Biochemistry Exam 3 PDF

Biochemistry Exam 3 1. Know the roles of platelets and blood clotting factors in hemostasis. The first step of clotting involves the physical aggregation/clumping of circulating blood cells called platelets. Platelets are small non-nucleated cells that circulate in the blood in an inactive fo...

Biochemistry Exam 3 1. Know the roles of platelets and blood clotting factors in hemostasis. The first step of clotting involves the physical aggregation/clumping of circulating blood cells called platelets. Platelets are small non-nucleated cells that circulate in the blood in an inactive form. They are activated on contact with the sub endothelium and are therefore prothrombotic. Platelets are formed by budding from membrane of megakaryocytes. Irreversibly inhibited platelet enzymes cannot be replaced by the cell. Platelets short lived. Inactive platelets have surface receptors for several molecules that can activate platelets. Include collagen, thromboxane A2 (TXA2), and ADP. These receptors coupled to membrane bound phospholipase C -- produces second messenger IP3 leading to Ca2+ release and platelet activation. Inactive platelets have receptors for PGI2 which are G protein receptors coupled to adenylate cyclase. Produces second messenger AMP which antagonizes activation of platelet, by inhibiting release of Ca2+. PGI2 and cyclic AMP decrease rate of platelet aggregation. TXA12 and ADP increase rate of platelet aggregation and facilitate coagulation. Drugs that block these two things inhibit platelet aggregation. 2. Understand what triggers blood clotting and where it occurs, and be able\ to describe the sequence of events leading to clot formation. Blood clotting can be triggered by external trauma or internal injury to the endothelial cell layer. The major processes of hemostasis are vasoconstriction, platelet plug formation (adhesion, activation, and aggregation), and coagulation cascade. Vasoconstriction -- restricts flow of blood through narrowed blood vessels. It happens quickly, directly reduces volume of blood loss, and promotes platelet aggregation and blood coagulation. Platelet aggregation - results in formation of platelet plug. Happens quickly, and is fragile because only held together by non-covalnet bonds. Fibrinogen (non-covalent) binds platelets together to create the platelet plug. Activation of a platelet is irreversible process and changes its shape. Changes in cytoskeleton so that platelets go from spherical to irregular, elongated, and amoeboid shape. New receptors appear such as fibrinogen and von Willebrand factor. Secretory granules fuse with cell membrane. Phospholipids from inside of platelet cell membrane flip out to cell surface. Blood coagulation results in formation of secondary clot. This is slower, includes entire blood volume, blood s transformed from fluid to gel, and formation of covalent protein cross-links fibrin gives the clot mechanical strength. Blood clotting could occur on intrinsic or extrinsic pathway. Then meets up with common pathway. Intrinsic pathway -- contact activation of factor XII by exposure to negatively charged molecules ex. collagen. Involves 12, 12a, 11, 11a, 9, 9a, 8a, and calcium. Get to 10 and then 10a. Then common pathway starts. Extrinsic pathway disruption of endothelium exposes platelets to extravascular tissue factor which is also known as thromboplastin. Extrinsic factor involves factor 7 to 7a and then 10 to 10a. Common pathway 1oa with factor 5, phospholipids and calcium forms prothrombinase complex which converts prothrombin to thrombin. Thrombin cleaves circulation fibrinogen to insoluble fibrin and activates factor 13. Factor 13 covalently crosslinks and stabilizes clot and forms secondary hemostatic plug. Prothrombin is produced in liver, present in blood. Prothrombin is viamin K dependent and factors are II, VII, IX, X. Calcium needed for clotting to occur. Citrate and EDTA good chelators. Not useful as clotting inhibitors in vivo because of other functions. Hemophilia A = deficiency of factor 8. Hemophilia B = deficiency of factor 9. vitamin K dependent 3\. Understand the roles of calcium and vitamin K in blood clotting. Clotting factors that bind Ca2+ all have modified amino acid y-carboxyglutamate. Vitamin K required co-factor for y-glutamul carboxylase. Enzyme that catalyzes this reaction found in endoplasmic reticulum of liver cells. If clotting factors not gamma carboxylate, cleavage product will not be active because can't bind Ca2+ properly. A major inhibitor of factor Va is protein C. Protein C is vitamin K dependent and therefore K can impact coagulation pathway. If factor Va not working properly, resistant to inactivation and can ocntinue to enhance factor Xa's conversion of prothrombin to thrombin. If vitamin c is not controlled, there is excessive formation of blood clots. 4\. Understand and be able to describe natural and pharmacological\ anticoagulants. Antithrombin III is natural inhibitr of coagulation. Inhibits thrombin and factor Xa. ATIII regulated by an accelerator, heperain. Heparin catalyzes irreversible inactivation of thrombin so isused as anti-caogulant. Aspirin and warfarin are two drugs that are inhibitors of coagulation. They hep with platelet aggregation, vasoconstriction and blood coagulation. Heparin is an anticoagulant. Helps with fibrinolysis and stops your body from making bloodclots. Warfarin is a vitamin K antagonist. It does not act on the blood but acts on the liver cells that synthesize clotting factors. Warfarin is slow to take affect as an anticoagulant. It is slow for recovery from warfarin. Fibrinolysis the the breaking down of vascular clots (antithrombotic) and breaking down clots during wound healing. Heparin binds to antithrombin and causes a conformational change that causes increased antithrombin action against thrombin and factor Xa. Heparin helps decrease clotting ability of blood. Apsiring inihibts coagulation because inhibits platelets. Thrombocytopenia -- not enough platelets. Glanzman's thrombasthenia -- defective fibrinogen receptors. Petechia -- small reddish hemorrphages on skin from platelet deficicncy. 5\. Know how the bleeding time, PT, and PTT tests work. Bleeding time is a test of primary hemostasis. Test measures time taken for blood vessel constriction and platelet plug formation to occur. No clot is allowed to form, so that the arrest of bbledding is only on blood vessel constriction and platelet action. Test has a lot of variability so is not used much anymore. PTT test used to evaluate the intrinsic pathway so coagulation factors XII, XI, IX, VIII, X, V, II, prothrombin, and fibrinogen. PT test evaluates the extrinsic pathway so coagulation factors VII, X, V, II, and fibrinogen. These test are used most commonly. PT test uses blood from venipuncture. Blood decalcified and collected in tube with citrate ions to prevent clotting. Blood cells separated from liquid part of blood (plasma) by centrifugation. Add patient's plasma to reagent tissue factor, thromboplastin, that converts prothrombin to thrombin. Calcium chloride added to mixture to counteract sodium citrate and allow clotting to start. Test timed until plasma clots. A prolonged prothrombin time indicates deficiency in factors being tested. May also mean patient has vitamin K deficiency or is on coumadin (Warfarin). International normalized ratio = INR where 1 is equal to normal clotting time and 2 is equal to twice the normal clotting time. PTT test -- same process as PT test except instead of thromboplastin, kaolin and cephalin are added to start the intrinsic pathway of the coagulation cascade. Can be used to monitor heparin therapy. Increased levels in a person with a bleeding disorder indicate clotting factor may be missing or defective. 