells - The thymus possesses a thin Dense Irregular CT capsule from which trabeculae (each of a series or group of partitions formed by bands or columns of CT) extend into the parenchyma (functional tissue of an organ as distinguished from CT and supporting tissue) of the organ that divides it into incomplete lobules ** each lobule has a peripheral darkly stained zone known as the cortex and a central light zone known as the medulla The capsule and trabeculae contain: - blood vessels - EFFERENT (but not afferent) lymphatic vessels - nerves

Antigen presentation for the purpose of T lymphocyte development (Positive and Negative selection) occurs in the

Thymus (a primary lymphoid organ)

In a patient with medullay carnimoa what hormones would be elevated in plasma

Thyrotropin and Calcitonin

Most secreted thyroid hormone is transported in the plasma as

Thyroxine (T4), bound to thyroid binding globulin

What are the two Plasminogen Activators

Tissue Plasminogen activator (tPA) & Urokinase - they convert plasminogen --> plasmin which aids in fibrin polymer becoming Fibrin degradation products *** streptokinase can also be used as an activator - these can be inhibited by plasminogen activator inhibitor 1 and 2

Extrinsic pathway is activated by

Tissue factor III (which is exposed by damage)

Why is B cell isotype switching important for an effective immune response

To produce antibodies that can perform different functions

How do platelets function in blood clotting

To seal wounded endothelium - platelets help to temporarily seal off the site of a wound by sticking to the exposed, damaged edges of the blood vessels * Platelets are activated upon exposure to collagen of basal lamina and CT underlying endothelial cells of blood vessels ** which is normally hidden except when endothelium is injured WHEN PLATELETS BIND TO WOUNDED ENDOTHELIUM: - they become activated, release their granules and these factors react with the clotting factors in the blood (like fibrinogen) to form blood clot

Aggregations of nodular and internodular tissue in the walls of the pharynx

Tonsils - these tissues are the immune systems FIRST line of defense against ingested or inhaled foreign pathogens 3 types: 1. Palatine*: in the lateral walls of the oral pharynx (near the palate) 2. Lingual: at the base of the tongue 3. Pharyngeal (adenoids): at the rood of the nasopharynx ** tonsils most commonly refer to palatine tonsils- which are masses of lymphatic material situated at either side of the back of the human throat Tonsilitis= inflammation of the tonsils- gives those white thins on your tonsils bc the characteristic morphology of the tonsils

In the absence of RAG1/RAG2 (recombinationg-activating genes 1 & 2) there will be a lack of

Total number of lymphocytes both CD4 and CD8 as well as B lymphocytes, Monocytes, and NK cells ** without this cells are unable to undergo rearrangement

A group of enzymes that catalyze the transfer of an amino group from AA's too alpha-ketoacids

Transaminases ** ALWAYS requires Vitamin B6 ex: Pyruvate takes a nitrogen from AA with help of B6 and makes Alanine ** note this is not in the plasma but will be seen with tissue damage

L-selectin

Transmembrane protein on lymphocytes - binds CARBOHYDRATE ligand expressed on endothelial cells in high endothelial venules (HEVs) ** used to attract lymphocytes to secondary lymphatic organs in high endothelial venules (LYMPHOCYTE HOMING)

Peripheral tolerance and termination is dealt with

Treg cells - these are made in the presence of anti-inflammatory cytokines like TGF-beta and/or IL-10 ** NOTE: TGF-beta is seen as anti-inflammatory here, BUT in other areas it can be seen as inflammatory- so which form is dictated by what cytokines it is associated with

Most potent activator of thyroid hormone receptor is

Triiodothyronine (T3) - thyroxine (T4) was the most abundant form of circulating thyroid hormone - it is delivered to target cells via the circulation- in target tissues, it is converted to T3 (triiodothyronine), which is the most potent activator of the thyroid hromone receptor * liothyronine= generic drug name for T3

What is the most specific marker of an MI (myocaridal infarction)

Troponin 1 REMEMBER!!!!: Troponin I is a PROTEIN, NOT an enzyme!!!! CK-MB IS an enzyme soo if the question reads: what enzyme is most indicative of an MI the answer will be CK-MB ** Troponin is the most sensitive and specific for an MI ** CK-MB is relatively specific but NOT as specific as Troponin - Lactate dehydrogenase is not as specific as troponin (High LDH1 and LDH2 indicates MI) - Aspartate transaminase (AST) is NOT specific for heart damage

T or F: Cortisol generally requires at least 2 hrs and more typically several hrs for its effects to be observed

True!

T or F: glyceraldehyde 3-phosphate dehydrogenase is NOT common to the glycolytic and gluconeogenic pathways

True!

T or F: many hormones must be carried through the blood

True!

True or false: imbalance of Hb with Beta and gamma-Hb chains is not bound to alpha chains

True! - Beta and gamma-Hb chains CAN form homo-tetramers (therefore less precipitation than in beta-thalassemia ) - shortened RBC lifespan and aborted production just like in Beta-thalassemia

T or F: In the ZG and the ZF, the same enzyme converts a precursor into a glucocorticoid

True! - Corticosterone (in ZG) ** in ZG it takes one more enzyme to go beyond the glucocorticoid step into the mineralcorticoid aldosterone - Cortisol (in ZF)

T or F: One is unable to differentiate the zone in whihc an Adrenal Cortical Adenoma is growing by viewing it grossly

True! 3 zones of the Adrenal Cortex all with lipids and steroid hormone synthesis - an adenoma in these 3 locations will look the same- they are indistinguishable- so cannot distinguish if the adenoma would be producing androgens, glucocorticoids, or aldosterone

T or F: both Acetyl-coA and palmitate CANNOT be used as gluconeogenic precursors

True! Acetyl-coA cannot be a gluconeogenic precursor as it is effectively degraded early in the TCA cycle, and there is NO enzymatic mechanism to convert it to another gluconeogenic precursor - Pamitate is a fatty acid that would be converted to acetyl CoA and therefore also cannot be converted to a gluconeogenic precursor

T or F: removal of hormone is as important as secretion of hormone

True! Metabolic clearance rate (MCR)= volume of plasma cleared of a hormone per unit of time (inversely related to the half-life- the faster the clearance rate, the shorter the half-life of hormone in plasma) - Water-soluble hormone have greater MCRs than lipid-soluble hormones - hormone need to be temporary so their effects can occur and can disappear when no longer needed *** Kidney and Liver are MAJOR sites for hormone extraction and degradation- breakdown products appear in the urine or the bile. - target tissues also can degrade many hormones

Serotonin and Melatonin come from which AA

Tryptophan

What are the 4 types of Complement Receptors

Type 1 complement receptor (CR1, CD35): - Found on: mononuclear phagocytes, neutrophils, B and T cells, and erythrocytes - Function in phagocytosis and clearance of immune complexes Type 2 complement receptor (CR2, CD21): *** involved in B cells activation - so it is found on B lymphocytes and acts as a coreceptor for B cell activation Type 3 complement receptor (CR3, Mac-1, CD11bCD18): - Found in mononuclear phagocytes, neutrophils, NK cells - Functions in phagocytosis and leukocyte adhesion to endothelium (via ICAM-1) Type 4 complement receptor (CR4, p150, 95, CD11cCD18): - Found on Mononuclear phagocytes, neutrophils, NK cells - Function in phagocytes and though to function in cell adhesion **** Types 1,3,4 are complement receptors that sit on phagocytic cells that enable cells to grab microbes with added tagging called complement

Pharmacological challenges of Type I DM vs Type 2 DM

Type I DM (hypoinsulinemia due to pancreatic Beta-cell destruction) - requires replacement therapy - trying to maintain a balance between "tight-control" of blood glucose and excessive risk of hypoglycemia - is a significant challenge to titrate the replacement dose and coordinat with dietary intake and metabolic needs Type II DM (primarily loss of target tissue responsiveness to insulin but really multifactorial) - enhancing target tissue responsiveness to insulin and/or increase insulin release - taking other steps to prevent hyperglycemia - most patients will require combination therapy - refer to current ADA standards for guidance ** Goal: is to minimize episodes of hypoglycemia in both types

The insulin receptor is a

Tyrosine Kinase Receptor It is composed of 2 alpha subunits and 2 beta subunits linked by disulfide bonds - Alpha chains are entirely extracellular and bind to insulin - Beta chains penetrate through the plasma membrane and transduce the signal

What two amino acids allow for the production of hormones

Tyrosine and Tryptophan Tyrosine with help of BH4 becomes --> L-DOPA --> Dopamine (DA)--> Norepinephrine (NE) --> Epinephrine (EPI) *** all these products have inhibitory effect on BH4 Tryptophan with help of BH4 becomes Serotonin (5-HT)--> Melatonin (MT) ** serotonin has inhibitory effect on BH4 ------------ Deficiency in BH4 may be misdiagnosed as Phenylketonuria - loss of any of the 3 enzymes that recylce BH4 - decreased levels of catecholamines and serotonin - elevated levels of phenylalanine - Suadi Arabia, Taiwan, China, and Turkey the major cause of elevated Phenylalanine is the BH4 deficiency

Galactose-phosphate uridyl transferase makes

UDP-galactose as part of the pathway that converts the galactose to glucose

primary follicle/nodule

UNactivated lymphoid follicle - contains small, inactive B cells (edges are hard to spot) - no light staining germinal center

Microbial Ligands recognized by PRRs include

Unique Microbial structures - Pathogen- associated Molecular Patterns: PAMPs - Damage-associated Molecular Patterns: DAMPs (damage to tissues products released that can also induce activity) - also have MAMPs and BAMPs

Where do WBCs function?

Unlike RBCS they DO NOT function in the blood, rather they DO FUNCTION IN THE TISSUES!! ** WBCS are a normal component of CT ** they dont function in the blood but they do use blood to transport themselves from the bone marrow where they are made to their major sites of activity in tissues * they leave the bloodstream by migrating between endothelial cells of the blood blood vessels- diapedesis (the crawling), extravasation (the whole process)

Characteristic Flow of an Immune Response to an Extracellular Bacterial Infection

Upon first contact with the body the bacterium must first pass through physico-chemical barriers (ex: skin and fatty acids) - once it passes this is activates complement system which can lead to lysis, phagocytosis (macrophages & neutrophils) or inflammation - inflammation increases the recruitment of neutrophila and monocytes/macrophages and makes more complement which again can increase lysis and phagocytosis - this is all from the innate immune system--- - Dendritic cells which are also part of the innate immunity also increase phagocytosis which leads to the adaptive immune response - Antigen presentation/activation of T lymphocyts which can lead to increased production of neutrophils and monocytes in the bone marrow or activation of B lymphocytes which make antibodies

Recommended daily allowance of calcium for adults

Upper limit is 2.5-3.0 g/day - amount absorbed into the body is depenedent upon plasma calcitriol - BUT this allowance ensure there will be adequate calcium to absorb, should body need it- left over serves as stoool softener

Sites of action of Oxytocin

Uterus (stimulates frequency and force of contractions) - highly dependent on estrogen - 8 fold increase in sensitivity to oxytocin in last half of pregnancy - 30 fold increase in receptor sites - antagonized by progesterone Breast (role in milk ejection) - secretion stimulated by suckling or mechanical stimulation - contraction of myoepithelium pushing milk from alveolar channels to collecting sinuses Brain (animal studies implicate role in trust, social bonding) - being investigated for social phobies and autism - "cuddle" or "love" hormone

Difference between the two main Vasopressin (ADH) receptors

V1 (on arteriolar smooth muscles) - mediate the pressor effect of vasopressin through IP3/DAG- calcium as a second messenger system V2 (on basolateral membrane of cells in the distal and collecting duct) - antidiuretic effects are mediated by increase in cAMP * extrarenal V2 receptors mediate the release of coagulation factors- VIIIc and Von Willebrand Factor

V1 vs V2 (vasopressin receptors)

V1: - smooth muscle contraction - phospholipase C (PLC) stimualtes calcium mobilization - associated with vasoconstriction, thus "vasopressin" V2: - water balance - stimulates adenylyl cyclase and cAMP - associated with water retention, thus "ADH" ** more sensitive to slightly elevated ADH levels than V1 is - BOTH work to increase blood pressure

The intracellular receptor that binds to calcitriol is the

VDR (Vitamin D Receptor)

Difference between Variants and Alleles in reference to Hb

Variants are Hb with changed AA content (usually from point mutation) - More than 1000 variants are described, most neutral (OMIM lists 522 alleles of the Beta-Hb gene) - Each variant is caused by a different allele at the DNA/gene level Alleles include both those causing variants and those with reduced expression ** heterozygote frequency can be very high in some populations ** variants are at the protein level, alleles are at the DNA level

Primary hormone regulating body fluid osmolality

Vasopressin: antidiuretic hormone (ADH) - its release from the posterior pituitary is stimulated by: increased plasma osmolality and hypovolemia or hypotension Actions: - In the renal collecting duct, it increases the permeability of the cell membrane to water - it is a potent vasopressor/vasconstrictor - As a neurotransmitter it plays a role in secretion of ACTH, CV (cardiovascular) system regulation, body temperature, other visceral functions - Promotes release of coagulation factors - increases platelet aggregation --- Therapeutic Uses (V1 receptor mediated) - post-operative ileus - bleeding esophageal varicies - vasodilatory shock - post cardiac arrest ---- Pharmocokinetics: - not absorbed orally - IV onset: within 15 minutes (needs continous infusion) - half-life: 10-20 minutes - metabolism: hepatic and renal (minor) Adverse effects: - facial pallor, nausea, belching, cramps, arrhythmia, reduced CO, peripheral ischemia - water intoxication ------------ Therapeutic uses (V2 receptor mediated): - central Diabetes Insipidus - bleeding disorders - primary nocturnal enuresis - post lumbar puncture headache this one can be onset: oral (1hr), nasal (15-30min), SL (30min) half-life: 2-4hrs (duration of action 6-14 hrs) elimination: renal Adverse effects: - water intoxication, hyponatremia

Fludrocortisone

Very potent mineralcorticoid with high glucocorticoid activity; used primarily for its mineralcorticoid effects - promotes increased reabsorption of sodium and loss of potassium from renal distal tubules It is given: - orally - eliminated by the liver - half-life ~3.5hrs (biologic half life 18-36hrs) Adverse effects: - Same as those seen with glucocorticoids - obviouslt skewed towards mineracorticoid features