1. Describe the structure, function, and key steps in the biosynthesis of heme. Heme is a dietary constituent and a prosthetic group of several classes of proteins. Heme helps with oxygen binding proteins as hemoglobin in the blood and myoglobin in muscle tissue. Heme helps as electron transfer protein for example cytochrome C to help with oxidative phosphorylation. Heme helps a variety of other oxidases and oxygenases in specialized cells such as cytochorome P450 in liver (detoxification). Heme from diet is degraded to release iron. Heme structure is porphyrin ring with Fe2+ ion bound in center. Heme B found in hemoglobin and myoglobin and found in 99% of the human body is Heme B. Porphyrin ring consists of 4 pyrrole rings. Nitrogen atoms on inside create cage for Fe2+. Porphyrin ring is flat, planar structure. Absorbs visitble light so heme containing proteins are colored ( ex. hemoglobin, cytochromes). Each cell that needs heme has to make its own, so heme synthesized in most cells. Heme mainly made in bone marrow (precursor of red blood cells) and liver. To make heme, formation of d-amio levulinic acid (d-ala) from glycine and succinyl coA is first step. Combination of 2 molecules of d-ala to form pyrolle ring molecule, porphobilinogen. Last step is addition of Fe2+ to form heme. The first and last 3 steps of heme synthesis pathway take place in mitochondria and intermediate steps occur in cytoplasm. Most important step invovls d-ala synthase which is rate limiting and regulated by free heme. Second and last step improtnat because d-amino levulinic acid dehydratase and ferrochelatase are very sensitive to lead poisoning. 2\. Know the regulation of heme biosynthesis. Regulation is different in liver and bone marrow. In liver, feedback inhibited by increased free heme. Regulates transcription and translation of d-ala sybthase. Inhibits d-ala synthase enzymatic activity directly. Red blood cell precursors in bone marrow have extremely active heme biosynthesis. Heme synthesis increased by erythropoietin (in response to low O2 levels) and by iron inducing transcription, d-ala synthase 2. 3\. Understand the effect lead (Pb2+) on heme biosynthesis. Lead inhibits secnd and last steps of heme biosynthesis. Ala dehydratase contains zinc and is very sensitive to lead so second setp and anything after that would be affected. Leaad replaces Fe2+ in ferrochelatse so affects last step to form heme. Deficincy of heme synthesis leads to microytic anmia whihch is small red blood cells and abnormally low amount of hemoglobin so lead poisoning can be very harmful. Beause heme is not being produced, d-ala synthase is not inhibited and d-ala is overproduced. D-ala is a neurotoxin especially n developing brain so high blood levels lead to intellectual disability. There are also hereditary defects in heme synthesis such as porphyrias which result in low heme production because d-ala synthesis is de-pressed. 4\. Understand iron uptake, transport, and storage, and explain the consequences of\ iron deficiency and iron overload. Heme can be recylcled within a cell but not between cells. Iron essential for heme sysntheis. No known mechanism for active excretion of iron. Absorption of iron in intesitn is very inefficincet. Control point is tranfer of iron from intestinal cells into the blood. FPN and HP are control points for iron uptake. Ferroportin is controlled by peptide hormone helpidin. Hepcidin down regulates ferroportin so with high hepcidin there is low iron intake. With low hepcitidin there is high iron intake. Hepcidin is secreted by the liver. If high iron load in liver than low iron uptake. If low iron load in liver such as hypoxia, anemia, erthropoeisis, then high iron uptake. Most iron in blood bound to transport protein transferrin. Has a high affinity for iron and transferrin is repsoible for transport of iron from blood into cells, vira specific transferrin receptors. Free iron toxi so free iron levels kept low both inside cells and in the blood. Iron in cells stored in form of ferriting, especially in the liver. Feritin is made of lagre protein shell. Levels of blood ferritin are proportional to intracellular ferritin. 5\. Describe the degradation of hemoglobin and metabolism of bilirubin. Conversion of heme tobilirubin in the macrophages of the rough endoplasmic reticulum. Porphoryin ring spontaneously opens to form biliverdin which is green in color. This releases carbon modoxide and Fe2+. Biliverdin is thenreduced to bilirubin which is yellow in color. The heme cabon skeleton cannot be metabolized further than bilirubin and bilirubin is insoluble in water. When bilirubin accumulates it is called jaundice. Bilirubin is then released from macrophages and taken up by liver cells. In the blood, bilirubin bound to serum albumin. Then it reaches liver cells. In the liver cells, bilirubin is conjugated with glucuronic acid to make it water soluble. Bilirubin diglucuronide is then secreted into the bile, and passes into the intestine. In the intestine, bilirubin reduced to colorless water soluble derivative urobilnogen that can be converted to stercobilinogen. Some of the bile pigments produced in the intestine are reabsorbed into the blood and re-excreted through the liver and kidney. Hemoglobin broken down by macrophaes in liver and spleen. Globin protein and iron in heme are recycled. Porphyrin ring is partially degraded and xcreted. Heme degradation and excretion occurs in compartamntalized stages. Short summary: Hemoglobin is broken down into heme, which is converted to biliverdin, and finally into unconjugated bilirubin (which is not water-soluble). In the bloodstream, unconjugated bilirubin binds with serum proteins---most commonly albumin. The unconjugated bilirubin is then taken up by the liver. 6\. Explain why neonatal units in hospitals use UV lights. Bilirubin is toxic in infants who lack a blood brain barrier allowing bilirubin to accumulate in fatty tissues of central nervous system. Phototherapy used to mobilize tissue-bound bilirubin in neonates with jaundice. Soluble bilirubin photoproducts can be excrete din urine, thereby getting rid of bilirubin cabron system. 7\. Know why feces are brown and urine is yellow, and why bruises change color. In the gut, stercobilingogen is oxidized to stercobilin, a brown pigment. Extcreted in feces, producing brown color. Most urobilinogene passes through liver back into intestine, but some is taken up by kidney where is is oxidized to urobilin, a yellow pigment, which is excreted in the urine and gives it a yellow colon. Bruises change color becase hemorrphage in tissue occurs and red blood cells come first and release hemoglobin. Proteases dissolve globin rleaseasing heme into tissue and producing bluish-black color of fresh bruise. Over a few days becase the rocess is slow for metabolized in extracelllar matrix, it is converted to biliverdin causing bruise to change from blue to green. As biliverdin is slowly converted to bilirubin in the extracellular matrix, the bruise turns yellow. Colors of bruise persist for any days because the extraceullular matrixalcks binding proteins to speed up process. If high levels of bilirubin accumulate in the blood, you get jaundice which gives yellow pallor to skin.There is hemolyti jaundice from high rates of hemoglobin synthesis and degradation. There is bile duct obstruction which can also cause jaundrice/ can result in feces which is chalk white. Inadequate conjuration of bilirubin in liver can also cause jaundice. Hemostasis cases Case 1: Identify cause of case: baby fell and is bleeding from mouth. Bleeding stopped briefly with cold compress but then starts up again. Bruises noticed on arm when went to doctor. Examined injured gum area bleeding started again. History of uncle who died of blood disorder when youn. \ \ Testing results show normal platelet count, bleeding time, and PT. PTT  greatly prolonged.