Since the blood clot formed by platelets is only a temporary solution to stop bleeding, what is needed

Vessel repair! The aggregated platelets help this process by secreting chemicals, primarily: - Platelet-derived growth factor (PDGF) and - Transforming Growth Factor beta (TGF beta) ** these substances promote invasion of fibroblasts from surrounding CT into the wounded area to form a scar and also repair of blood vessel endothelium ** local applications of these factors in increased concentrations through platelet-rich plasma (prp) has been used as an adjunct to wound healing for several decades

PTH increases the production of

VitD while VitD decreases the production of PTH * calcitriols indirect effect on PTH comes from increasing plasma clacium, which through Gi and Gq inhibits PTH

Macrocytic Anemia can be secondary due to

Vitamin B12 or Folate Deficiency

Most appropriate use for VitD supplementation in a normal, healthy person

Vitamin D itself (cholecalciferol and ergocalciferol) which has no known biological activity

Apparent volume of fluid required to contain the total amount of drug in the body at the concentration measured in the plasma

Volume of distribution - more lipophilic drugs tend to have a higher apparent volume of distribution at steady-state (because they become accumulated in various organs) - more ionized or serum-protein bound drugs have a lower apparent volume of distribution (because protein binding and ionization both tend to keep drugs from crossing cell membranes to get out of the blood)

Platelet granules contain

Von Willebrand Factor - promotes adhesion of platelets to endothelial cells, also produced by endothelial cell Platelet Factor IV - stimulates blood coagulation & other factors

What inhibites the vitamin-K reductase and effective levels of vitamin-K dependent coagulation components- and will extend the PT (prothrombin time)

Warfarin (Coumadin)

Pharmokinetics (PK)

What the body does to the drug - addresses the way the body interacts with a drug from absorption through excretion- primary 4 components are: absorption, distribution, metabolism, excretion ** knowledge of this is essential for creating a drug delivery regimen that will maintain the drug at the active site at concentrations within the therapeutic range

Iloprost

When administered for pulmonary arterial hypertension, this prostaglandin analog may cause caugh and bronchoconstriction ** it is administered by nebulizer- direct airway exposure

Parathyroid cells are detectors and secretors all in one

When extracellular calcium is HIGH More calcium sensors mobilize intracellular Ca2+ and decrease PTH compared to baseline - modulated via Gq and Gi, leading to decreased PTH mRNA transcription and PTH production - Gq: increases PLC which results in more calcium inside the cell - Gi: reduces aenylyl cyclase activity, which results in less cAMP - levels vary with ECF Ca2+ Calcitrol (the active form of VitD) also inhibits PTH gene expression and PTH production and secretion- while activating the transcription of more calcium sensors (CaSR) * unlike regular sensors these inhibit secretion, the more of them you have at the cell surface, the more the process of PTH secretion will be inhibited

What is the most important blood count following RBC indices

White blood cell count- tells you your Total leukocyte count (TLC) in a volume of blood ** can be done by manual methods or by automated cell counters Nml: 4,500-11,000/mm^3 Not that a Child <2 weeks will have significantly wider range (~5.0-21.0 x 10^3/microL) it is displaced upwards

Describe some toxicities associated with Glucocorticoids

Withdrawal of Therapy: - Flar up of treated disease - Acute adrenal insufficiency (mild- fever, myalgia, arthralgia, malaise; severe (can lead to coma), taper over weeks, months, sometimes as much to a year) - Pseudotumor cerebri Continued use of supra-physiological dose: - Fluid and electrolyte handling: Hypokalemic alkalosis and hypertension - Metabolic: hyperglycemia, glycosuria Long term toxicity of glucocorticoids: - Increase susceptibility to infection - Peptic ulcer disease (cocomitant NSAID or aspirin) - Myopathy - Behavioral changes (nervousness, insomnia, changes in mood, overt psychosis) - Cataracts - Osteoperosis/Osteonecrosis (calcium and vitD) - Effects on growth and development

Actions of Parathyroid hormone

Works to Increase concentration of calcium in the blood by: - Getting calcium out of bone (note the PTH mobilizes calcium salts out of bone- NOT collagen like cortisol does) - Decreases loss of calcium in urine - Indirect effect= increase prodcution of VitD (Calcitriol) which enhances absorption of calcium from intestine ----- The price: PTH inhibits renal phosphate reabsorption, so decreased concentratin of phosphate in the blood

Blood smears are commonly stained with

Wright Stain (methylene blue and eosin) Methylene Blue: -a basic dye: so stains acidic structures blue (like hematoxylin) it will stain ""basophilic"- base loving structures: - DNA in nucleus - RNA in cytoplasm - Specific granules of basophils Eosin: - an acidic dye (like H&E): so it stains basic structures pink/red It will stain "acidophilic" or "eosinophilic" structures: - Hemoglobin (which is not overall basic- but it does have regions of basic AA) - Specific granules of eosinophils (contains the major basic protein)

Do eosinophils and basophils contain different substances in their granules

YES!

Are tumor cells capable of secreting hormones

YES! ex. Small cell carcinoma can lead to secretion of excess ADH leading to Syndrome of Inappropriate ADH secretion (SIADH)

Can neutrophils survive in anaerobic environment

YES! * neutrophils contain few mitochondria as they use mainly glycolysis to generate ATP - the ability of neutrophils to survive in an anaerobic environment is highly advantageous, because they can kill bacteria and help clean up the debris in poorly oxygenated regions, ex: inflamed or necrotic tissue ** neutrophils contain a lot of glycogen (which is used as a fuel source for glycolysis)

With Massons Trichome Stain

You visualize the following: - Red keratin and muscle fibers - Blue or green Collagen (*Collagen Type I is bid in blood vessels) and bone - Light red or pink cytoplasm - Dark brown to black cell nuclei

The mineralcorticoid aldosterone is found in the

Zona glomerulosa

Propranolol

a beta adrenoreceptor antagonist - can effectively help control the cardiac symptoms of hyperthyroidism without directly altering the thyroid status - it does not treat hyperthyroidism itself, but it does help prevent some of the unpleasant and possibly dangerous effects, such as tachycardia

A NK cell will NOT kill a cell if

a cell expresses MHC class 1 and KIR (killer inhibition receptor) are engaged

The presence of dicarboxylic acids is a characteristic of

a deficiency in acyl-CoA dehydrogenase * looking at length one can differentiate if it is a deficiency in medium chain length acyl-CoA dehydrogenase (MCAD) - the fatty acids that accumulate undergo omega oxidation to get more energy - the inability to completely degrade the fatty acids results in a low energy state of the liver - It therefore has insufficient energy to sustain gluconeogenesis - this results in hypoglycemia (bc there would be insufficient energy for gluconeogenesis)

Inflammasome

a multiprotein complex in the cytosol of many cells (especially monocyte-derived phagocytic cells like monocytes, macrophages, and dendritic cells) that proteolitically activates the inactive precursor of IL-1beta or IL-18 It is composed of 1. A detection component, usually a NOD-like receptor (NLR) 2. An effector component which is caspase-1 (this cleaves the inactive form pro-IL1beta) 3. An adaptor component linking the other two components ** once a signal is detected by the NLR, caspase-1 is activated and precursor IL-1Beta (or IL-18) is cleaved into its active form and is ready for secretion - which can lead to acute inflammation *** secretion of IL-1Beta (or IL-18) requires TWO signals: one activating the NF-Kbeta pathway and one activating the inflammasome- both are triggered by microbial products (ex. reactive oxygen species, K+ efflux, crystals, etc.)

ACTH is

a peptide hormone that operates through cAMP and PKA in the adrenal cortex -ACTH stimulates production of the ACTH receptor and of key proteins in steroid synthesis * other factors affecting expressing of the ACTH receptor are ACTH, glucocorticoids, and angiotensin II

Prolactin (PRL)

a protein hromone (~198 AA very large!) of the anterior pituitary gland that was originally names for its ability to promote lactation in response to the suckling stimulus of hungry young mammals - it is not only synthesized in pituitary gland, but also in the CNS, immune system, the uterus, and even the mammary gland - moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in the homeostasis and immunregulation (immunostimulation)

Permissive effects

a second hormone (the permissive hormone) acts on a cell to (typically) enhance or (rarely) inhibit the responsiveness of the cell to a primary (and different) homrone) - either way, the permissive hormone helps the primary hormone maintain homeostasis - abnormal levels of the permissive hormone often result in abnormal function of the primary hormone Ex's: 1. Thyroid hormones increase the number of adrenergic receptors in the cardiomyocytes, allowing the catecholamines to regulate tone 2. Glucocorticoids enhance the effects of GH (during hypoglycemic states) on skeletal muscle myocytes to regulate glucose metabolism. One way to do this is to increase responsiveness of the myocytes by producing more receptors to GH 3. Glucocorticoids decrease GLUT-4 expression, weakening insulin effects in several tissues. This too is a permissive effect albeit in the opposite direction --- * whether you are altering the receptor number for some hormone or the number of enzymes within the cell, you are setting the stage as it were for a stronger or a weaker response to some other signal molecule that could bind to those receptors - when the signal does arrive, only if ALL the intracellular machines of the target cell are already present and primed and ready to go, will the signal molecule be able to induce a sig. effect within the cell (that hormone or neurotransmitter that is the signal molecule gets the credit for the action, BUT the permissive hromone (ex. thyroid hormone) made it possible

What maintains the biconcave shape of a RBC

a specialized cytoskeleton of actin-spectin (spectrin protein binding to actin) ** this provides the mechanical stability and flexibility necessary to withstand forces experienced during circulation ** NOTE: ankyrin binds spectrin to plasma membrnae and this can be defective in Hereditary Spherocytosis

What measures the function of the INTRINSIC pathway and the common pathway. In vitro extension by heparin

aPTT (partial thromboplatin time)

Bleeding time could help to indicate an abnormality in

abnormal platelet function ** commonly caused by Aspirin, uremia, Von Willebrand disease

Adrenal development and function requires ACTH. Glucocorticoids suppress ACTH secretion via negative feedback. If the axis has been suppressed due to chonic administration of exogenous drugs then

abrupt drug withdrawl can be fatal (corticosteroid therapy less than 7 days is unlikely to cause axis suppression) NOTE: - glucocorticoid hormone receptors (GRs) are widely distributed across tissues, where their actions vary considerably. - adrenal cortical hormones are steroids and act by regulating protein synthesis (some effects of adrenal steroids or analogs used as drugs may take some time to be effective- effects may last varying amounts of time after the drug is withdrawn, depending upon the half-life of regulated proteins - for disease, optimal dose is detemine by trial, error, and re-evaluation; goal is to find lowest effective dose for management of condition. Use adjunctive therapies or steroid sparing therapies when possible

Pompe Disease

absence of lysosomal enzyme that hydrolyzes the glycosidic bonds to glucose (not G1P) called alpha (1-4) glucosidase. When this enzyme is defective, glycogen accumulates in vacuoles in the lysosome - associated with massive cardiomegaly and often leads to early death from heart failure * this is a defect in glycogenolysis

First-pass effect

absorbed drug goes immediately to the liver where it may be metabolized before reaching the rest of the body and its target - this refers to the fact that ALL orally administered drugs have to pass through some aspect of the GI tract AND the liver (any or all of these locations may inactivate some fraction of the administered dose before it has a chance to reach the target location) ** this greatly affects the drug bioavailability of orally administered drugs

The most ypical hyperglycemic state is the transient period known as the

absorptive state

Fibrin degradation products would indicate

accelerated destruction of fibrinogen ** commonly due to DIC (disseminated intravascular coagulation)

Deficiency in Galactose-1-Phosphate uridyltransferase leads to

accumulation of galactose in the blood - in the eye this leads to formation of galactitol with an accompanying osmotic imbalance across the lens, and the formation of cateracts - the high galactose levels block phosphoglucomutase in the liver, and leads to insufficient glycogen degradation - this can be distinguished from the non-classical galactosemia which is a defect in galactokinase (this has the issues with cataract formation but no accompanying feeding and liver problems)

Pyruvate carboxylase is regulated allosterically by

acetyl-coA and ATP (activations) - this works in the liver to activate gluconeogenesis - presence of acetyl-CoA in the liver indicates that sufficient energetic reserves for glucose biosynthesis are being manufactures * gluconeogenesis cannot operate without a ready supply of energy- typically the source for this is free fatty acids

Main function of neutrophils is to

act as the first line of host cellular defense against BACTERIAL infections ** they defend tissues outside the blood by killing their targets * neutrophils are among the FIRST cells to appear in acute bacterial infections *** dead neutrophils and bacteria are the main ingredients of pus

Anywhere there is a secondary follicle (F)- with a light staining germinal center- is seen in secondary lymphoid tissue this signifies the presence of

activated B cells ** their presence means your immune system has encountered a foreign antigen and is generating antibody secreting plasma cells and memory B cells ** this is why you get swollen lymph nodes when fighting infection

Regulators of acetyl CoA carboxylase

activated by: Citrate and insulin inhibited by: Palmitoyl CoA, Glucagon, AMP

Synthesis of Thromboxane A2 (TXA2) is initiated by

activated platelets - TXA2 increases platelet activation and aggregation - Its synthesis is inhibited by Aspirin- which is an irreversible inhibitor of the COX (cyclooxygenase enzyme) - would inhibit platelet aggregation: NOT an anticoagulant but it is an antiplatlet drug Arachiodonic Acid (from the ends of phospholipids) is converted to Thromboxane A2 and Prostacyclin via the COX enzyme

Unbound hormone aka Free Hormone is the

active form - binds receptors as free - cross into interstitium from vessels or into cells - reduced half-life

Adrenal insufficiency can be both

acute and chronic

Fasting for a porlonged period and becoming critically ill can result in the

adaptive respone of reduced T3 formation

What are the steps following after an antigen with or without APCs enters with afferent lymph

after entering in with afferent lymph it moves in the subcapsular sinus and the APCs phagocytose antigen - The naive T and B cells enter the lymph node from blood through high endothelial venules in paracortex, migrate to cortex - In the cortex, APC present antigen to naive T cell ACTIVATES it and the activated T cell ACTIVATES naive B cell, forms a secondary follicle, some B cells transform into plasma cells - Antibody-secreting plasma cells migrate to medulla; effector T cells exit node in the lymph

What is the role of Haptoglobin (Hp)

after intravascular hemolysis of RBCs the Hb must be bound to Haptoglobin because Hb is toxic on its own in the body - Heme is then passed to hemopexin and taken into macrophages to be degraded

when a drug interacts with a biological receptor and activates that receptor to carry out its biological activity it is reffere to as an

agonist

Collagen type 3 fibers (reticular fibers) are

agyrophilic- "silver loving" NOTE: the regularly spaced, circumferential ribs encircling the sinus endothelium are readily distinguished from the random distributed reticular fibers of the surrounding splenic cords

In a serum electrophoresis on the extreme left you will have

albumin and on the extreme right you will have gamma globulin (predominantly immunoglobulins)

Gamma-glutamyltransferase (GGT) is induced by

alcohol * GGT is found mainly in cell membranes of: - Liver and bile duct**** - kidney - pancrease - several other organs Causes of raised (enzyme induction) GGT: - drugs and alcohol ex: anticonvulsants - also increased in cholestatic liver disease - hepatocellular damage

The ratio of aspartate and alanine transaminases (AST/ALT) is commonly elevated in

alcoholism

A decrease in 11 hydroxylase can cause deficiency in

aldosterone (mineralcorticoids)

Cinacalcet is an

allosteric modulator of the calcium-sensing receptor - it does NOT bind to the same site in the receptor as Ca does - it gives the receptor an enhanced effect to decrease PTH relative to the effect of the same level of serum Ca in the absence of Cincalet ------ Most likely to treat Secondary hyperparathyroidsim in renal failure, can also be helpful in primary hyperparathyroidism - cinacalcet reduces PTH secretion.