\ \ What could be a potential defect? defect in intrinsc clotting mechanism becayse of PTT being prolonged. Defect in factors VIII, IX, XI, or XII WHat is a one time gene therapy used to reat hemophilia A and how does it work? Roctavian used as one time gene therapy product adminstered as single dose by intravenous infusion.\ \ Consists of viral vector carrying gene for clotting Factor VIII. Gene expressed in liver to increase blood levels of FVIII and reduce risk of uncontrolled bleeding. Can make patients with severe hemophilia A go to moderate or mild.\ \ Created in 2023.\ \ Think Rock of Ages roctavian of 8 What medication is used to treat hemophilia B? How does it work? Hemgenix Hemgenix is a one-time gene therapy product given as a single dose by IV infusion. The gene is expressed in the liver to produce Factor IX protein, to increase blood levels of Factor IX and thereby limit bleeding episodes. Case 2: Idenitfy issue with case: 74 year old women has bruising. Takes coumadin (warfarin). Has a high international normalied ratio (tells us how long it taks for her blood to clot). Began taking antibiotics. WHat issue does she have? How can we get her back to nomral range? Vitamin K levels went down because warfarin is inhibiting the VKOR. Reduction in Vitamin K not enough clotting factors. Supratherapeutic INR values are common in warfarin-treated patients. Antibiotic woman is taking is most likely the cause. This patient\'s INR will return to the therapeutic range more quickly if she receives low-dose oral vitamin K (as opposed to simple warfarin withdrawal) What are the differences between heparin and warfarin? Heparin for anti-thrombin III. Warfarin for kitamin K epoxide reductase Case 3: IDentify what is wrong in case: 4 year old boy presneted with brusiing on arms and legs. Bruising appears without injury. Had bad notebleed episode in past with transfusion of one unit of blood. Family history of bleeding on maternal side.  Patient on no medication. \ \ Coagulation tests show PT and PlT normal. PTT high.\ \ What kind of issue can this be? Intrinsic pathway issue. Factor 12, 11, 9, 8  Case 4: Identify issue with case: 83 year old man rapidly gorwin squamous cell carcinoma. had testing that showed elevated PTT and slightly elevated PT. No banormal coagulation, no histor of excessive bleeding, no clot formation in the past. How to test patient to find what is wrong? What factors are most likely the issue? An inhibitor screen is performed by mixing the patient's plasma with pooled normal plasma and running a PTT. If the PTT corrects then this means that a factor or factors were deficient in the patient's plasma and were replaced with the pooled normal plasma resulting in a correction of the PTT. Failure to correct indicated that inhibitor present. In a patient without a bleeding history, lupus anticoagulant and certain factor deficiencies are high on the differential. The most common specific factor inhibitors are to FVIII and FIX. 8 or 9. These generally arise in hemophilia patients treated with factor concentrates. It is very rare for a patient to develop an inhibitor to factor XI or XII. Case 5: Identify what patient has in case: 46 year old women has surgery and gets antibiotis. Patent begins to bleed from surgical wound. Pre-operative coagulation screen tests were normal. Patient on metformin for type 2 diabetes and amlodipine for hypertension. Blleding from surgical site with no infection.\ \ Tested PT, PTT, and Plt. PT levels too long. \ \ What deiciencies are possible? If PT prolonged, factor 7 deficincy, liver disease, warfarin effect or vitamin K deficicny all possible Case 6: Idenfity issue with case: 21 year old college student reports bruising easly. Ha never occured before.Has bleeding gums, frequent nosebleeds, havey periods, spotting between mensrtual ccles, and petechial rash on both legs. Patient says rash delvoped after running. Petechia are little red dots or hemrphages can be seen after yelling loudly in throat. Has petechia on lower extremiteies and on gumline.\ \ Has history of iron deficincy and taking no iron supplements.\ \ Lab tests show super deificnt platelet count.\ \ What does she most likely have? Thrombocytopenia which is platelet count blelow lower limit of normal. What is the difference between direct and indirect bilirubin? **Indirect: Some bilirubin is bound to a certain protein (albumin) in the blood.** **This type of bilirubin is called unconjugated, or indirect, bilirubin**. Indirect = insoluble\ \ Direct: In the liver, bilirubin is changed into a form that your body can get rid of. This is called conjugated bilirubin or direct bilirubin. Direct = soluble Understand differences among specimen\ types Types of specimens are venous blood, capillary blood (pediatrics), arterial blood, urine, and cerebral spinal fluid. Plasma is the liquid part of blood and serum is similar to plasma but has no clotting factors. Be knowledgeable about factors affecting lab\ results Factors that can affect lab results include time of collection and effctsof eating before a lab test. Pre-analytical variables account for up t 75% of lab errors. From tie when test is ordered by physician untul sample is read for anaylusts are pre-analytical vriables. If someone eats before a lab test that they should be fasting, lipemia could occur where serum or plasma has a milky look. Would affect results. Hemolysis of blood test sample leads to improper results. Causes red cells to be ruptured during collection ad will have high levels of potassium, magnesium, and phosphorous. Understand and interpret constituent tests in:\ -- Lipid Panel Total cholesterol, high density lipoprotein cholesterol, low-dentistry lipoprotein cholesterol and triglycerides.  -- Basic Metabolic and Complete Metabolic Panels Basic metabolic panel -- Multiple chemistry tests grouped and reported as a single profile for ease of ordering. Includes electrolytes and tests of kidney function. Some things tested include sodium, potassium, chloride, carbon dioxide content, blood urea nitrogen, serum creatinine, and serum glucose. Complete metabolic panel - The basic panel plus other tests such as Total Protein, Albumin, Total Bilirubin, Total Calcium, Alkaline Phosphatase, Aspartate Aminotransferase (AST). -- Liver and Pancreatic Function Test Panels Liver function tests include alanine aminotransferase and aspartate aminotransferase. In acute livr injury such as viral hepatitis or alcohohol issue, both ALT and AST used as measure of degree of liver inflammation or damage. -- Complete Blood Count Involves counting white blood cells, red blood cells, and platelets. Complete blood count tests include hemoglobin, hematocrit, total red blood cell count, mean corpuscular volume, red blood cell distribution width, total white blood cell (leukocyte) count, and platelet count. 1\. Know the categories of hormone function and mechanisms for intercellular\ communication. Four categories of hormone function: 1. Regulation of utilization and storage 2. Maintenance of complex internal environment 3. Regulation of reproduction 4. Regulation of growth and development Five basic mechanisms of intercellular communication 1. Endocrine -- uses circulatory system to transport ligands 2. Paracrine -- acts on nearby cells 3. Autocrine -- signaling acts on the signaling cell itself 4. Neural 5. Contact-dependent 2\. Identify the general features of hormone classes including their composition, biosynthesis, release and action, mode of transport. The three structural classes of hormones are polypeptides, steroid-related, and amines. Mneumonic is PSA for peptides, steroid, and amines. Examples of peptide hormones are ACTH, glucagon, growth hormone, unsuing, IGF-1, oxytocin, prolactin, vasopressing, TRH. These then stimulate FSH, LH, and TCH. Syntehsized from transcription and translation of genes. Syntehsized on RER as pre-pro-hormones which are inactive, the active form stored in membrane bound vesicles and are released by exocytosis. Glycoproteins contain carbohydrate. Bind to cell surface receprtors and activate second messenger systems to elicit responses. Examples of steroid hormones are aldosterone, cortisol, estradiol, progesterone, and testosterone.Most are syntehsizd from cholesterol except retinoic acid. Thyroid hormone acts like a steroid hormone. Steroid hormones are not stored, diffuse across cell membrane. uSe carrier prtoteinds for transport in blood. Examples of amines are epinephrine, norepinephrine, T4, T3, and melatonin. Derived from amino acids like tyrosine or tryptophan. And thyroid hormones. 