Calcium release in the liver is triggered by

alpha-adrenergic stimulation by epinephrine ------- In muscle, it is due to increased calcium triggering muscle contractions

what two things could inhibit plasmin

alpha2-antiplasmin and alpha2-macroglobulin

Cortisol regulates levels of insulin sensitive GLUT-4 proteins, which then

alters ability to respond to insulin in skeletal muscle and adipose- this leads to hyperglycemia

Hereditary fructose intolerance leads to

an accumulation of Fructose-1-phosphate (F1P), which effectively traps the phosphate pool so it is unavailable for ATP synthesis and unavailable for glycogen phospharylase as a substrate - there is little glycogen degradation- results in fasting hypoglycemia ----- Case: infant switched from breast feeding to formula and fruit juices begins to vomit and have severe hypoglycemia after eating- hereditary fructose intolerance is a congenital defect in metabolism that the infant may have

Parasite

an organism that grows, feeds, and is sheltered on or in a differed organism while contributing nothing to the survival of its host - parasites are of diff. types and range in size from tiny, single-celled, microscopic organisms (protozoa) to large, multi-cellular worms (helminths) that may be seen without a microscope ** Bacteria can also be parasites, BUT eosinophils generally fight MULTICELLULAR parasites like WORMS, which can be quite large (a tapeworm, for example, may be up to 20 ft long)

Treg cells express

anti-inflammatory cytokines (IL-10 and TGF-beta) to promote tolerance and prevent inflammation, as well as CTLA-4 to inactive Th cells and terminate adaptive immune responses ---- NOTE: Treg cells originate from two locations - in the thymus: some self-reactive thymocytes that escapre negative selection, but become Treg cells prior to exiting the thymus - or in the periphery: Ag presentation (MHC-II-restricted) in the presence of TGF-beta *** note that Treg cells express CD25 and CTLA-4 on their surface

Leukemias

are malignant clones of leukocyte precursors - they occur in lymphoid tissue (lymphocytic leukemias) and in bone marrow (myelogenous and monocytic leukemias) - in these diseases, there is usually a release of large numbers of immature cells into the blood - leads to lack of some cell types and excessive production of others (which are often abnormal in function) - the patient is usually anemic and prone to infection

Thymus-independent (TI) antigens

are some bacterial antigens that can stimulate naive B cells in the absence of T cell help ex: polysaccharides and lipopolysaccharides Signal #2 comes from antigen itself - without T cell help, antibody repertoire agianst TI antigen is limited: there is NO class switching and NO affinity maturation NOTE: signal #2 (CD40-CD40L) is necessary for B cell activation by both T-dependent and T-independent antigens

Insulins overall effects on the whole-body are

associated with the absorptive state - overall decrease in glucose and ketoacids (fuels_ - decrease in plasma fats - nurtients used to promote overall energy storage and anabolism

Every bit of lymph is filtered through at least ____ (~100-200 in the body) before the fluid is dumped back in the blood circulation

at least one lymph node ** this is the way that the immune system constantly monitors drainage from tissues for pathogenic invaders *** lymph nodes are a SECONDARY lymphatic organ- this means an antigenis respons is initiated and antibodies are produced against any "non-self" antigens present (in lymph in this case)

Permissive hormones

augment or inhibit the action of other hormones

When do lymphocytes acquire their antigen specificity

before they encounter antigen

Epinehrine has a higher affinity for

beta receptors (beta 1 and beta 2, but it can also bind alpha 1 and alpha 2 receptors) * NE with alpha receptors (alpha 1 and alpha 2, but can bind to beta 1 receptors) * meaning that these two hormones, depending on their relative concentrations at the taget tissue, can mediate different effects through different receptors and second messenger systems

How much of the total calcium in the body is contained within cells

between 1-2 percent

Describe the shape of RBCS

biconcave shape * this shape maximizes their surface area/volume ration, therefore maximizes O2 and CO2 exchange ~~ normal it is about 8 microns wide (um) - <6um= a MICROCYTE - >9um= a MACROCYTE

Carbon monoxide is different from CO2 in that it

binds to the same sight where O2 binds (when instead CO2 binds to AA in the globin chain) Carbon monoxide binds to heme 200x higher affinity than oxygen - it forms Carboxyhemoglobin (CO-Hb): note that smokers have a higher circulating level of CO-Hb ** this increases your risk of blood clots- you can treat this with Hyperbaric Therapy (3 Atm with oxygen)

highest medical warning from FDA

black box warning - serious or life-threatening risks

A DA (dopamina) antagonist will

block the effect of DA thus may increase prolactin secretion - Hyperprolactinemia consequences include: gynecomastia, inappropriate lactation, infertility in both males and females ** Hyperprolactinemia can be treated with the prototype dopamine agonist-- BROMOCRIPTINE (a semi-synthetic ergot alkaloid whose selectivity for D2 is > than D1) and also Cabergoline (which is preferred) ** remember D2 receptors when activated by a DA agonists decrease prolactin release Bromocriptine is: - well-absorbed - extensive 1st pass metabolism through the liver (7% reaches circulation) - half life 2-8 hrs - it normalizes prolactin in 70-80%; decreases tumor size in 50% Adverse effects of the drug: nause, vomiting, headache, postural hypotension, nasal congestion, CNS effects - start low and tirate- this leads to tolerance over time Other uses: - Parkinsons disease, uncontrolled Type 2 diabetes

Lymphocytes can be found in the

blood and in the thymus There are 3 types of lymphocytes: - T cells - B cells - NK cells ** these three can be told apart by immunocytochemistry (because diff lymphocytes express different surface markers) BUT you CANNT tell them apart on H&E stained sections ** Lymphocytes are the most abundant (by far) cell type of lymphoid tissue

Insoluble fibrin that has been converted from soluble fibrinogen is a

blood clot ** a fibrin containing network trapping blood cells * clotted blood breaks fibrinogen --> fibrin

Blood collected without an anticoagulant will form a

blood clot ( a fibrin-containing network trapping blood cells) ** the rest of the liquid left behind = Serum (a protein-rich fluid lacking fibrinogen but containing albumin, immunoglobulins, and other components)

Hemostasis is the process of

blood clotting - occurs when small blood vessel (capillary) is damaged - clot seals the blood vessel until it regenerates * occurs in just 3-6 minutes

Platelets function in

blood clotting and wound repair

Blood flow in the white pulp of spleen

blood enters splenic artery --> trabecular artery --> central arteries/arterioles (which are surrounding by T cells of the white pulp called "periarterial" or "periarteriolar" lymphoid sheath (PALS) - B cells in these sheaths can form nodules - and around these nodules are located the marginal zone sinuses ** emerging from the white pulp, the central arteriole branches as the penicillar arterioles, which lead to sheathed capillaries. From these the blood flows into either a closed circulation passing directly into splenic sinuses or an open circulation, being dumped from the vasculature into the lymphoid tissue of the red pulps splenic cords * from there viable blood cells reenter the vasculature through the walls of the sinuses

After injury to a blood vessel the damage to smooth muscles and blood vessel and stimulation of pain receptors can lead to

blood vessel spasms and constriction * vasoconstriction

Granulocyte production and storage occurs in the

bone marrow

After birth blood cells derived from stem cells are found in the

bone marrow (the bone marrow also produces (T cells) that migrate to the lymphoid organs where they become immunocompetent

Cortisol has a direct long-loop negative feedback on

both ACTH from pituitary and CRH (CRF) from hypothalamus - angiotensin II is modulator of CRH (CRF) secrtion- it is related to stress response- by relieving stress, one reduced the excitatory action of these stressors *** cortisols actions relieve stressors that also drive secretion --- when active- cortisol causes: - supressed function of the immune system - gluconeogenesis in the liver - protein catabolism in muscle - lipolysis in adipose tissue (fat mobilization) - stabilizes lysosomes ** all of these actions relieve stress

the body requires a continuous supply of glucose because of the

brain and RBCs

Methylmalonyl CoA is an intermediate in the

breakdown of odd-chain fatty acids and branched chain amino acids and a few others

The mobilization of GLUT-4 transportes for a direct increas in glucose uptake is ONLY applicable to those tissues-- including

cadiac muscle, skeletal muscle, and adipose tissue, but NOT hepatocytes- which express GLUT-4 transporters * In tissues that DO have insulin receptors but DO NOT have GLUT-4 transporters (ex. hepatocytes) insulins promotion of enzymatic effects that increase anabolism and otherwise utilize glucose indirectly increase the conc. gradient for glucose ** this change in gradient causes increased glucose uptake by facilitated diffusion through whatever glucose transporters thse cells do have (GLUT-2 transporters in hepatocytes) Bottom line: with or without GLUT-4, if there are enough GLUT-2, glucose transport into the target cell increases and glucose utilization does too

The hormone FGF-23 reduces activation of

calcidiol (inactive metabolite) to calcitriol ** PTH on the other hand stimulates calcitriol production - Hypocalcemia and hypophosphatemia also promote its production --- NOTE: calcidiol is the form of VitD that is assayed in blood tests

The high affinity ligand for VitD receptor activation is

calcitriol -- calcidiol can bind the VDR with very low affinity (this only results in biological response when the levels of calcidiol are excedingly (nonphysiologically) high

In severe exercise, ___ will rise rapidly

calcium - Calcium will bind to calmodulin which then will activate phosphorylase kinase, and in turn activates glycogen phosphorylase by its phosphorylation - Epinephrine will augment this effect when it reaches muscle via the cAMP/PKA phosphorylation of phosphorylase kinase

Totipotent

can become both embryo and extra-embryonic cells/tissues ex. Zygote

Fructose-1-phosphate

can feed into glycolytic intermediates and could, in principle, be a gluconeogenic precursor, BUT this rarely happens in practice as fructuse is typically present in the fed state and glycoclysis active

Light-colored skin has fewer melanocytes and

can produce VitD faster than dark-colored skin * if sunlight production of VitD everyday is adequate, dietary VitD not necessary

Complement activation (AKA complement fixation) consists of a

cascade of proteolytic enzymes that generate inflammatory mediators and opsonins (sequential proteolysis of complement proteins which in turn generate complexes that also posses proteolytic activity (similar to the coagulation and kinin systems)- some components of the complement system can mediate several proteolytic reactions thus ensuring a rapid amplification of the response - some biologically active cleavage products resulting from complement activation covalently bind to microbe surfaces, antibodies bound to microbes and other antigens, as well as apoptotic bodies (macrophages must clear these dead cells) - by products of complement activation stimulate inflammation (cytokine and complement response trigger inflammation) - complement is inhibited by host regulatory proteins NOT normally present on microbes (this is what allows complement to act on everything but our bodies- because we have inhibitors that inhibit its function on our cells)

Medulla of the Adrenal (suprarenal) gland secretes

catecholamines (mostly epinephrine (epi), some norepinephrine (NE))

Iodine Deficiency

cause of endemic goiter. Used to be common in many mountainous and inland regions: Alps, Himalaya, Great lakes region, congo basin - low T3 and T4, high TSH - goiter is caused by chronic overstimulation of the thyroid gland by TSH - Now rare in europe and america, but still common in exotic places

Aplastic Anemia

caused by bone marrow failure

Hemolytic Anemia

caused by destruction of RBCs

Megaloblastic (macrocytic) anemia:

caused by impairment of DNA synthesis

Acute Hemolytic Transfusion Reaction

caused by mismatch in the blood types: because of preformed antibodies against RBC - mechanism: FAST destruction of blood cells by preexisting antibodies consists of: fever, chills, nause, CP, back pain, pain at transfusion site, hypotension, dyspnea, oligurea, dark urine - mortality rate is high (40%) Could be caused by: - ABO mismatch OR - mistmatch in any other blood group if there has been prior exposure (ex. Thalassemia- repeat recipient) ***** this is the ONLY transfusion reaction that can be caused by ABO mismatch ** fever can also be an early sign of acute hemolytic transfusion reaction- as such, a patient with fever starting during transfusion should be monitored extre carefully for other signs