3\. Describe effects of plasma binding proteins on steroid hormone levels and\ actions on target cells. Steroid and steroid related proteins are bound to carrier proteins in the blood. The steroid carrier proteisn buffer changes in blood steroid levels and modulate biological avialbalility. Some peptide hormones (like IGFs) are also bound to carrier proteins. 4\. Describe the key features of signal transduction through cell surface\ receptors. Hormone binding to cell surface receptors induces a conformational change in the receptor which lead to changes in levels of 2^nd^ messengers inside the cells. Glucagon and epinephrine bind to GPCRs which in hepatocytes leads to an increase in cAMP, activation of PKA and increase in liver glucose output. GPCRs coupled to Gaq stimulate which leads to an increase in IP3, Ca2+, DAG, and activation of protein kinase c. Binding of hormones (eg insulin) to tyrosine receptors, activate the receptor's tyrosine kinase activity which phosphorylates tyrosine's in the receptor and other proteins. GH and PRL binding to there receptros mediates tehre affects through associated tyrosine kinases. 5\. Describe essential features and significance of feedback regulation,\ secretion patterns of hormones and hormone degradation. Secretion patterns of hormones Hormones fluctuate in response to changes in the environment. Episodic fluctuations: hormones are secreted in response to discrete episodes (eg scukling aof an infant stimulates PRL secretion). Circadian (diurnal) secretion vary over a 24 hour period (ex. cortisol levels are highest in the morning). Ultradian (pulsatile) secretion havea periodicity ½ to 2 hours. (LH secreted with periodicity of 1 ½ hour). Note that hormones can exhibit more than onesecretion pattern. Degradation Peptide hormones are degraded by proteases mostly via receptor-mediated endocytosis. Steroid hormone degradation: 1. Occurs inside the cell where dteorids are made water-soluble and inactive by conjugation with glucorinide, hydroxyl and sulface groups. 2. Regulated by the life time of the carrier protein-hormone complex. Feedback Many hormones are regulated by feedback inhibition (ex. cortisol inbhibits CRH and ACTH). 1\. Know the biosynthesis, major actions and regulation of oxytocin and vasopressin. Oxytocin and vasopressing: peptide hrmones synthesid in cell bodies in the hypothalamus. Released from nerve terminal endings in the posterior pituitary. Oxytocin stimulates uterine contractions during partutition and contraction of myoepithelial and milk ejection during lactation. Release stimulated by suckling, "let- down" reflex, cervical stretch from uterine contraction (positive feedback loop). Estrogen stimulates oxytocin release; progesterone inhibits oxytocin release. Vasopressin (antidiuretic hormone, ADH): Humans require arginine vasopressin. ADH decreases osmolality of the ECF by increasing water resporotpin in the kidney vby sittmulating vasopressing V2 GPCR receptors, increase in cAMP/PKA and increase in inertion of aquaporin 2 channels into the luminal plasma memrnae of kidney collecting duct cells. Stimuli: greter than 2% increase in osmolality ( ex. NaCl) of ECF, greater than 10% decrease in blood pressure. Sesnsitiu to osmolality increases with decreased blood pressure. Inhibitors of angiotensin converting enyme are drugs used to lower blood pressure to decrease angiotensin II levels, 2\. Understand the differences between neurogenic and nephrogenic Diabetes insipidus. Diabetes insipidus (DI): inadequate production or utilization of ADH. Physical causes: damage to pituitary stalk, brain damage. Genetic causes: Neurogenic DI vasopressin deficiency, mutations in neurophysin 2 part of ADH prohormone; Nephrogenic DI kidney resistant to ADH, causes mutations in either vasopressin V2 receptor or the AQP2 channel. VP (ADH) promotes H2O reportion in kidney collecting duct cells and if VP not working right then water cannot pass through as needed. 3\. Identify all hormones comprising the hypothalamic/pituitary axis, their actions on target tissues and their regulation. Hypothalamic hormones are peptides released from neurons in coordinated pulsatile secretion pattern. TSH (AP): stimulates thyroid gland to produce T3/T4 which increase fuel metabolism and basal metabolic rate. Feedback inhibited by T3. ACTH (AP): stimulates the adrenal gland to produce. Cortisol which raises blood glucose. Feedback inhibited by cortisol. FSH/LH (AP): stimulates estradiol/testosterone production n ovary and testes. LH stimulates progesterone in ovary. Feedback inhibited by estriol. A rise in serum progesterone is best indicator that ovulation occurred. Males: testosterone promotes spermatogenesis. Females: Estradiol regulates menstrual cycle, progesterone maintains pregnancy. Prolactin (AP): directly stimulates milk production in mammary gland. Suckling stimulates release by decreasing dopamine release from the hypothalamus. Bromocriptine (dopamine analog) inhibits prolactin release. Growth hormone (AP): increases growth, lean body mass and raises blood glucose. Stimulated by decreased blood glucose and amino acids via somatocrinin, inhibited by increased blood glucose via somatostatin, and IGF-1. GH stimulates IGF1 (liver and other tissues) and together they promote growth in all tissues. Tumor in anterior part of pituitary gland casues increased IGF-1. 4\. Describe the relationship between pro-opiomelanocortin and the hormones derived from it. POMC is the prohormone for ACTH, a-melanocyte stimulating hormone (a-MSH). ACTH contains amino acids encoding a-MSH which stimulates melanin production in melanocytes and can lead to hyperpigmentation of the skin. 5\. Recall the metabolic and growth promoting effects of growth hormone and insulin-like growth factor and the factors that regulated their secretion. GH stimulates lipolysis of triglycerides in adipose and release of insulin like growth factor 1 (IGF1), it inhibits glucose uptake in muscle. Together GH and IGF1 promote growth in all tissues. GH release is stimulated by low blood glucose via somatocrinin release from the hypothalamus. 6\. Recall the general effects of overproduction and underproduction of growth hormone and the physiologic basis for these conditions. Underproduction: dwarfism, inability to maintain blood glucose with fasting. GH tumor before puberty:: gigantism, growth of long bones and all tissues. GH tumor after puberty: acromegaly, growth of cartilage and soft tissues. Physical changes: increase size of hands and feet, protruding jaw, enlarged tongue, increase spacing between teeth. Metabolic changes: elevated blood glucose, dyslipidemia, insulin resistance. Respiratory changes: airway obstruction, sleep apnea, snoring. Know the general structure, biosynthesis, metabolic effects and regulation of thyroid hormone. Thyroid structure -- thyroid cells have iodide in them. either tetraiodothyronine (T4) or triiodothyronine (T3). Derived from the amino acid tyrosine. Thyroid hormone biosynthesis Metabolic effects - Thyroid hormone results in an increase in the basal metabolic rate ( the amount of energy your body needs to maintain homeostasis), increase in O2 consumption, increase cardiac output, stimulates metabolism of fat, carb, and proteins, and induces many enzymes. In children, thyroid hormone responsible for growth and maturation of skeletal bone and vital for development of the CNS. Thyroid hormone biosynthesis -- Synthesized in follicular lumen. Iodide is passively transported into lumen. Thyroid hormone synthesis requires thyroglobulin and iodide. Thyroid peroxidase is enzyme needed to Thyroid peroxidase assists the chemical reaction that adds iodine to a protein called thyroglobulin, a critical step in generating thyroid hormones. Feedback regulation of thyroid -- Primary hypothyroidism is a defect in thyroid gland. Secondary hypothyroidism is a defect in pituitary Tertiary hypothyroidism is a defect in hypothalamus. When thyroid hormone levels are low, the hypothalamus releases TRH, stimulating the pituitary to release TSH, which then prompts the thyroid to produce more T4 and T3. The pituitary gland makes, stores, and releases thyroid-stimulating hormone. Recall the general effects of overproduction and underproduction of thyroid hormone and the physiologic basis for these conditions. Hypothyroidism, caused by an underactive thyroid gland, typically manifests as bradycardia, cold intolerance, constipation, fatigue, and weight gain. In contrast, hyperthyroidism caused by increased thyroid gland function manifests as weight loss, heat intolerance, diarrhea, fine tremor, and muscle weakness. Describe the function and regulation of glucocorticoids; the consequences of overproduction and the physiologic basis for these conditions. Rate limiting step of adrenal cortical steroid hormones is cholesterol to pregnenolone. Catalyzed by p450scc. Cortisol or glucocorticoids are named for ability to raise blood glucose. Cortisol is chronic stress hormone. Cortisol stimulates PEPCK which is rate limiting step for gluconeogenesis. Cortisol produced and released by adrenal glands. Hypothalamus secretes corticotropin-releasing hormone (CRH) which prompts pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH stimulates adrenal cortex to produce cortisol. When cortisol levels rise, they inhibit CRH and ACTH release through a negative feedback loop, maintaining hormone balance. Cushing's syndrome is hypercortisolism and results in weight gain, fatigue, muscle weakness, pink or purple stretch marks, fragile skin, and high blood pressure. Describe the function and regulation of aldosterone, its role in RAAS. Aldosterone stimulates Na+ resorption and K+ excretion. RAAS increases Na+ and BP, decreases K+. Angiotensin II stimulates increases blood pressure, stimulates aldosterone synthesis/release, and stimulates ADH release. Aldosterone is a steroid hormone. Increases Na+ channels, K+ channels, Na/K ATPase. Net effect of aldosterone is increase Na+ retention and increase K+ secretion. Describe the consequences of primary adrenal insufficiency. Addison's disease is adrenal insufficiency. Results in muscle weakness and fatigue, weight loss and decreased appetite, darkening of skin (hyperpigmentation), low blood pressure, even fainting, salt craving, and low blood sugar (hypoglycemia). Describe key features of eicosanoid metabolism and the effects of glucocorticoids, aspirin and NSAIDs on eicosanoid production. PLA2 activity is decreased by glucocorticoids. Aspirin is an anti-thrombotic agent. Thromboxane's: increase platelet aggregation; are synthesized by platelets. Prostacyclin (PGI2): Decreases platelet aggregation; is synthesized by endothelial cells of blood cells. Cyclo-oxygenase is irreversible inhibited by aspirin. Reversibly inhibited by nom-steroidal ani-inflammatory drugs. Cyclo-oxygenase converts amino avoids into PGH2 a precursor for prostaglandins and thromboxane. Arachidonic acid is a precursor for leukotrienes and prostaglandins. 1.Describe the unique molecular features of collagen and how they\ influence its function in both normal and disease states. Main unique features: triple- helical structure, hydroxyproline and hydroxylysine, cross-linking to provide strength for collagen fibrils, and heterogeneity with 28 different types of collagen to fulfill specific roles. Collagen is the most abundant protein in the body. Collagen is 33% glycine, 13% proline, and 9% hydroxyproline. Glycine is small and flexible, forming tightly packed turns. Proline/hydroxyproline are rigid, providing strength. Collagen is stabilized by both hydrogen bonds and covalent bonds. Post translatonlational modificaitons of prolines and lysines requires vitamin C to procede. Needed for collagen formation. Can get scurvy if vitamin c deficiency. Results in inability to form hydroxyproline and hydroxylysine. Results in unstable triple helix. Disease symptoms are capillary fragility (bruising, bleeding gums), poor wound heaing, poor bone growth in children. Collagen is a glycoprotein and therefore glycosylation does affect immunogenicity that has implications to autoimmune diseases. Pro-a collagen chains are starting material in the synthesis of mature collagen. Chains are woven into long rigid right turned triple helices which form the base unit for all collagens. Different pro-a collagen chains can be mixed and matched to form different types of collagen. Covalent bonds in collagen are formed between lysins that come in close proximity using 2 different types of collagen. These two types of crosslinks can be bonds that form within 1 triple helix or between adjacent triple helices. Diseases due to defects in collagen include scurvy which is a vitamin C defect. Results in poor bone growth and capillary fragility as well as poor wound healing. Ehlers-danlos syndrome is another vollagne defect disease and causes hyperextensivility of skin, easy bruising, and extreme flexibility in joints. Another collagen defect disease is ostesogenesis imperfecta which involves adefective collagen I. Multiple bone fractures, bone deformaties, and blue sclera can result. Different types of collagen play different roles. Some collagen connects collagens to cells and other matrix components, some produced by chondrocytes, required for normal bone growth, some unique to basement membranes, some associated with muscular dystrophy, some connect epidermal basement membrane with dermal connective tissue, some expressed in connective tissue-producing cells, and some proteoglycan expressed in endothelial and epithelial cells. 2.Define the steps involved in biosynthesis of collagen. Steps of collgen biosyntehsis 1. Pre-pro a chains are synthesized in ER where signal peptide is cleaved. 2. 2\. Prolines and lysines in pro-a chains are hydroxylated 3. Glycosylation of pro-a chains occurs in ER with galactose and then glucose 4. Triple helix containing procollagen forms inside the glgi. 5. Cleavage of extension peptides occurs outside the cell as does assembly of tropocollagen units into collagen fibers. 3.Understand how collagen assembles into distinct structures. Gaps between adjacent collagens have same amount between triple collagen units. Make dar and light gaps between adjacent triple collagens. In tendons, firbillar collagen is arranged in parallel bundles. In cartilage, no regular arrangement; associated with glycosamioglycans. In skin, planar sheets of microfibrils layered at many angles. In cornea, planar sheets stackd crossways for strength. They overlap in many directions. 