In adults, naive T cells are hypothesized to be primarily maintained by

cell division of existing naive T cells

For water soluble hormone the receptors are on the

cell surface

Antibody-dependent cell-mediated cytotoxicity (ADCC) is a process in which antibody-coated cells are killed by

cells with Fc receptors for IgE

Effector T cells

change gene expression profiles and thereby gain the capacity to express proteins they will need to perform their effector functions - CD4 T cells (T helper cells (inflammation) or T regulatory cells (shut down inflammation) these secrete cytokines (IL-4 & IFN-gamma) and express surface molecules (ex. CD40L) - CD8 T cells (Cytotoxic T lymphocytes): secrete cytokines (IFN-gamma), express surface molecules (FasL) and release cytotoxins- proteins that are used to kille infected cells (pore formation by perforin)

A focused aim statement should include a

change, a direction and quantitiy of change, a time frame for the project, and some indication of relevance or importance of the project

In complement C3 and C4 are responsible for

clearance of immune complexes

No Coagulant the blood will be

clotted --> yellow liquid up top= serum (supinatant from cogulated blood) ** has NO fibrinogen

If a marathon runner hits a "wall"- his muscle glycogen stores will be

completely depleted - if this occurs upon finishing the race his main fuel source will be free fatty acids - as time progresses muscle glycogen and TAG stores become depleted and contribute less while free fatty acid release increases and circulating glucose is used more - this glucose is derived from gluconeogeneis and from liver glycogen stores - to improve a runners ability to carb load and his use of fatty acids they could improve their aerobic conditions- leading to faster mobilization and utilization (helps to preserve glycogen stores during the race- wont hit the wall as fast)

In liver cirrhosis

concentration of albumin decreases - while alpha 2 and gamma increase

Contraindication

condition or situation that makes the use of a particular drug inadvisable - Absolute: use in certain patients is absolutely inadvisable - Relative: inadvisable but not completely ruled out if risks are outweighed by the benefits

Unlike all other anterior pituitary hormones, prolactin typically has

constitutive secretion (contant secretion unless inhibited) - Hypothalamo-Pituitary-Mammary axis- - when PRL is high- short loop feedback happens - dopamine secretion then goes up and then it reduces prolactin * pathologically high levels of TRH have been shown to dramatically increase PRL secretion * PRL also inhibits the gonads, to temporarily reduce fertility during breastfeeding NOTE: prolactin only feeds back on the hypothalamus- it does not feed back directly on the pituitary lactotropes

In process modeling you are looking for

contributing factors and root causes

Ceruloplasmin (an APR) is an enzyme that transports

copper It is used in detection of Wilsons disease - Copper deposition - Kayser-Fleisher rings (rings in the eyes) - Hepatic damge - arthritic changes

With the help of several hydroxylases progesterone can become both

cortisol or aldosterone

Propylthiouracil is an effective therapy for hyperthyroidism by regulating the

coupling of diiodotyrosyl residues (or di- and monoiodotyrosyl residues) to form thyroxine (or triiodothyronine) * Thioamide drugs, including PTU, inhibit thyroid peroxidase which is important for two key steps in thyroid hormone synthesis: the oxidation of iodide to its active form, and the coupling of iodotyrosines - both of these reactions occur in the extracellular colloid space surrounded by follicular cells

Chemotaxis

crawling along a soluble concentration gradient towards its source

Superantigen activation

cross-links TCRs with MHC-II molecule in such a way that CD4+ T lymphocytes are activated independent of the presence or absence of peptide int he peptide-binding groove (Antigen) - it does so by recruiting B7 and CD28 (which provide the signal independt of the antigen) - results in: non-specific activation of CD4 T lymphocytes which leads to excess secretion of proinflammatory cytokines that affect vascular permeability - sometimes up to 25% of lymphocytes are activated and this increases inflammatory cytokines like TNF-alpha which are what increase vascular leakage and can lead to shock and death - BUT if you survive this shock or death you are left with depletion of CD4 T lymphocyte popylation leading to immunosuppression ** Typical examples of superAg are the staphylococcal and streptococcal toxic shock syndrome toxins and staphylococcal enterotoxins (SEs) but other organisms such as virsuses and fungi can produce superAg NOTE: some superAg can also cross-link class I MHC and the TCR of CD8 T lymphocytes, with similar consequences

How do both culture and context influence health care systems

culture= patterns of learned group-related perception & context

Each stage of cell differentiation is modulated by a combination of

cytokines and other growth factors

Left unchecked, complement activation can

damage normal host cells and unnecessarily prolong inflammation hence the complement system is normally tightly regulated

Hypoalbuminemia

decrease blood albumin - causes H2O to leave from the blood vessel to the ECF- causing ECF to expand- leads to edema Why would someone develop this? - reduced synthesis of albumin maybe due to damage to the liver- (IL6/stress response) - altered distribution (increased capillary permeability, decreased lymph clearance) - increased catabolism (increased breakdown of albumin due to chronic infections/trauma) - abnormal losses (burns, renal disease, GI bleeding/loss, hemorrhage ** all these above things could cause hypoalbuminemia

Hemtocrit, Hemoglobin, Transferrin saturation, Serum Ferritin are all ___ in iron deficiency

decreased

Alpha Thalassemia

decreased or absent alpha chains - excess unpaired beta, gamma, or delta chains ** there are 2 alpha globin genes on each chromosome 16 ** clinically significant: alpha thalassemia results from 3-4 alpha gene deletions *** production of alpha-globin is decreased due to a gene deletion or inactivation ----------- - Deletion of a single alpha globin chain= silent carrier (asymptomatic)- hematological findings include slight microcytosis and decreased MCV - Deletion of 2 alpha-globin chains= alpha-thal trait (asymptomatic or mild anemia (~Beta thal trait)- hematological findings include mild microcytic anemia and decreased MCV - Deletion of 3 alpha-globin chains= HbH disease (beta4) common in asians- moderate microcytic anemia and HbH on electrophoresis - Deletion of all 4 alpha globin chains (comon in south east asia)= Hydrops Fetalis (HF) and Hb Barts (gamma4)- this is lethal in utero without blood transfusions, severe pallor, generalized edema and massive splenomegaly (~HDN), lifelong transfusion dependence, hemachromatosis without Fe chelation, Rx= BM transplantation) - Hb Barts has increased affinity for oxygen ** ~HDN= similar to hemolytic disease of the newborn

Thrombin time (TT) would show

deficiency/abnormal I, inhibition of II by heparin or FDPs ** common in heparin therapy

Increased albumin is due to

dehydration

Glycogen synthase is activated via

dephosphorylation

Granulocytopoiesis

development of granulocytes (neutrophils, basophils, and eosinophils) ** mitotic phase takes ~ 1 week; post-mitotic phase also takes ~1week 1. Myeloblast - looks like lymphocytes but often has 3-5 prominent nucleoli 2. Promyelocyte - Azurophilic (non-specific) granules 3. Myelocyte **(can tell cells apart at this stage) - Oval or flat nucleus, specific granules appear; last stage at whcih cell division is possible 4. Metamyelocyte - specific granules continue to accumulate, nucleus indented, C or V shape 5. Band/stab cell - eosinophil and basophil stab cells exist but are rarely found, mainly band cells are immature neutrophils 6. Mature eosinophils, neutrophils, basophils

Tissues and organs of the lymphatic system include

diffuse lymphatic tissues, lymphatic nodules, lymph nodes, spleen, bone marrow, thymus

Once activated, the life-span of an effector T lymphocyte (ex. TH cell) is

dramatically shortened (this is normal to avoid tissue damage and chronic inflammation) UNLESS if the cell iscontinuously being re-stimulated by antigen (antigen persists)- T cells are given survival signals and continue performing their functions, such as cytokine production ( a great clinical correlation of this is strep throat) As long as there is Antigen there is inflammation and as long as there is inflammation there is CD80/CD86 (B7) expression ----but if you were to start getting rid of antigen, then these co-stimulatory molecules will go down and you will go back to homeostasis---

Cori disease (aka Glycogen storage disease III)

due to a defect in the debranching enzyme in glycogenolysis - this can include the 4:4 transferase activity, or the glucosidase activity, or both. It can affect liver or muscle- the liver type can result in fasting hypoglycemia and glycogen with abnormal structure * leads to fasting hypoglycemia

Anemia of renal disease

due to lack of kidney hormone erythropoietin, which is needed to stimulate the bone marrow

Activated B cells undergo differentiation into

either Plasma cells which make antibodies or Memory cells that are prepared for later exposure Plasma Cells: - terminally differentiated antibody synthesizing and secreting machines - IgM is NO longer surface-bound but secreted No longer can respond to antigen - lose surface IgM (BCR) - Stop MHC class II expression - express CD27 Memory Cells: - survive for long periods - allow for more rapid and robust secondary antibody response - express CD27

In folate chemistry for donating methyls

either serine or glycine is used, not both at once ** serine and glycine can be broken down in the reaction of THF --> 5,10N-methylene-THF..they can also be used for the synthesis of glycine and serine; the reactions lie near equilibrium are are reversible by mass action - FIGLU is formiminoglutamate.. it is formed from the breakdown of histidine. The N5-Formimino-THF can be converted to either 5,10 methylene THF or N10-formyl-THF ** then the reaction of 5,10-methylene-THF to 5-methyl-THF is biologically irreversible (HIGHLY EXERGONIC) **this is why the following methionine synthase reaction is so important. Without it, folate gets trapped as 5-methyl-folate and cannot be reconverted to THF Methionine synthase (AKA homocysteine methyltransferase) then uses B12 as a cofactor - it catalyzes synthesis of methionine from homocysteine- the added methyl group comes from 5-methyl-THF **5 methyl-THF trap hypothesis is that B12 deficiency fails to regenerate THF from 5-methyl-THF (5-methyl-THF then accumulates and creates a folate insufficiency) ** thus signs and symptoms of B12 and folate deficiency are similar. Both result in MACROCYTIC anemia sxs need to be investigated to see if the deficiency is due to folate or B12

Peripheral tolerance

eliminating or rendering T lymphocytes unresponsive to "ubiquitous" antigen once they have left the thymus and reached the periphery

Steroids are "classical" hormones that are produced by

endocrine glands and transported by the blood - made in the adrenal cortex, gonads, and placenta - derived from cholesterol (makes them lipid-soluble= therefore no vesicular storage) - transported by plasma proteins: transcortin (glucocorticoids), sex-hormone binding globulin (estrogens, androgens) - act on transcription factors (on nuclear receptors) - have oxidative side chain cleavages - hydroxylations (P450-dependent) * inactivation mainlt in the liver

IL-1Beta, the gene products it activates, as well as complement fragments ALL coordinate to induce

endothelial activation and transendothelil migration in post-capillary venules, which are responsible for the cardinal signs of inflammation: heat, redness, swelling, and pain

Paracrine functions of proinflammatory cytokines include

endothelium activation and macrophage activation

The sole function of a TCR is

engaging and antigen - but it must have a signal to have this engagment- but CANT signal because cytoplasmic tail- soo it is associated to other peptide chains (these 6 chains: 2 epsilon, 1 delta, 1 gamma, 2 zeta- make up CD3 which is a marker for T lymphocytes) so that it can do this signal transduction to the nucleus - allow the nucleus to know that is has engaged an antigen

A human cell contains 28,602 different proteins, 2,709 of these are

enzymes - they are distributed in the cytosol, nucleus, rER and sER, golgi bodies, mitochondria, lysosomes, plasma and organellar membranes ** most enzymes are present in cells at much higher concentrations than in plasma (bc they are confined to the area in which they have to do their work) - changes in plasma enzyme levels may help to detect and localize tissue cell damage or proliferation, or to monitor treatment and progress of disease * in the absence of cell damage the rate of release of plasma enzymes depends on: - the rate of cell proliferation (indicative of a tumor) - the degree of induction of enzyme synthesis

The reticulocyte leaves the bone marrow and passes into the bloodstream becoming an

erythrocyte * the mature form, has lost all polyribosomes - the reticulocyte will lose its mitochondria and ribosomes within a day or two to become a mature erythrocyte

Iron absorption and use is regulated by

erythropoietin

Renal failure is usually due to a

erythropoietin deficiency

Syndrome of Inappropriate ADH secretion (SIADH)

excess ADH from the posterior pituitary gland or from another source ex: Carcinoma mostly in the lungs (Small cell carcinoma) results in excess water retention by the kidneys -- Initial immediate improvement: requires sharp restriction of daily water intake

Hemostasis: Coagulation and Clot Stabilization is triggered by

exposure of blood to collagen this pathway includes: - prothrombin - calcium - fibrinogen - fibrin - polymerization

IgD

expressed on surface of naive B cells - secreted form has NO known function

TFPI (tissue factor pathway inhibitor) inhibits

extrinsic pathway - it is activated by the presence of thrombin

TNF, IL-1, and IL-6 can act on the brain to induce

fever

Vimentin is found in

fibroblasts/reticular cells

Glucose-6-phosphatase is inhibited by

free glucose at high intracellular concentrations (~100mM) BUT this is way too high to be physiologically relevant ** remember glycogen phosphorylase in liver cells is allosterically inhibited by high intracellular free glucose conc.

Thyroid Follicle

functional unit producing T3 and T4. Consists of follicular lumen surrounded by a single-layered cuboidal epithelium (columnar when stimulated) - Lumen filled with "colloid" consisting of the glycoprotein thyroglobulin - Low turnover of follicular cells: one mitosis/8 years

Which globin is highest in the fetus

gamma - alpha and beta are highest in adults- this is seen at 24 weeks * alpha is high most of life

We will be tested on drugs by their

generic name - offical name of a drug given to it after approval by the Food and Drug Administration (FDA) ex. Ibuprofen

Low CHO/High protein involves

glucagon for gluconeogenesis

A decrease in 17 hydroxylase can mean a decrease in

glucocorticoids (cortisol) and Sex steroids (testosterone)

The zona fasciculata (ZF) of the adrenal (suprarenal) gland secretes

glucocorticoids (ex. cortisol) --- - ZF is arranged in straight CORDS, one or two cells thick - polyhedral - cells in more superficial portion of layer are mainly SPONGIOCYTES (any of the cells of the adrenal cortex that have a spongy appearance due to lipid vacuoles) - deeper cells appear more denser

In presence of low blood glucose, cortisol stimulates

gluconeogenesis

ATP is required as an energy source, and thus is a substrate for some

gluconeogenic enzymes - BUT this is not really a substrate for the process; rather it is providing energy for the process

One of the major function of epinephrine is to affect

glucose metbaolism and supply in the plasma *NOTE: that levels of glucagon, insulin, and cortisol among others will also impact glucose metabolism --- Adrenal catecholamines stimulate fatty acid and glycerol backbone release from adipose tissue - the carbs are then converted into new glucose via gluconeogenesis (BUT the major hepatic conversion of adipose stores is of fatty acids into ketoacids) - both newly made glucose and ketoacids can then be used as fuel sources elsewhere in the body - via beta 2 receptors, epinephrine stimulates glucaon secretion - via alpha 2 receptors, epinephrine inhibits insulin secretion - epinephrine also stimulates both muscle and liver to break down glycogen for additional glucose supply in plasma - any skeletal muscl that is actively working during this release might have its local needs supersede this general schematic so think of this as a function of all the nonworking muscles during the energy mobilization phase of response to catecholamines *** this effect is acute - further secretion of more epinephrine and norepinephrine will be required for these effects to be maintained for a longer time period, at which point glucocorticoids might become more important

Vasopressin/ADH is mature when the ___ is removed leaving the amino group

glycine -- Preprovasopressin has the amino portion cutt off, removal of glycine from this portion yields vasopressin- the other portion of the prevasopressin yields Neurophysin II, also the COOH portion yields glycoprotein which makes copeptin - Neurophysin II is the transport protein for vasopressin/ADH *** NOTE: it is different from the monomeric Neurophysin I which carries only one oxytocin. Neurophysin II dimerizes and it is able to carry 2 vasopressin

A priority of muscle is to replenish

glycogen stores after exercise - strenuous excercise for several hours will substantially deplete muscle glycogen - so any food eaten after strenuous exercise will be stored as glycogen in the muscle

In presence of low blood glucose, both NE, E, and Glucagon induce

glycogenolysis - BUT glucagon ALSO does gluconeogenesis

Insulin promotes

growth - works on many cell types to lower BG, FAs and AAs and promote their storge - when these molecules enter blood during the absorptive state, insulin directs their cellular uptake and conversion into glycogen triglycerides (fat) and protein

GH binding protein (GHBP) transports

growth hormone

Free heme is carried by

hemopexin (Hpx)

Deficiency in the liver enzyme (in glycogen metabolism) leads to

hepatosplenomegaly, eventual cirrhosis and cardiac problems - found in infancy, very rare

Intracellular phosphate concentration is 100x

higher than extracellular - mostly found in bone - Of all its concentration throughout the body 90% is free, 10% is bound

Breakdown of TAGs in skeletal muscle during exercise occurs in respons to

hormonal or contraction signals, NOT because of fasting (you can exercise in either fed or fasted state)

Pharmacogenomics

how genetic differences may affect the absorption, metabolism or response to drugs - gene variants can play a huge role in efficacy and safety of drug administration to individuals ex. cyp2D6 (cytochrome P450 2D6) has many different noraml variants in individuals- thus a sig. number of patients may either metabolize these drugs more slowly or much more quickly than expected. The result would be either an accumulation of a toxic amount of the drug, or failure to achieve a therapeutically-useful blood level

Catalyses do

hydrolytic cleavage of various esters of choline

Calcium and phosphate together are key components to production of the major crystalline salt of bone,

hydroxylapatite

Major risk/adverse effect of calcitriol is

hypercalcemia - bc endogenous feedback regulation of calcitriol formation has been bypassed

ultra-short feedback loops

hypothalamic-released substances directly reduce further hypothalamic release of substances - no known physiological ultra-short loops

The advantage of lipid-soluble hormones is that

if you can get them into the cell, the cell machinery for gene transcirption and translation will always be there- so these hormones can exert their effects. The cells receptors are intracellular, either in the cytoplasm or in the nucleus Ex. Steroids, thyroid hormone, retinoic acid (active Vit A) and calcitriol (the active form of Vit D) either diffuse across or are transported across the cell membrane - some receptors start in cytoplams, others in the nucleus - they DIRECTLY regulate gene transcription *** disadvantage of these routes is slow speed (slower to start and slower to stop than water soluble hormones who use a second messenger)

The ability of a lymphocyte to produce a normal immune response following exposure to an antigen is referred to as

immunocompetence

Most proteins are synthesized in the liver with the exception of

immunoglobulins

Where is there a high occurence of Sickle cells alleles (HbS)

in historical malaria areas (heterozygote advantage) - Plasmodium Falciparum Malaria- HbAA (homozygot normal) has medium survival HbAS(heterozygote) has a higher survival than HbAA HbSS(homozygote for sickle cell alleles) has a lower survival ** high freq. of Thalassaemia in the mediterranean and east Asia probably have the same cause - as does some enzyme deficiencies

Describe the proccess of cross-presentation in MHC-I restricted Ag presentation

in some cases material taken up through endocytosis "leaks" into cytosol ** this leaked material can be processed by proteasomes and enter the MHC-I-restricted Ag presentation pathway *** so MHC-I is supposed to work on things that are intracellular- so this cross-presentation is referring to extracellular material that ends up being presented by MHC-I molecules on a cells surface, usually a pAPC ** this is one of the reasons behind graft rejection - the major rejection process is done by CD8 lymphocytes

Sjogrens syndrome

inability of the immune system to make tears or saliva

Sideroblastic anemia:

inability to use iron for heme synthesis, for example in deficiency of vitamin B6

APRs ___ in the presence of inflammation

increase - Albumin is a negative APR (acute phase response) so it decreases in the presence of inflammation while other proteins will increase

Primary effect of calcitriol in humans

increase absorption of calcium and phosphate from the GI tract lumen

Insulin responds to

increase glucose after a meal (its is secreted from the beta cells of the pancreas) its effects: - promotes glucose use, particulary in skeletal muscle and adipose tissue - upregulates GLUT4 in skeletal muscle and adipose - promotes general anabolism - activates LPL in adipose tissue ---- In fasting state: both insulin and BG levels decline, and glucagon increases

Pregnant women on thyroid replacement therapy usually need an

increase in dose while they are pregnant - though to be due to increased circulating levels of TBG (thyroid binding globulin) - the adequacy of thyroxine dose is monitored by measuring TSH during pregnancy, just as at other times - if the T4 does is NOT adequate as pregnancy proceeds, TSH will go up, signaling the need to increase the dose

Factor I deficiency can lead to

increase in fluid-phase C3 convertase C3bBb - leads to serum C3 depletion - which leads to increased susceptibility to pyogenic infections mainly, but atypical haemolitic syndrome (aHUS) is sometimes seen (secondary to lack of Factor H binding..) * this increases infection by thin walled organisms * this is mostly in the alternative pathway * fluid-phase C3 convertase refers to an active C3 convertase that has NOT yet been stabilized by properdin

All sympathetic effects ultimately work to

increase nutrient supply to muscle and adequate supply of oxygen and glucose to the brain

Effects of thyroid hormone

increased cardiac output, brain maturation, fertility in adults of reproductive age

When growth hormone levels are elevated, one of its effects is

increased plasma glucose - which then increases insulin (which then helps get the AAs into the cell and promotes production of the ATP that will go into peptide bonds)

A deficiency in the alternative pathway component Properdin may result in

increased susceptibility to BACTERIAL infections (especially thin-walled bacteria)

Genetic deficiences in terminal components of complement (C5, C6, C7, C8, C9) can lead to

increased susceptibility to disseminiated meningococcal (Neisseria meningitidis) infections and Neisseria gonorrhoear infections ** again, thin-walled organisms which tend to be more affected by complement lysis

The metabolism of ethanol by the liver

increases NADH/NAD+ ratio reducing its ability to perform gluconeogeneis (increases drunkness, this works via alcohol dehydrogenase)

Primary function of thyroid hormone

increases metabolic rate and increases growth and maturation

A hallmark of allergic disease is

infiltration of the tissues with increased numbers of eosinophils (eosinophilia) - result of co-ordinated action of cytokines causing selective trafficking of eosinophils into allergic tissue Ex: - Allergy, cow's milk intolerance, and gluten sensitivity cause increased numbers of eosinophils in the bowel mucosa - Asthma causes increased numbers of eosinophils in the lung tissue

Prolactin (PRL) is under tonic _______ control of dopamine (DA)

inhibitory Dopamine goes up, PRL goes down DA goes down, PRL goes up ** Tonic: state of continuous unremitting action - this is not a muscle contraction, but it is a state of continuous, unremitting action of stopping the anterior pituitary from secreting too much prolactin - in absence of DA frm hypothalamus, prolactin levels would rise to abnormally high values in plasma and produce pathological effects *NOTE: many interacting hormons (TRH, OXY, VIP) have consititutive effects that stimulate the anterior pituitary to release PRL (Normal PRL is <20ng/mL)

Complement participates in both the

innate and adaptive immune responses

first line of defense

innate immunity - this is pre-formed (constitutive, natural, native) - rapid response - NON-specific: its receptors are encoded in the germ line, has identical receptors, not clonally distributed - NO memory - triggers the adaptive response

Intraepithelial lymphocytes (IELs) act as

innate lymphocytes - they are mostly CD8 cells (which are cytotoxic T cells) - they can kill infected epithelial cells spontaneously

Vitamine D receptor is found

inside the cell, bound by calcitriol

Lymph is fluid that leaks out of capillaries and becomes

interstitial fluid then enters lymphatic vessels- it is then filtered through lymph nodes and rejoins blood circulation ** 90% of leaked fluid re-enters capillaries ** 10% becomes interstitial fluid/lymph

For lipid soluble hormones the receptors are

intracellular

Glycogen metabolism is regulated by

intracellular free glucose - glucose conc. inside cells directly reflect plasma glucose conc. because the GLUT2 transporters act by facilitated diffusion transport across cell plasma membranes

Quality improvement

involves everyone and affects everyone

Transferrin saturation is a good indicator of

iron deficiency or overload Serum iron/TIBC (total iron binding capacity)= transferrin saturation

Some alcoholics are at risk for

iron overload

Lactate Dehydrogenase (LDH)

is an enzyme found in glycolysis * it has 5 subtypes/isoenzymes - LDH 1 and 2 are elevated in acute myocardial infarction (MIs) - LDH5 is elevated in hepatic disorders (Acute Hepatitis)

Tfh (T follicular helper cell)

is defined by the cytokines IL-21 (and IFN-gamma or IL-4) - these target B cells to produce anitbodies against extracellular pathogens

Life span of a RBCs

is limited- 120 days * the avg RBC will pass through the heart ~500,000 times - their cell membrane will eventually rupture; or the aged cell is phagocytosed in the spleen, liver, and bone marrow ** 1 % of RBCs are replace daily and these new ones are called RETICULOCYTES

PGE3

is made from ecosapentaenoic acid which is found in fish and algal oil - seeds, nuts, and red meat have very little ecospentaenoic acid

Jaundice (AKA icterus)

is not a disease, but a common symptom (due to disorder of heme degradation) - Yellow discoloration of sclerae, nails, and skin *reflects increased bilirubin levels in the blood and deposition (normal bilirubin= 2-17micromolar (1.0mgl/dL)- jaundice occurs with > 40 micromolar) Causes of jaundice include: - Hemolysis (prehepatic jaundice) - Biliary obstruction - Neonatal jaundice - Congenital defects ** premature babies are unable to conjugate bilirubin and excrete- so it will cross over the BBB faster (they have less mechanisms to keep it from the CNS)- may lead to brain damage-- there is a type of phototherapy that helps to cure this

alpha-fetoprotein (an APR)

is produced in the fetal liver In pregancny it is is increased it indicated: neural tube defect. If it is decreased in down syndrome (Down is downs) * if it is increased in elderly non pregnant it may indicate hepatocellular cancer

The role of PEP carboxykinase in gluconeogenesis

it converts oxaloacetate to phosphoenolpyruvate

the medulla is lighter than the cortex because

it has a fewer number of cells

IGF-1 effects on the liver

it has none!

If you have two hormones and one is metabolized faster than the other,

its clearance will be greater than the other (higher MCR) first hormone will have shorter half-life

Cori cycle

lactate is taken up by the liver for synthesis of glucose

TNF, IL-1, IL-6 act on the bone marrow to increase

leukocyte production

Aspirin inhibits COX1 and COX2 but does NOT inhibit

lipoxygenase- which produces leukotrienes which cause smooth muscle constriction - Leukotrienes are implicated in asthma symptoms and cause smooth muscle constriction and thus bronchoconstriction

Ketone bodies are produced in the

liver

Glycerol kinase can only be found in the

liver - The liver can utilize glycerol released from adipose tissue or by the action of lipoprotein lipase for TAG synthesis, as as a gluconeogenic precursore - BUT the liver has priority as other organs do not have glycerol kinase and cannot use it- this is presumably beacuse of the importance of glycerol as a gluconeogenic precursor during fasting, ensuring that the liver will get full use of it

Complement proteins are primarily synthesized by

liver (hepatocytes) [** especially when liver is stimulated by proinflammatory cytokines (especially IL-6)] BUT some complement proteins are synthesized by - monocytes - macrophages - epithelial cells - fibroblasts

Memory T lymphocytes is produced by

long-lived memory B cells and memory T cells - these are generated during the primary immune response against the pathogen from a subset of effector cells - after primary adaptive immune response, pathogen-specific memory cells outnumber their naive counterparts by several orders of magnitude - memory cells have capacity to respond to specific antigen faster and better than naive cells *** memory CD8 T lymphocyte development relies on CD4 T lymphocyte help and IL-2 stimulation since CD8 T lympphocyts that DO NOT express CD40 cannot become memory T cells where as those that express CD40 can

Most common feeback loops in the H-P axis are

long-loop - the output of peripheral gland provies negative (and on one occasion positive) feedback on the hypothalamus and/or pituitary gland. - Estradial, testosterone, progesterone, IGF-1, cortisol, T3 and T4 provide this feedback ** hormone produced in peripheral gland goes back to hypothalamus so the regulated variable is the peripheral hormone