4.Explain how the distinct structural features of elastin result in radically\ different physical characteristics. Elastin is similar to collagen with high percentage of glycine and proline. Unlike collagen, no repeating patters. Alternating coiled-coil domains and hydrophobic domains create elasticity. Covalent bonds provide streenth. Therefore it has some siddferent physical properties from collagen. Post-translational modifications of lysine resideues in elastin fibirls include desmosine which results from identical chemical reactions is unique to elastin. Desmosine is an amino acid fround uniquely in elastin and is made from lysine. Elastin also has large hydrophobic domains. Fibrillin is an extracellular matrix protein and has multpke binding sites for growth factors. This limits their availability in tissues. Fibrillin provides scafford for elastin deposition. Fibrilin/elastin microfibrils facilitate flexibility of skin ligaments, and blood vessles. Fibrillin microfibrils provide limited elasticity, the majority comes from elastin. Fibrillin is a glycoprotein, which is essential for the formation of elastic fibers found in connective tissue. Fibrillin is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide a scaffold for deposition of elastin. Elastin highly elastic and flexible so if not working properly can cause issues with escape of air into pleural space, dislocation of lens within the eye, and numerous cardiovascular problem. A disease with elastin related defcects is marfan syndrome.Cuased by genetic defects in Fibirilin in FBN1 mutation. Disease results from interesterence with growth factors binding o fibrinlin. 1\. Recognize the major components of bone and their role in its function. Bone and teeth compostion include collagen microfibrils and hydroxyapatite crystals. Collagen offers bone shape and strength. Hydroxyapatitie offers bone hardness. Collagen has sites for nucleation of hydroxyapatitie crystals. The hydroxyapatite crystal can go in spaces between bone. The crystals then harden to give body strength. Pyrosphoshatase removes inhibitor of hydroxyapatide formation. With the inhibitor, pyrophosphate inhibits crystal formation hcih is needed to make bone. 2\. Understand the major stages of bone formation and explain control of\ mineralization. Bone is a living organ. Includes osteoblasts which help build bone and osteoclasts which help break down bone. 3\. Identify how the different components of bone are organized. Collagen is organizes into brick like shapes in bone. The bone includes osteon/haversiand system for both nerves and blood supply passage to go through. There is compact or cortical bone. This is dense, has osteons that provide structural support. There is spongey or trabecular bone. It is porous and has shock absorption. 4\. Recognize the cells that regulate and maintain bone. Osteoblasts help regulate and maintain bone. Osteoblasts differentiate from stroma and regulate osteoclast differentiation. Osteoclasts are respobisble for bone resportption. Ostocytes are embedded in the bone matrix. Bone lining cells on bone surfaces. 5\. Understand bone resorption and remodeling and their role in tooth\ movement and orthodontics. RANKL and m-CSF are important for osteoclast differentiation and need Ca2+ to work. If this process goes wrong and too many osteoclasts are made than bone resorption occurs. Osteoclasts needed to sustain serum Ca2+ levels. Works in concert with osteoblasts for maintenance of healthy bone. Osteoclasts also help mediate bone erosion in osteoporosis, arthritis, and other conditions. Crosstalk between RANk and inflammatory cytokinescause bone erosion during arthritis. Bone erosion can occur with artritis where osteoclasts eat up bone due to foreign collagen. Reaction of arthritis. In orthodontics, alter tension of bone from movement of teeth. Jaw needs to slowly restructure to accommodate for movement of teeth. On the pressure side, osteoclast activity increases, leading to respotion. Tension sid esoteoblsat activity increases leaving to bone deposition. 6\. Understand mineralization and differences in composition of the\ calcified layers of the tooth. Enamel has 90% hydroxyapatite and 0% collagen. Is the hardest layer, is highly mineralized and is hardest tissue in the body.. Dentin has 70% hydroxyapatite and 18% collagen. Is the second strongest layer. Cementum is third strongest. Bone is around same hydroxyapatite and collagen as cementum. Enamel is made by ameloblasts which pump out calcium phosphate crystal to make enamel. This makes enamel extremely strong. There are different compositional differences between layers of teeth and bone in rest of body. 7\. Explain the pattern of bone loss with age and menopause, the current\ model of a cause of osteoporosis in postmenopausal women, and how\ osteoporosis increases tooth loss. Bone density decreases with age. More bone loss in women than men especially during menopause. In women during meopause, there are more osteoclasts due to lack of estrogen. As hormones change to accommodate normal menopausal changes, estrogen levels start to fluctuate and then drop. Since estrogen helps prevent bones from getting weaker by slowing the natural breakdown of bone, its reduction during menopause significantly speeds up bone loss. estrogen acts on bone by decreasing the production of interleukin-6 (IL-6), a cytokine that increases bone resorption, by osteoblasts or bone marrow cells. Anorexia can also effect and decrease bone density. Osteoporosis affects teeth because jaw degradation from osteoclasts cayse gum atrophy, widening gap between gum and tooth, and more porous bones. 1\. List and explain the functions of calcium in signal transduction, cell\ metabolism and bone and teeth as covered in the handout and lecture. Calcium is most abundant mineral in body. Serum calcium is tighly regulated (2.212 to 2.55 mM). Clacium serves two very different key roles -- role of messenger conveying signals received at cell surface to inside of cell and in form of calcium ohosphate, the role as the major structural component of bone and teeth. Ca2+ activates cells. Can activate blood platelets. Receptors activate and cause release of calcium all around cell. Calcium isa controlled cellular functon. Calcium function in cells used for contraction of skeletal, cardac, and smooth muscle, neurotransmitter release, T cell activation, and many other pathways. Calcium helps twith multiple signaling pathways, controls enzyme actiavatin, drives relocalization of many intracellular molecules, and plays a structural role in bone. Ca2+ -calmodulin mediates thrombin stimulated retraction o blood clots. 2\. Explain the role of bone, the GI tract and kidney in calcium homeostasis. Osteoclastic activity promoted by PTH, vitamin D and is inhibited by calcitonin. Vitamin D and PTH necessary for calcium absorption in intestine. PTH promotes calcium reabosprtpn and phosphate excretion. For bone remodeling, bone resportion done by osteoclasts. Bone formation done by osteoblasts. Osteoclasts associated with immobilization, weightlessness, and continuous PTH. Osteoblasts associated with gravity, weight bearing exercise, and intermittent PTH. Bone resorption and bone formation are tightly coupled. Osteoclasts express receptors from RANKL. Osteoblasts secrete ligands and RANKL. Osteoblasts secrete OPG which neutralizes RANKL. Osteoblasts couple bone resorption and reformation. Osteoclasts erode bone matrix at ruffled border. 3\. Explain the role of parathyroid hormone, vitamin D and calcitonin in\ calcium homeostasis. Low blood calcium triggers PTH release. High Ca2+ inhibits PTH release. Essentially, if have low calcium need more calcium to be made. If have high calcium, don't need more calcium to be made. If tehre is high extracellular calcium, then increased PTH proteolysis. This is how calcium levels are regulated extracellularly. This process involves G proteins. If there is acute low extraceullar calcium, increased release of acive PTH. If chronic low extracellular calcium, increased PTH mRNA made so that long term more parathyroid hormone can be released. In the intestine, if PTH released, vitamin D synthesis increases, calcium absorption from food increases, blood calcium increases. Vitamin D helps to drive calcium resorption in blood and modulates osteoclast function. Calcitonin works to inhibit bone resorption and stimulate Ca2+ excretion. Calcitonin lowers blood calcium but thisis only protective measure for severe situation. Calcitonin made in thyroid gland and major action on osteoclasts in bone. Calcitonin not relevant in minute to minute regulation of calcium. Provides protection against excessive bone resorption. 