In fatty acid synthesis, acetyl CoA is carboxylated using CO2 to form malonyl CoA, the carbon that is added is

lost in the next step

When T cells are first out of the thymue they have

low-affinity IL-2R ** it needs both signals 1 and 2 to increase the expression of IL-2 (clonal expansion of the adaptive immune system) - this increase in IL-2 allows for expression of IL-2Ralpha chain which forms a high-affinity IL-2R ** NOTE: you also need signals 1 and 2 to be responsice to the cytokines from signal 3

decreased levels of alpha1-antitrypsin could signify

lung damage

Adaptive immune reactions for most tissues occurs in the

lymph nodes - for blood infections, primary site of adaptive immune response is the spleen - for mucosal infections, MALTS are where adaptic immune reactions are primarily held

Lymphocytes are 20-25% of the leukocytes in the blood but they are the main type of cell found in the

lymph! Hence the name: Lymphocyte! * lymphocytes recirculate between blood, tissues, and lymph - they do this as part of the immune system that monitors the tissues ** they are the only cells that is able to enter to tissue and go back into the blood (blood --> tissue --> lymph)

Primary lymphatic organs are where

lymphocytes are formed and become immunocompetent (but naive) 1. Thymus 2. Red Bone Marrow

2,3-bisphosphoglycerate (2,3-BPG)

made from 1,3 bisphosphoglycerate (glycolytic intermediate) 1:1 with hemoglobin (normal) - it is an allosteric regulator of Hb: binds with highest affinity to deoxyhemoglobin in the respiring tissues (not lung)- it induces off loading of oxygen into tissues (so decreased affinity of Hb for oxygen) * An increase in 2,3 BPG: hyperthroidism or chronic anemia- it is also seen to be very high in blood of smokers * A decrease in 2,3 BPG: seen in high altitude pulmonary edema and dialysis due to loss into filtrate

Gluconeogenesis enables the liver to

maintain blood glucose levels during starvation

B cells job

make antibodies (Antibody= Immunoglobin= B cell receptor (when surface bound)) 1. Resting B cell (membrane bound Ig) 2. Encounter with antigen (bacterium) 3. Stimulated B cell gives rise to antibody-secreting plasma cells which secrete antibodies

Lymphoid tissue is the tissue that

makes up the ADAPTIVE immune system - consists of groups of cells, tissues, and organs that generate immune responses against their own transformed cells and foreign invaders ** lymphoid tissues are widely distributed bc pathogens can enter the body at any point ** lymphoid tissue is a CT characterized by a rich supply of lymphocytes

Decreased albumin

malnutrition, chronic infections, burns, hemorrhage, impaired liver function, nephrotic syndrome, pregnancy, malnutrition (only need 1 amino acid missing to get hypoalbumin)

Direct effect of cortisol

many are "anti-anabolic" - converts protein to glucose - accelerates protein mobilization and degradation (exception: liver) - converts AAs into glucose precursors - inhibits protein synthesis - inhibits glucose uptake and decreases glucose utilization during hypoglycemia - enhaces glucoagon release - tendency to raise blood glucose ** cortisol is main hormone responsible in "muscle wasting" because of its strong effects on body-wide protein breakdown and AA conversion into energy sources (liver is the exception to this rule- it still builds proteins under cortisol stimulation) - skeletal muscle breakdown (esp. in excess) and liver, blood protein buildup; effect on CT too - cortisol has a double effect on adipose tissue, both increasing lipolysis directly and through increased glucagon secretion and its effects on blood glucose, indirectly- (lipolysis and a net shift in cellular metabolism from a mostly-carb usage to a more lipid-metabolizing mode (esp. in starvation) - glucocorticoids decrease insulin sensitivity, indirectly reducing insulins ability to decrease blood glucose and promote glucose entry into tissues - in skeletal muscle cortisol helps to increase gluconeogenesis and other means to increase blood glucose (driect and indirect)

Stimulation by IL-1Beta triggers the synthesis and secretion of

many inflammatory mediators - IL-1Beta signals through the NF-KBeta pathway, as well as the stress-activated protein kinase (SAPK) pathway p38 and JNK, members of the mitogen-activate protein kinase (MAPK) pathways ((cross talk with MAP kinase pathway)) ** leads to transcription of IL-1Beta responsive genes: - IL-1Beta - IL-6 - TNF-alpha ** these are the most important for inflammation

"Ring of Waldheyer"

masses of lymphoid tissue form a ring of defense against everything entering through the mouth

Beta-oxidation, the breakdown of fatty acids to acetyl-CoA takes place in the

matrix of the mitocondria

Treatment of hypersecretion of growth hormone

may call for - surgery or radiation (usually caused by pituitary tumor) - drugs that inhibit GH secretion (Octreotide and Lanreotide) ----- You cant somatostatin bc its half life is 1-3min (would need a continuous infusion) so you use - Octreotide: short acting subcutanous, long acting intramuscular - Lanreotide: long acting deep subcutaneous

Beta-globulin

may separate into Beta1 and Beta2 peaks - Beta-2 microglobulin: binds MHC I related proteins, MHC I, QA and CD1- invovled in recognition of self vs non self, hemochromatosis protein (HEF protein)- regulates transferring binding to is receptor - Plasminogen: zymogen of plasmin and angiostatin; plasmin activated clotting an fibrinolysis - sex hormon binding globulin: androgen and estrogen binding protein - transferrin: high affinity iron binding protein (B2 peak and tail) also has immunoglobins IgA and IgM - IgA: rare in plasma, mono or multimeric. Regulates Fc receptor mediated inflammatory responses; includes antibody dependent cell-mediated cytotoxicity (ADCC) and degranulation of granulocytes - IgM: pentamerix, 10 antigen binding sites- regulates opsonization

Pregnancy Category X

means it is absolutely contraindicated in pregnant females - fetal abnormalities or human fetal risk - risks in pregnant women clearly outweigh the potential benefits (includes drugs like warfarin, metotrexate, and statins) NOTE: - Pregnancy category A is the most safe then you have B, C, D and X which is the worse

Prototype drug

member of a drug class (drugs of the same general chemical category and same general mechanism of action) that most others are compared to - usually but not always it is the first drug developed in a class or the one first used clinically - it is the drug for which there is a lot of clinical experience - often no longer the best or most commonly used (but features of new drug are compared to prototype to show their advantages)

Mononuclear Phagocytes System

members of family play a major role all over the human body - all develop as monocytes in bone marrow - then enter the bloodstream - then leave the blood and enter CT where they develop into macrophages ** the characteristics of the CT surrounding the newly formed macrophages determine their exact final differentiation ex: if it is dermis they can further differentiate into Langerhan's cells (microglia in nervous system) and then the enter the epidermis; if it is bone, they can become osteoclasts (etc)

B cells with the longest life span are the

memory cells

An added advantage of adaptive immunity is the development of

memory- which prevent re-infection

The principal role of folate is to act as a single

methyl group donor Folate (gets its nitrogens reduced along this path)--> Dihydryo-Folate (DHF) --> Tetrahydro-folate (THF) ** this is active part of folate that is used for chemistry** it can become either 5,10N-methylene-THF which becomes 5-methyl-THF or 10N-formyl-THF - 5,10N-methylene-THF gives methylene for synthesis of pyrimidines - 5N-methyl-THF give methyl for methylation of DNA, proteins, and lipids - 10N-formyl-THF gives formyl for the synthesis of purines

Measurement of ___ is diagnostic for B12 deficiency

methylmalonate * homocysteine is elevated in both folate deficiency and B12 deificiency but methylmalonic acid is elevated ONLY in B12 deficiency

Complement is activated by

microbes and by antibodies bound to microbes and other antigens

A decrease in 21 hydroxylase could mean a deficiency in

mineralcorticoids (aldosterone, corticosterone) and glucocorticoids (cortisol) but and increase in ACTH and testosterone ***this is commonly tested in USMLE ** can lead to Congenital Adrenal Hyperplasia (CAH) - leads to virilization (condition where females develop features associated with male hormones (androgens) as one of the things)

The zona glomerulosa (ZG) of the adrenal (suprarenal) gland secretes

mineralcorticoids (ex. aldosterone) ---- - it is made of closely packed columnar or pyramidal-shaped cells; some contain vacuoles - arranged in CLUSTERS surrounding capillaries

Beta-oxidation of long-chain fatty acids takes place in the

mitochondria - very long chain beta-oxidation takes place in peroxisomes ** peroxisomal oxidation is for >C22, or branched-chain FA, by oxidation using oxygen (O2) as a substrate

Upon depletion of dietary glucose

mobilization of liver glycogen occurs (you only have a 24hr supply of this liver glycogen (will be depleted after 1 day)- Glycogen breakdown supplies glucose initially- peaks delivery around 4hrs into fasting, then declines slowly- the cross overpoint for source of glucose switching from mostly glycogen to mostly gluconeogenesis is about 16hrs) - lipolysis is activated (free fatty acids become the major energy source for skeletal m., liver, adipose tissue, cardiac muscle, as well as other tissues- increase steadily as glucose drops)- - Gluconeogenesis increases slowly after the absorptive period (peaks after a day, then decreases in starvation) - Protein degradation contributes to gluconeogenis and ketogenic precursors - then Ketogeneiss sets in after several days ----------- Similar thing listed in stesp: 1. After postprandial glucose is absorbed, liver glycogen stores supply glucose to the baseline level (4-5mM) 2. Gluconeogenesis begins to contribute but increases slowly in its contribution 3. At about 16 hrs after a meal, gluconeogenesis becomes more important than liver glycogen stores 4. At 24 hrs, liver glycogen stores are exhausted and body becomes reliat on gluconeogenesis for all glucose 5. After a day of fasting (starvation), ketone bodies begin to rise in circulation. These increase and level off after 3 days 6. Ketone bodies a produced in the liver from fat beta-oxidation and the Ac-CoA being produced 7. Ketone bodies reduce the reliance of the brain on glucose (the brain can utilize ketone bodies). This effect slows protein breakdown (protein sparing phenomenon)

Teriparatide handles

moderate dose "spikes" of PTH - net bone formation - MOA: same as PTH USE: - severe osteoperosis at high risk of fracture - initial therapy for osteoperosis? - administered by SQ injection - enzymative breakdown in the liver followed by renal excretion - short half life Adverse effects: hypercalcemia, kidney stones, elevated uric acid, orthostatic hypotension BLACK BOX WARNING: osteosarcoma = limit use to no more than 2 yrs and DONT use in those with increased risk for this

Adrenal Medulla is a

modified sympathetic ganglion - Catecholamins are class of water-soluble amine hormones that are derived from tyrosine: includes NE and E (the two that are major secretory products of the adrenal medulla) * since 4 epinephrine are secreted for every 1 norepinephrine, it is common to only mention epinephrine as being secreted - these stimulate sympathetic response from cells and tissues that are relatively poorly innervated but relatively well perfused and also stimulate secretion of neurotransmitters from other sympathetic motor neurons throughout the body to generate a response --- * in most cases, epinephrine binds preferentially to beta receptors and norepinephrine to alpha receptors but both can bind to either - the sensitivity of these receptors can vary, which can fundamentally produce distinct effects depending on whether the high sensitivity receptors are bound (lower concentrations in plasma) or both sets of receptors are bound (higher concentrations in plasma)

Lymphocytosis can accompany

monocytosis in many disorders associated with chronic immunologic stimulation (ex. tuberculosis, brucellosis); viral infections (ex. hepatitis A, cytomegalovirus, epstein-barr virus), bordetella pertussis infection

MHC-I is found on

most somatic nucleated cells (APCs) ex: all cells of the body, except for RBC, sperm and ova

Main role of the citrate/pyruvate shuttle is to

move acetyl CoA from the mitochondria to the cytosol - while citrate is transported it is just an intermediary

Omenn Syndrome

mutations of RAG1 and/or RAG2 result in severe combined immune deficiency - this results in a complete lack of circulating T and B cells due to an early block in lymphoid development - as well as a lack in antibodies

The terms short loop and long loop are used for

negative (and occasional positive) feedback control of the hypothalamo-pituitary-peripheral gland axes ** reference point at which control conditions are measured it the part of the brain called the hypothalamus ALL hypothalamo-pituitary-peripheral gland feedbak loops have their origin point here

Sympathetic Autonomic Pathways are both

neural and endocrine

Vitamin B12 deficiency is very similar to folate deficiency but folate does not show the

neurological symptoms

When naive T cell binds to peptide: MHC on a cell that does not express CD80/86, the cell becomes

non-responsive to antigen (anergic) and cannot subsequently become activated; these usually eventually dies from apoptosis or become Treg cells (depending on context) - Peripheral Tolerance- ** Self reacted T cells being killed in the thymus= Central tolerance - if they escape to the periphery and act against self antigen in absence of co-stimulation- the cell will be partially reactive or die (irregular T cell)= Peripheral Tolerance NOTE: some T cells are let in with the ability to become autoreactive because some microorganisms express antigen that closely resembles self antigen

A normal calcium intake usually exceeds

normal calcium absorption into the body * normally feces and urine are the routes by which calcium exits the body- in pregnant and/or lactating females there are two other exit routs for calicum: from mother to fetus across the placenta and from mother to neonate from milk * remember Ca2+ can function as a stool softner

Phosphoglucose isomerase is

not regulated and maintains equilibrium based on "mass action" of substrate concentrations

Compared to prototype H1 antagonists (Diphenhydramine), the second generation antagonists (Cetirizine, Fexofenadine, Loratidine) are

notably less sedative and have greatly reduced "off-target" effects - they do not effectively enter the CNS (thus less sedative) - more selective for H1 receptors (thus, less other off-target effects; ex: little or no muscarinic effects) ------ Pharmacological effects: reduction in symptoms of nasal allergies and allergic dermatosis caused by histamine release --- Pharmacokinetic properties of the group - oral administration ONLY - widespread distribution EXCEPT for CNS (in contrast to first generation H1 antagonists)

Myoglobin has

obly one subunit and one heme group

GH signal transduction occurs

on cell surface, not intracellular - membrane-bound dimer - it requires binding of GH at two sites - receptor then dimerizes and activates cytoplasmic Janus kinases - second messenger cascade from there involving ERK1/2 and STAT, increasing transcription of target genes **JAK/STAT pathway - translation results in production of many proteins assocaited with growth and metabolism

paitent compliance when taking drugs is usually much better for

oral medicine

Plasma cholinesterase (BuChE) (AKA butinol cholinesterase is measured in

organic phosphate poisoning * it breaks down esters like ACh * it also degrades drugs such as scoline and cocaine - it is found in plasma and synthesized in the liver NOTE: acteylcholinesterase (AchE) (which is found predominantly in nervous tissue and erythrocytes) ONLY degrades ACh (plasma cholinesterase can degrade ACh and others) ** Organic phsophatases like nerve gases work to increase ACh- therefore they inhibit the activity of cholinesterases (they induce bronchiospasm, bradycardia, muscle paralysis- this is what you do with roach spray)