4\. Explain the effects of hyper- and hypo-secretion of parathyroid hormone\ on calcium homeostasis. Hyperparathyroidism results in kidney stones, bone fragility, cardiac hypertrophy, and increases absorption from bones. This is because parathyroid hormone stimulates osteoclast to degrade bone. Body uses bone as reservoir to fill in gaps between meals. Hypoparathyroisim associated with multiple neurological effects, heart failure, muscle cramps. Can be causd by injury, loss of magnesium, and aklalosis. Lower PTH means less osteoclasts degrading bone and less calcium entering blood stream. Decrease resorption of calcium from bone and decrease from urinary tract. 5\. Explain the effects of low and high plasma calcium levels on calcium\ homeostasis. **Low plasma serum - The parathyroid glands release parathyroid hormone (PTH) in response to a decrease in serum calcium**. Stimulates calcium from gut to raise serum calcium. Inhibits secretion of calcium from kidney. Body wants to increase calcium for make up for low calcium. High plasma cacium- Decrease osteoclasts to decrease calcium resorption. Bones harden instead of soften. NO PTH, no calcium absorbed because vitamin D is gone. Body wants to get rid of calcium to correct for high calcium levels. 6\. Explain the effects of deficient and excessive vitamin D intake on\ calcium homeostasis. If low vitamin D, some resorption of calcium from bones. Bone density decreases overtime. In low calcium state. Can get disease such as rickets which has low cserum calcium, dental deformities, imparired growth, increased bone fractures, muscle cramps, short stature, and skeletal deformaties. If excess vitamin D, it is rare that this happens unless somebody intakes a lot of vitamin D. Absorb more calcium from gut. Stimulate osteoclast function. Some releaf of calcitonin. Blood calcium levels not affected much but bone density affected. 1\. Know the three main pairs of salivary glands and their secretions. Parotid -- serous secretions Sublingual -- mucous secretions Submandibular -- mixed serous and mucus secretions 2\. Understand for what the fluid characteristics of saliva are essential. Saliva important for buffering, maintenance of tooth integrity, antimicrobial activity, tissue repair, digestion, assistance with taste, facilitates mastication, swallowing, and speech. 3\. Know how stimulation of salivary glands changes the composition of\ saliva. Stimulation results in decrease in overall protein concentration, resulting in thinner, less viscous saliva. Na + and Cl- are higher. When salivary secretion goes up, bicarbonate goes up and pH is higher. 4\. Understand the biochemical roles of salivary mucins. Salivary mucins are highly glycosylated proteins. Aryehydrophilic an contain much water. Provide an effective protective barrier against desiccation. Variability of complex oligosaccharide side chains in mucins provides wide possibilities for interactions with oral surfaces, oral microorganisms and other salivary proteins. Muc5B is primary gel forming mucin in oral cavity. Helps protect teeth from bacteria. MUC7 is the non-gel forming mucin. Is efficient as bacterial agglination and clearance. Drectly bidns to microorganisms to facilitate their removal by swallowing. 5\. Understand whole saliva, salivary flow, salivary clearance, and the\ effects of hyposalivation. Whole saliva -- Constantly covers had and soft tissues of oral cavity is a complex and slightly acidic fluid. COmpaints components of non -glandular origin such as desquamated oral epithelial cells, food debris, microorganism,s and blood derived compounds. About 90% of total saliva produced is from major salivary glands. Salivary clearance -- the process by which saliva dilutes and eliminates food substances such as sugars and acids from the oral cavity. Saliva flow rate -- a lot of saliva produced each day. Salivary flow stmuated by chewing, mechanical stimulation, nusea, or tasting or smelling foods. Things that affect salivary flow and decrease it are drugs suc as anticholinergics, fear, sleep, and xerostemia. Hyposalivation -- In patients s with sevre and persistant reduction in unstimulated and stimulated whole saliva flow the retentn of food substances and microorganisms in the oral cavity is prolonged. Resutls in shift in oral microbiota favoring growth of aciduric and acid tolerating bacteria. 6\. Understand the relationship of enamel pellicle, saliva, and microbiota. The acquired pellicle is a layer of salivary glycoproteins that precipitates on the enamel surface of teeth. It is a thin transparent protein sheath. During acid demineralization the acquired pellicle may retard the diffusion of acids into enmel and calcium and phosphate out of enamel. The enamel pellicle is mainly comprised of adsorbed salivary proteins such as mucins, lactoferrin, lysosome, a-amylase, and secretory IgA. Help play a role in lubrication, mineral homeostasis of tooth surfaces, compostion of initial colonizingmicroorganisms which form initial layer pf dental plaque on tooth surfaces. Oral microbiota includes resident species with genus Streptococcus being most abundant. Oral cavity offers warm and moist enivronmntt which makes it a suitable resident for many different microrganisms. Saliva contributon to acquired enamel pellicle heplps to odulate the initial adhesion and colonization of microorganisms. Saliva facilitates clearance of microorganisms and dietary carbohydates from oral cavity but also supplies colonizing bacteria with nutrients through breakdown of dietary starch. Saliva also prouides anti-microbial acidity through numerous proteins. Salivary mucins have capacity to bind and aggregate microorganisms. Saliva also plays important role in clearnance of desquamated epithelial cells from oral cavity which helps eliminate microorganism from saliva. 7\. Understand salivary buffering. When salivary secretion goes up, bicarbonate goes up and pH is higher. Salivary buffer capacity includes bicarbonate, phosphate, and proteins. The bicarbonate concentration and thus the pH increase when the salivary flow rate increases. Role of salivary buffer is to maintain salivary pH at relatively constant level. The most important buffer in saliva is bicarbonate. Saliva protects enamel against the demineralizing effects of acid. Eating food stimulates salivation and increases salivary flow rate. When flow rae increases, the buffering capacity of saliva increases. 