Megakaryocytopoiesis

origion of platelets (CFU-GEMM --> CFU-Meg) - the nucleus become highly polyploid, it contains up to 30x as much DNA as a normal cell (chromosomes replicate but the cell doesnt divide - giant cell, invaginations of plasma membrane form demarcation membranes with platelet granules inside of each * These break off to form platelets- platelets do not contain nuclei, but they do contain granules that contain: - Platelet-derives growth factor - Fibroblast growth factor - Von Willebrand factor (which promotes adhesion of platelets to endothelial cells) - Platelet Factor IV (which stimulates blood coagulation) IN ADULTS - platelets originate in the Red Bone Marrow by fragmentation of the cytoplasm of mature megakaryocytes (megakaryocytes arise by differentiation of megakaryoblasts)- each megakaryocyte produces betwen 5,000-10,000 platelets ** Soo megakaryocytes form thin processes that cross the wall of the sinusoid and fragment at their tips, liberating the platelets

PTH increases the activity of

osteoclasts (to stimulate bone resorption- reduces mineralization of bone and have overall calcium release) - PTH and calcitriol stimulated production of RANKL in osteoblasts (PTH normally, calcitrol only in emergency) - RANKL binds to RANK osteoclast precursors - leads to recruitment of mature osteoclasts from precursor cells - Net increase in osteoclast activity leads to Ca2+ and posphate release into ECF

Cortisol is a natural inhibitor of an

over active immune system by inhibiting the synthesis of prostaglandins and leukotrienes that usually stimulate the immune system - cortisol inhibits phospholipase A2 thereby inhibiting the production of arachiodonic acid (synthesis of all prostaglandind and leukotrienes requires arachidonic acid as a precursor) - glucocorticoids, like cortisol, DO NOT have the same effect as androgrens which are the steroids that body builders take to become bulky

21-Hydroxylase deficiency would result in

overproduction of androgens but deficiency in glucocorticoid and mineralcorticoid production can lead to: - hyperkalemia (kidneys begin taking up K+ because losing Na+) - salt craving (no mineralcorticoids- loss of salt leads to salt craving) - virilization (from increased androgens)

Amylase and lipase are

pancreatic enzymes that are indicative of pancreatitis * Amylase and lipase (intestinal) are produced by the pancreas for digestion of starch and fat * Amylase is also found in the saliva * Amylase AND lipase are increased in the plasma in acute pancreatitis and are necessary to differentiate between different causes of abdominal pain * both enzymes are excreted in the urine and are elevated in plasma in renal failure

Glucagon is a

peptide hormone secreted by the alpha cells in the islets of langerhans in the pancreas into the hepatic portal circulation - effects many of the same metabolic processes as insulin, but most of glucagons actions are opposite those of insulin - major site of action for glucagon is the liver, with a lesser role at other tissues (ex. adipose tissue)

In the absence of insulin,

peripheral tissue glucose use decreases, thereby conserving glucose for essential tissues, such as the brain

Leukocyte Adhesion Deficiency

phagocytes lack (CR3) CD18 so they are unable to interact with ICAM-1- the patient is prone to infection because they are unable to do the margination and pavementing step of phagocyte mobilisation in the inflammation response ** like a police being left at the station with a call to attend to but he has no vehicle to get there

Barriers to infection are

physical, chemical, biological - physical: skin - chemical: killing of microbes by locally produced antibiotics (ex. epithelial cells secrete peptides) - biological: killing of microbes and infected cells by intraepithelial lymphocytes

MHC is

polygenic * meaning it has many different MHC genes for MHC-I and MHC-II- there are many different versions or alleles (sometimes numbered in hundreds) of the same gene withint the population- (this leads to an increase of Ag peptides that can be displayed by an individual, as compared to a single MHC molecule) - Human MHC genes are called human leukocyte Ag (HLA)- they are on every cell, but named this way bc found first on leukocytes NOTE: MHC is located on chromosome 6

Most genetic traits and allelic frequencies differe in their indcidence btween

populations

ADH and oxytocin are released from the

posterior pituitary

Gamma-globulin

predominanty immunoglobins (on right in electropheresis band) - IgA - IgM - IgG: 75% of free immunoglobins in area, has 2 antigen binding site- functions include rols in agglutination, opsonization, pathogen recognition, type II and III hypersensitivity etc.

What does decay acelerating factor (DAF or CD55) do?

prevents the assembly of the C3 convertase of all 3 complement fixation pathways (lectin, classical, and alternative) by dissociating C4b from C2a as weel as C3b with Bb

What does protectin (CD59) do?

prevents the incorporation of C9 by interfering with C8 into the membrane attack complex (MAC) thereby preventing stable pore formation of the late stage of complement fixation

Pyruvate is one of the

principal gluconeogenic precursors

Oxytocin

produced in PVN (paraventricular nucleus) - Target tissues: smooth muscle of uterus and mammary glands - its receptors are GPCR-linked, utilizing PLC and calcium - it stimulates MLCK and smooth muscle contraction ** mostly associated with partuition and labor, and milk letdown and secretion in nursing - for lactation- suckling triggers afferent impulses (OXY binds to OTR to cause milk ejection "letdown")- milk is actively ejected through a neuroendocrine reflex - labor and parturition in the utereus- dilation triggers afferent impulses (also a neuroendocrine reflex) (OXY binds to OTR to cause myometrial contractions) ** OTR= oxtytocin receptors

On any given day the majory of RBCs that are present were

produced weeks to months earlier

Urea is a

proxy for nitrogen- whose principal source is protein degradation - if a person eats carbs for a day then undergoes prolonged fasting their urea will be increased followed by a slow decline over many days (protein sparring phenomenon)

Somatically generated receptors found on B and T lymphocytes are

randomly generated during development

Glucagon is NOT activated

rapidly during exercise (it can be slowly), and it does NOT act on muscle, only on the liver

Basophilic leukocytosis (basophilia)

rare, often indicative of a myeloperoliferative disease (ex. chronic myelogenous leukemia) * usually poor prognosis

Cells acquire iron by

receptor-mediated endocytosis * not that heme and other iron-containg proteins are synthesized in individual cells, so all cells require that iron be delivered to them Steps of this cellular absorption 1. Transferrin (Tf)- bound iron binds to receptors 2. Receptor-mediated transferrin endocytosis 3. Free iron is released, reduced, and transported to cytoplasm (DMT) 4. Re-oxidized iron can be stored in ferritin (as Fe3+) 5. Iron can be translocated to mitochondria for incorporation into: - Heme - Iron-sulfur clusters

The cognitive (recognition) phase of innate immunity is mediated by

receptors on innate immune cells named Pattern Recognition Receptors (PRR's), these are - limited in number (dozens) ** think bc you are already born with them so they must be limited - specificity is predetermined and fairly broad (generally respond to groups of organisms) - SAME for all cells - Little of NO expansion upon stimulation

Both Hemophilia A (lack of factor VIII) and B (lack of factor IX) are

recessive sex-linked trait (more common in men) Sxs: -prolonged bleeding even from minor injuries -excessive bruising -bruised and swollen joints -excessive clumsiness and falling Treatment: - intravenous injection of clotting factors - donated plasma - synthetic clotting factors

Recommended intake of iron per day

recommended - 8mg for males - 18mg for females ** absorption and distribution is tightly regulated: about 1mg/day is absorbed Sources of iron: - liver, and lean meat: give heme iron (heme iron is absorbed with 30% efficiency) - beans and spinach: non-heme iron (non-heme iron which is mostly in vegetables is absorbed with <10% efficiency through the DMT-1 intestinal transporter) ** Absorption of Non-heme iron is facilitated by gastric acid and Vitamin C (reducing agent to convert it to its ferrous form) and reduced by phytate, tannins, and antacids (found in other foods)

Corticotrope

regulation with CRH in the hypothalamus, secretes the tropic hormone ACTH acts on an MC2R (GPCR) - target endocrine gland= zona fasciculata and zona reticularis of the adrenal cortex ** cortisol is the peripheral hormone involved in negative feedback

Lactotrope

regulation with Dopamine (inhibitory) and PRL-releasing factor (Stimulatory) which secrete prolactin acts on prolactin receptor (JAK/STAT-linked cytokine receptor) - NO endoncrine target organ- not part of an endorcine axis - no negative feedback hormone

Somatotrope

regulation with GHRH (stimulatory) and Somatostatin (inhibitory) which secrete GH acts on GH receptor (JAK/STAT linked cytokine receptor) - target endocrine gland (liver - Negative feedback with IGF-I and GH (short loop)

Gonadotrope

regulation with GnRH, secretes FSH and LH acts on the FSH and LH receptors - target endocrine gland (ovary- theca and granulosa, testes- leydig and sertoli cells) ** estrogen, progesterone, testosterone, and inhibin are involved in its negative feedback

Thyrotrope

regulation with TRH in hypothalamus, secretes the tropic hormone TSH acts on the TSH receptor (GPCR) - target endocrine gland= thyroid epithelium ** Triiodothyronine involved in negative feedback

A single MHC-I allele can only bind peptides with

related anchor residues (ex. aromatic aa such as Tyr, Phe, and Trp are related; other examples would be Val, Leu, Ile, and Met which are all hydrophobic or Lys and Arg which are hydrophilic) - this explains why a limited number of MHC-I molecules (max of 6 in case of humans) can present extremely high numbers of different peptieds: as long as the anchor residues are present for any given MHC allele, there can be variation in the parts separating the anchor residues - the main known source of these peptides is the proteasome (or immunoproteasome under inflammatory conditions)

Hormone sensitive lipase is activated in the fasted state to carry out

release of free fatty acids from adipose tissue

Deficiency of Factor XII (12) DOES NOT

result in bleeding because you can still activate factor XI (11) with the thrombin created in the extrinsic/common pathway

Deficiency of Vitamin B12 (aka cobalamin)

results in anemia - malabsorption may be commin in older people - often malabsorption due to loss of intrinsic factor (IF) resulting in pernicious anemia - the anemia is partly because of B12's role in salvaging methyl-THF back to THF via the methionine synthase reaction ** later stages show neuropsychiatric symptoms (ex. Ataxia) RDA= 2.4micrgrams but several (2-5) mg are typically stored, thus deficiency may not be apparent for a long time

In the blood bank, blood is separated into its components. If RBC are used for transfusion, they are most often in

saline solution, not in serum because the amount of serum injected normally is too small to matter in transfusions: - people with blood of type O are universal donors - people with type AB are universal recipients * normally, transfusions are carefully matches, except maybe in extreme emergencies- when they will just use type O

The ratio of freely dissolved to bound Ca2+ is even less in tissues like bone, in which almost ALL of the calcium is found in

salts * Calcium-Phosphate salts - ectopic calcification occurs when solubility product (SP) exceeds the critical solubility product * Hydroxyapatitie aka Hydroxylapatite= primary form of bodily calcium and phosphate

Toxicology

science of adverse effects of chemicals on the body - the intent is to adminster drugs to achieve a therapeutic effect with the least possible toxicity * all drugs have some level of adverse side effects - these can variety between patients and situations in terms of their frequency of occurence and/or in their severity - just beacuse a drug has the potential to cause a particular adverse effect does not mean that it will cause that effect in all patients utilizing that particular agent

MHC-I restricted activation of naive CD8 T lymphocytes by pAPCs occurs in

secondary lymphoid tissue 1. activated CD8 T lymphocytes become armed with CD95L (FasL) on their surface, and synthesize perforin, granzyme, and granulysin among others which accumulate in granules and are delivered to target cells (infected cells or tumor cells) to kill them by apoptosis (activated CD8 cells are referred to as cytotoxic T lymophcytes of CTLs) 2. CD8 T cells are activated in secondary lymphoid tissue but exert most of their function in the periphery where infected cells or tumor cells are present; CTLs can exert their function in secondary lymphoid tissue as well when the infected cells are found in these tissues (ex. HIV infections or lymphomas)

MHC-II restricted activation of naive CD4 T lymphocytes by pAPCs occurs in

secondary lymphoid tissues (just like MHC I activation of CD8) - activated CD4 T lymphocyte can the provide help in the form of CD40L and secretion of cytokines to other leukocytes either in the secondary lymphoid tissuse (ex. 1) help pAPCs activate CD8 lymphocytes and 2) help activate B lymphocytes to induce germinal centers and antibody production or in the periphery (ex. 3. macrophage activation for the killing of intracellular microorganisms, either phagocytosed or through macrophage infection)

TH17

secretes the cytokines IL-17 and IL-22 - these do neutrophil recruitment and activation against extracellular bacteria and fungi

The process of MHC-I restricted antigen presentation selecting and activating CD8 lymphocytes and MHC-II restricted antigen presentation selecting and activating CD4 lymphocytes allows the adaptive immune system (in this case T cells) to distinguish between

self and non-self (as well as tumor cells) ** this occurs as part of T lymphocyte development, T cell activation, as weel as effector cell activation (such as B lymphocytes and macrophages)

Activated platelets secrete chemicals including

serotonin ADP Thromboxane ** platelets become activated and stick together after exposure to collagen fibers on an injured blood vessels

Decreased alpha2-globulins could lead to

severe liver disease, wilsons disease, malnutrition

The zona reticularis (ZR) of the adrenal (suprarenal) gland secretes

sex steroids- (androgens, mainly dehydroepiandrosterone (DHEA) ------ - ZR is made of irregularly shaped cords of cells - Cells slightly smaller than in the other layers - Often difficulat to demarcate junction between zona fasciculata and reticularis

Zona reticularis (ZR) of the adrenal (suprarenal) gland secretes

sex steroids- androgens, mainly dehydroepiandrosterone (DHEA)

Cytokines and chemokines always achieve their effects through

signaling, and the first step in cytokine signaling is cytokine-receptor binding

Collagen Type III is stained with

silver stain

The sinusoids "SEA" from Red Bone Marrow are formed by

sinusoidal capillaries (most soucres call these sinusoidal capillaries; a few sources call them venous sinuses) - they are lined by endothelial cells sitting on a discontinuous basal lamina ** sinusoids are where RBCs, WBCs, and platelets enter the circulation after their production in the bone marrow

During carbohydrate metabolism, glucose enters the cell via

specific transporters - Hexokinase or Glucokinase catalyzes phosphorylation of Glucose --> G6P (this phosphorylation traps it into the cell) * to increase the uptake of glucose and its storage as glycogen and fat, muscle and adipose tissue express an insulin-responsive glucose transporter (GLUT4) in addition to GLUT1, which dramatically increases glucose uptake in the presence of insuliin * in these tissues, glucose transport is typically the rate limiting step in glucose entry * Beta-cells of the pancrease release insulin to signal the presence of glucose in the blood - in skeletal and cardiac muscle and adipose tisse: insulin induces the transport of GLUT4 from the endosome to the plasma membrane- this increases the uptake of glucose, and GLUT1 provides basal uptake NOTE: When insulin levels decrease, glucose transporters move from cell membrane to the intracellular storade pool, where they can be recycled - vesicles fuse to form an organelle called the endosome

In the liver GH

stimulates - protein synthesis - gluconeogenesis - IGF production, secretion ** unlike almost all other protein hormones, IGF is NOT stored in the liver NOTE: IGF-1 and GH rise and fall almost at the same time in plasma

In adipose tissue GH

stimulates: lipolysis Inhibits: glucose uptake

Effects of thyroid hormone in white adipos tissue include

stimulation of adipose cell differentiation

Purpose of the follicular lumen in thyroid follicle is to

store thyroglobulin for use in thyroid hormone synthesis

Pernicious Anemia

strictly defined as the loss of Vitamin B12 due to loss of intrinsic factor (IF) and poor absorption = Megaloblastic with low folate ** however it is often used to describe ALL cases of anemia from B12 deficiency ** loss of intrinsic factor can result from autoimmune disease attacking the parietal cells of the stomach or from surgical removal of part of the stomach, or a congenital deficiency Sx's: - tired and weak- fatigue - parasthesia (skin tingling) - glossitis (tongue soreness) - other symptoms typically associated with anemia can also include: - depression - low grade fever - diarrhea - dyspepsia - weight loss - neuropathy - jaundice - cheilitis eventually: cognitive impairment (CNS effects may occur in absence of anemia- treatment IM injections of cyano cobalamin or high oral doses)

Basophilic erythroblast

strongly basophilic cytoplasm, no visible nucleoli * basophilia caused by large number of polyribosomes involved in the synthesis of Hb

The adrenal androgen DHEA, whose direct effect is weak, is mostly found

sulfated in the plasma as DHEA-S, at concentrations over ten times greater than cortisol -- DHEA is an adrenal androgen from ZR (has highest secretion of all) Cortisol is a glucocorticoid from ZF ---- DHEA does not have a specific binding protein but unlike aldosterone it also has very few target tissues, and it serves as a source of precursors to the synthesis of more potent androgens and estrogens by the gonads

Antigens (mostly) are found on the

surface of cells, while antibodies are in solution * antigen is therefore associated with RBC (and WBC) fraction while antibodies are in plasma/serum fractions NOTE: antigens are present on ALL cells, not just limited to RBC (ABO blood type therefore needs to be checked before any transplantation)

Glycogen synthase should only be active with

surplus glucose and generally anabolic conditions it is activated by Insulin 1. insulin activation of protein phosphatase 1, leading to dephosphorylation of glycogen synthase 2. insulin activates PKB (Akt) which then phosphorylates glycogen synthase kinase rendering it inactive - inactive GSK prevents phosphorylation of glycogen synthase by GSK, leaving glycogen synthase active --- inhibited by glucagon in the liver- via cAMP/PKA cascade to phosphorylate and inactivate glycogen synthase inhibited by epinephrine via beta-adrenergic receptors-via cAMP/PKA cascade in liver and in muscle

When eosinophils release the Major Basic Protein (and other substances) into tissue, in addition to killing the parasites it can also cause to

surrounding normal tissue (collateral damage) ex. If this happens in the intestine, it can cause diarrhea and other irritations

Differential Leukocyte count (WBC diff)

takes 100 WBC and subdivides leukocytes by percentage of each type From Highest Percentage to Lowest: 1. Neutrophils - Segmented (mature)= 54-62% - Bands (immature)= 3-5% 2. Lymphocytes: 25-33% 3. Monocytes: 3-7% 4. Eosinophils: 1-3% 5. Basophils: 0.07% Mnemonic: Never let monkeys eat bananas

PTHrP; Parathyroid Hormone Related Protein can be used to

test for a possible hormone-secreting tumor - at such unregulated high levels, it can produce exaggerated effects similar to those of hyperparathyroidism including hypercalcemia * may play a role in development of hypercalcemia in malignancy - some lung cancers are associated with hypercalcemia - other cancers can be associated with hypercalcemia

Schilling Test

tests for absorption of vitamin B12, once normal B12 levels have been established

Globin in erythrocytes is a

tetramer of 2 alpha (or alpha like subunits) and 2 beta (or beta like subunits) Alpha and alpha-like subunits: - alpha (found in HbF and HbA): embryonic period --> adulthood (location of stem cell changes: yolk sac --> liver --> gut --> bone marrow) - zeta: embryonic period in stem cells of the yolk sac, important in alpha thalassemia Beta and beta-like subunits: - beta: liver stem cells --> gut --> bone marrow - delta: made only after birth (mutations result in beta thalassemia) - epsilon: embyronic period --> early years of life - gamma: fetal --> early life

Clearance

the RATE of removal of the drug from the body relative to concentration of drug in the blood (it is NOT the total amount of drug removed per time, because clearnace is dependent upon concentration) - is expressed as the volume of blood from which the durg is removed per unit of time (ex. ml/min) types: - hepatic clearance - renal clearance - total clearance- sum of both the above rates

Mechanism of action

the action of the drug at its molecular target while pharmacological effect refers to the observable consequences of the actions of the drug - so mechanism of action is basically the biochem behind what drug is doing in body ex. enhaces sodium-channel inactivation or binds cell wall AAs inhibiting peptidoglycan syntehsis - pharamcological effects would be the actual outcome a patient can see with taking the medication (ex. recuded seizures, killing off of the bacterial infection)

In Exogenous Hypercortisolism

the adrenal gland undergoes atrophy (becomes smaller)

In Endogenous Hypercortisolism

the adrenal gland undergoes hyperplasia (increases in size)

Diverse specificity of antibodies is reflected in the degree of amino acid variability in

the hypervariable, HV regions (AKA the complementarity determinant region, CDR) and the framework regions, FR, within the variable-region *** FR= framework it is variable but NOT as variable as the HV regions ** CDR determines how specific binding will be AKA hot spots ** these determine specificity

Which immunoglobulin region/domain determines the affinity, specificity and idiotype of the molecule

the light and heavy chain hypervariable domains

The more tightly hormones bind to transport molecules,

the longer are their half-lives

In a circumstance of fasting

the priority is energy mobilization - insulin reduced (bc hypoglycemia), GH elevated, IGF reduced; modulation at level of liver - protein synthesis and new growth is reduced

In a circumstance with high carbohydrate (CHO) intake and low protein:

the priority is energy storage - insulin is elevated, GH reduced - more energy is stored - little net effect on protein synthesis, growth

In a circumstance with high protein intake and high carbohydrate intake

the priority is growth enhancement - GH, Insulin elevates, so are IGFs - less energy to store - protein synthesis and growth increased

In the absence of MHC-II

there is no possible selection for CD4 cells

In the absence of CD3

there is no signal or signaling cluster on the TCR (there will be a lack in the number of lymphocytes including BOTH CD4 and CD8)

* Remember if calcium plasma is at 16.0mg/dL and it is going along with the noraml ratio of free to complex/bound calcium-

these values are 50-50% Ex. in this case 8.0mg/dL will be found as free calcium

If a pt comes to you with bronchial asthma it is likely that

they have an increased number of eosinophils in their lung tissue

PGF2, Prostamide F2a

this is Bimatoprost - found in some eye lash enhancing makeup and used to lengthen and darken the eyelashes and eye brows - also used in treatment of open angle gluacoma - it alters the fluid maintenance of the eye and can cause red itchy eyes as well as the darkening and lengthening of eyelashes and eye brows

Sympathetic autonomic ganglia are dervied from the

thoracolumbar roots - ability of the hormones of the adrenal medulla to travel even to those target tissues which are beyond the direct reach of sympathetic motor neurons, thuse completing the "whole-body activation" aspect of sympathetic control of involuntary body processes These hormones (adrenal catecholamines) are - secreted at the same time as the rest of the sympthathetic NS is active - water soluble - have very short half-lives

How do NK cells do Adaptive Killing

through Antibody Dependent Cellular Cytotoxicity (ADCC) 1. Virus antigen is presented on the infected cell 2. An antibody (like IgG) binds its Fab portion to the antigen 3. The antibodys Fc region binds to the FcgammaRIII (CD16) portion of the NK cell 4. This leads to NK activation-> NK expresses FasL --> release of granules (perforin/granzyme) 5. Caspase becomes activated 6. Fas and the target are destroyed *** FasL (Fas ligand) delivers the death signal to the Fas death receptor Apoptosis is an important part of immunity: - kill infected cells by inducing apoptosis - eliminate self-reactive lymphocytes during development - get rid of effector T cells after infection is terminated Apoptosis can be triggered through Fas - Fas and FasL are induced during an immune response - Binding of FasL to Fas induces apoptosis of Fas-expressing cell

The secretion of GH changed

throughout the day (Pulsatile Secretion throughout the day) - this pattern is modified by sudden need for energy as in strenuous exercise (episodic secretion) and is also highest near midnight and into the early monring (chronotropic control with circadian rhythm) * in children, most of the actual growth takes place during sleep ----- Stimulated by: - hypoglycemia - protein deficiency - exercise - trauma - peaks during sleep Normal levels of GH in adults: (in plasma) 1.6 to 3ng/ml Child or adolescent: 6ng/ml --- So GH increases metabolism (glucose metabolism- it prevents there from being too little glucose) and increases growth

Primary hypothyroidism

thyroid gland is underactive and does NOT respond appropriately to TSH presence or absence. TH levels are too low as a result - would expect high levels of TSH in the plasma bc feedback from TH would be minimal Ex. reaction of thyroid following radioactive iodine therapy or resection ex. Chronic iodine deficiency in the diet

Transthyretin transports

thyroxine in blood

Heme is the

tightly bound prosthetic group of Hemoglobin, myoglobin, the cytochrome P450, catalase, and many other proteins * it comprises one ferrous ion (Fe2+) in the center and a protoporphyrin IX (a tetrapyrrole ring) thus heme+globin protein= hemoglobin

Glycerol-3-phosphate is required for the synthesis of

triacylglycerols from fatty acids

T or F: T3 is the most biologically active in tissues

true ! (missing the top iodine, if it was bottom one would be RT3)

T or F: glycogen phosphorylase kinase phosphorylation of glycogen phosphorylase is not catalytic in nature

true!

T or F: glycogen is NOT a gluconeogenic precursor

true! - Lactate, Glutamine, Alanine, and Glycerol are though-

Adrenal Hypofunction

two types primary and secondary- both manifest with inability to retain sufficient water and sodium

Thalassemia

underproduction of one type of hemoglobin subunit * most mutations are in regulatory gene - alpha thalassemia: one of the 4 gene copies of a is not expressed - beta thalassemiia (MICROCYTIC anemia): one copy is mutated or not expressed or incorrectly spliced

In Adaptive Immunity- cognitive functions are mediated by

unique cell surface receptors: - specific to each cell (each B cell and T cell express receptors of only ONE specificity) - receptor is generated by recombination of genes encoding the receptor (germline gene rearrangement) - rearrangements are random, and are antigen independent - allows for high degree of diversity in antigen receptors (many lymphocytes of only ONE specificity) - expanded upon stimulation basically.... - specificity is guaranteed by having each cell ONLY carry receptors specific for ONE antigen - diversity is ensured by the staggering number of lymphocytes, each possesing specificity for only one antigen

Precaution

use of a particular drug in specific patients should be done with great care in certain situations ex. Truck driver should be aware that a drug may make him sleepy

PGE2

used to soften the cervix which allows for cevical dilation and thereby induces or accelerates labor. It also strengthens contractions

Methionine Synthase (aka homocysteine methyltransferase)

uses 5-methyl-THF as a substrate and ties together B12 and folate metabolism

Pharmacodynamics (PD)

what the drug does to the body - studies the effects, actions, and mechanisms of drugs in the body - drugs can either target self or non-self

What is the second set of induction tolerance that B cells undergo upon exiting the bone marrow

when self-reactive B cell recognized self-antigen in periphery - cell dies by apoptosis or the cell becomes anergic (incapable of future activation) NOTE: not all self-antigens are expressed in the bone marrow

Iron insufficiency (causing Anemia) is more common in

women (have higher dietary requirements) - lack of iron impairs hemoglobin synthesis and causes MICROcytic hypochromic anemia: leads to pallor, weakness, lassitude * lack of iron can also be caused by massive hemorrhage, chronic blood loss, menstruation, growth, or pregnancy

Do immature B cells exite the bone marrow?

yes! they receive signals for further maturation outside of the bone marrow - they circulate between the blood, secondary lymphoid tissues and lymph - in secondary lymphoid tissue, immature B cells receive singals (in form of cytokines) to survive and mature - exit secondary lymphoid tissue (via efferent lymph) and circulate again - exit secondary tissue as a mature B cell

In the 3rd-4th week of gestation blood precursor cells arise from the

yolk sac mesoderm

What is the avergae half-life for predominantly locally-acting biomolecules, with some water-soluble endocrine hromones

~2 min These include: Angiotensin II Endothelin-1 Epinephrine Prostaglandins

What is the half-life for a biomolecule that is involed in episodic release

~3-5min This is Insulin