8\. Know the main salivary enzymes: amylase, lysozyme, lactoferrin, and\ immunoglobulins. Upon stimulation, the parotid gland produces watery, amylase rich saliva. Submandibular and siblingual glands produce more viscous, slimy mucin rich asaliva. Salivary amylase aminly secreted rom serous acinar cells in parotid glands. Amylase helps break down ingested starch. Resulting lactic acid production lowers pH. Salivary lysosome exerts enzymatic activity via hydrolysis of B-1,4-glycosidic bonds between N-acetylmuramic acid and N-acetyl-d-glucosamine in the polysaccharide layer of the gra positive bacterial cell wall. Plays an important role in the innate immunity, providing protection against bacteria, viruses, and fungi. Causes lysis of bacterial by breaking down their cell walls. Lactoferrin is an iron binding glycoprotein. Originates from neutrophil granulocyes. Lactoferin binds and sequesters iron and consequently depreives the microorganisms of iron, which is essential for their growth. Salivary immunoglobins have two maor antibody classes in saliva which are IgA and IgG. Dimeric IgA is produced by plasma cells in stroma of salivary glands. IgA is most important defense mechanism of slgA binding to antigens in saliva, in oral mucosa, and in acquired enamel pellicle. Know the structure of dental enamel and hydroxyapatite. Enamel is hardest structure in body. Hydroxyapatitite of non-living enamel as well as living mineralized tissues is maintained by ion exchange via percolation. Mineral component evolves over time by ion exhcnage via fluids percolating htrough microposiry of hard tissue. Enamel rods organized as linear prisms oritnted perpendicular to DEJ. Rods made of hydroxyapattide. Statbility of enamel depends on hydroxyapatitie. Microporous dense eneamel permeable to water and ions but not to larger structures such as microbes, biofilm, and food. Dental enamel made up of biological apatitie. Acidity affects position of equilibrium by reacting with Poh4 and OHH ions making them unabivlable for recrystailziation. Ca2+, (PO4)-3, and OH- ions in dental enamel are constantly exchanging with free ions. Understand how acidity affects dental enamel to form caries. Below pH 5.5, net demineralization will occur. Effect of acids at enamel surface in plaque creats zone of demineralization. Understand formation of plaque. Newly formed pellicle is quickly invaded by bacteria in saliva and from surrounding surfaces which attach themselves to the pellicle. The initial stage of bacterial growth produces a thin aerobic lawn of bacterial in a protein matrix. Matrix derived from polysaccharide polymers synthesized by bacteria which holds growing colony together and provides favorable environment for continued bacterial growth. S plaque becomes thicker, the interior becomes increasingly anaerobic which favors growth of anerobcic species of pacteria, Plaque polysacchardies are made mostly of glucose wth some fructose polymers present. Most abundant glucose polymers in plaque are dextrans. Fully developed dental plaque produces an anaerobic microenvironment at underlying surface of tooth. Bacterial in anaerobic interior of plaque have little or no access to oxygen so they cannot egnerat energy by oxidative metabolism of fuels. Salivary buffers cannot diffcuse into plaque very fast, and metabolic acids cannot diffuse out quickly. Any carbohydrate in mouth can contribute to acid production via anaerobic glycolysis in plaque bacteria. Understand the effect of fluoride on dental enamel. Dental calculus -- salivar proteins inhibit precipitation of calcium phosphate. Calcium phosphate precipitation may occur in dental plaque leading to formation of dental calculus. Flouride effective for preventing demineralization. Fluoride ions at enamel surface increase rate of remineralization. Many plants and animals don't concentrate fluoride from their environment. Flouride levels in plants and animals depends on envuronemtne where they are grown or raides. In many places, levels of fluoride in naturally occurring water supply and in locatlly grown foods are below the optimal level for dental health. Efforts have been made to add fluoride to drinking water. Know the major type of oral cancer. Squamos cell carcinoma most common type. Arises from surface mucosal epithelium of the mouth and throat. Know where the major oral cancer is typically found. 1\. tongue 2\. floor of mouth How does oral cancer differ between men and women and by age? More common in men than women. More common in older people. Etiology of oral cancer Genetically damaged daughter cells pass mutations down and lead to uncontrolled division. Tumor suppressor gene inactivated by mutation or oncogene activated by mutation or amplification Know the major risk factors (carcinogens) for oral cancer. Tobacco (especially smoking), alcohol, actinic radiation, HPV, and iron deficiency. Clinical features of ora cancer and precancer Symptoms precancers: painless, asymptomatic, sore that doesn't heal. Advanced cancers: sore that doent heal, lump/mass, pain especially on one sie, pain radiating to ear or throat that does not go away, numbness/parasethsia, los of function. What does oral pre cancer look like? Usually no pain, no symptoms, location and appearance varies, higher concern for abnormalities in areas of mouth that are higher for oral cancer, which are sides of tongue and under tongue. Leukoplakia (white patch) Erythroplakia (red patch) Eukoplakia-erythroplakia (red and white patch) Oral cancer appearance and location varies. Could be persistent white patch- leukoplakia, especially thick. Persistant red/white patch erythroplakia. Red patch is worst. Look at inside corner of lip and under tongue. Oral precancer look alike that are not cancer Frictional hyperkeratosis -- rough white patch from friction of teeth or oral appliance. Oral yeast infection -- many cheesy, white patches that wipe away, red areas, bad taste or burning. Thermal burn -- painful heals quickly, days -- 1 week White coated tongue -- painless and temporary Cancker sore -- apainful, heals quickly, 2 weeks usually How to make a diagnosis? Biopsy is gold standard. Take sample and send off to lab. Other methods such as swab, light, and autofluorescence light not scientifically backed. Best to do biopsy. Evaluate for biopsy if any abnormality persists beyond 2 weeks. Appreciate the importance of oral cancer screening. Visual exam of oral cavity in asymptomatic people increases survival. Opportunistic screening. Do at every dental appointment. 1\. Know the difference among hypophosphatemia, hypophosphatasemia,\ and hypophosphatasia. Hypophosphat***[emia]*** Low serum phosphate levels^1^ Hypophosphat***[asemia]*** Low serum alkaline phosphatase activity^2^ Hypophosphat***[asia]*** Rare metabolic disease caused by loss-of-function mutations in the gene encoding TNSALP, resulting in persistently low ALP activity^1^ 2\. Understand how low TNSALP activity leads to loss of hydroxyapatite. During normal bone mineralization, TNSALP dephosphorylates PPi on osteoblast membranes, producing Pi. Pi and Ca^2+^ form hydroxyapatite (HA) crystals In HPP, low TNSALP activity leads to extracellular accumulation of PPi. PPi is a potent inhibitor of bone mineralization 3\. Understand tooth loss in hypophosphatasia (HPP). Clinical manifestations of HPP include - Defective mineralization of bone and teeth, leading to effects such as bone deformities, rickets, fractures, bone pain, loss of primary teeth, and overall poor dentition. Multiple systemic effects such as respiratory compromise, seizures, myopathy, and renal complications. HPP is a rare, inherited metabolic disorder caused by inactivating mutations in the ALPL gene encoding TNSALP Presentation and severity of HPP are variable, even among patients who share the same mutation^/^ Patients of all ages may be severely affected by HPP Biochemical hallmark of HPP is low ALP activity. ALP should be evaluated using laboratory-specific reference ranges that are age- and gender-adjusted. Timely and accurate diagnosis of HPP is critical, as misdiagnosis can lead to ineffective management that can potentially worsen HPP 4\. Understand role of inorganic phosphate (Pi) and inorganic\ pyrophosphate (PPi) in mineralization. **Inorganic Phosphate (Pi)**: Promotes mineralization by providing phosphate for the formation of hydroxyapatite crystals \[Ca10(PO4)6(OH)2\]\[Ca₁₀(PO₄)₆(OH)₂\]\[Ca10​(PO4​)6​(OH)2​\]. **Inorganic Pyrophosphate (PPi)**: Inhibits mineralization by preventing hydroxyapatite crystal growth. **Balance**: A precise balance between Pi and PPi is crucial for healthy bone and tooth mineralization. Imbalance (e.g., elevated PPi in HPP) disrupts this process, leading to hypomineralized tissues.