Human Physiology test #3

Clinical Application: Aneurysm

aneurysms are balloonlike swelling in an artery or in a weakened ventricular wall most commonly occurs in the aorta either as a thoracic aortic aneurysm or an abdominal aortic aneurysm can also occur in cerebral and other arteries a dissected aorta is a tear in the wall of tha aortic aneurysm, which often can be detected and corrected before it completely bursts may occur due to congenital defects and atherosclerosis -> hypertension and diabetes can increase the risk

Elvis

elvis was taking barbiturate -> reduce peristalsis in intestine and lowers heart rate • he also had an enlarged heart and colon which months of fecal matter (constipated) •died straining on the toilet doing the valsalva's maneuver -> increased thoracic pressure and stimulation of the parasympathetic nervous system -> decrease in heart rate -> with drugs lead to cardiac arrhythmia and death "died on the throne"

Vital Signs: Why would a middle-aged man faint?

patient came in feeling full in the head, shaking, and blue, he had passed out while watching TV before he fainted he felt his heart race and felt dizzy his S-T segment did not drop but rather stayed high -> Brugada's -> ventricullar fibrillation •hereditary, although most who have it will never know defect traced to a gene that produces a protein component of the Na+ channels in myocardial cells -> ions enter to slow treated with a ventricular defibrillator

Excercise application: Excercise and proper diet

people without risk factors of cardiovascular helath excercise moderately for 150 minutes each week, or engage in vigorous excercise for 75 mintues a week those with risk factors should engage in 40 minutes of moderate excercise 3-4x a week as well as have a diet that encompasses all food groups (low calorie/high nutrient items) to achieve the goal of lowering blood cholesterol, saturated and trans fats should be limited to 5-6% of total calories, compared to 40-50% found in fast food should also eat fish 2x a week -> rich in omega-3(n-3) fatty acids-> protection against heart disease •walnuts, soybeans, and rapeseed oil are also rich in EPA and DHA, the n-3 fatty acids found in fish. no diet can be getting off of bad habits (ex. if you smoke, stop)

Thymus

the thymus extends from below the thyroid in the neck into the thoracic cavity -> grows during childhood and regresses after puberty •lymphocytes from the fetal liver and spleen and from bone marrow postnatally seed the thymus and become transformed into T cells -> proceed to seed lymph nodes and other organs where they produce new T cells when stimulated by antigens -> non stimulated T lymphocytes have long life spans (months to years) -> T cells are continuously produced to provide efficient cell-mediated immunity -> important in cancer chemotherapy and HIV infection when the population of T lymphocytes has been depleted (thymus can replenish T lymphocyte population through late childhood) -> repopulation of T lymphocytes can bee seen in adulthood but much slower and is accomplished by secondary lymphoid organs rather than in the thymus -> due to the thymus becoming more a fatty organ as years go on

Ovulation

under influence of FSH stimulation -> graafian follicle grows forming a blister on the surface of the ovary -> increasing amounts of estradiol secretion -> triggers LH surge (day 13) -> surge causes wall of graafian follicle to rupture about day 14 overcourse of ovulation, a secondary oocyte arrested at metaphase II of meiosis is released from the ovary into the peritoneal cavity -> swept by cilia into uterine tube •lower abdominal pain when follicle ruptures is known as mittelschmerz ovulated oocyte still contains itss zona pellucida and corona radiata ovulation therfore occurs as a sequential effect of FSH and LH on ovaries -> positive feedback effect of estradiol on LH secretion (follicle is what sets the time) -> allows for graafian follicle to not be releaed until proper size and maturity

Dangers of Hypertension "silent killer"

excessive high pressure can lead to vascular damage -> most asymptomatic unless sufficient damage has occurred "silent killer" one problem is the high blood pressure increases the afterload -> more difficult for ventricles to eject blood -> must work harder -> pathological growth of their walls -> can result for hypertension, obesity, or valve defects and can result in arrhythmias and heart failure may also damage cerebral blood vessels -> CVA "stroke" (third leading cause of death in the USA) hypertension also leads to the development of atherosclerosis -> leads to heart disease and CVA

Exchange of Fluid between capillaries and tissues

exists at a dynamic equilibrium with interstitial fluid constantly moving to provide a fresh supply of glucose and waste removal filtration results from blood pressure in capillaries -> this hydrostatic pressure exerted on the inner capillary wall is ~37mmHg at the arteriolar end of system capillareis and drops to ~17mmHg at the venular end •net filtration pressure -> equal to the hydrostatic pressure of the blood in the capillareis minus the hydrostatic pressure of tissue fluid outside the capillaries which opposes filtration -> if equal there is no filtration (0) -> although the net pressure it typically low to allow for exchange •pressure varies from organ to organ -> the pressure falls as blood flows through the capillaries largely due to loss of fluid Glucose and similar size organic molecules as well as salts, and ions are filtered along with water into the capillaries -> plasma and interstitial fluid concentrations of these molecules are the same, however we see almost 4x as much proteins concentration in plasma ( 2g/100mL vs. 8g/100mL) -> caused by restricted filtration by capillary pores •osmotic pressure by plasma proteins "colloid osmotic pressure" caused by colloidal suspension is therefore much greater -> difference between these pressures is known as oncotic pressure "pertaining to swelling" -> although colloid osmotic pressure is also present in interstital fluid it is sufficiently small to be neglected -> therefore the oncotic pressure is equal to the colloid osmotic pressure of the plasma (~25mmHg) -> causes water to favor movement into the capillaries in the absence of other forces •opposing forces are known as starling forces and can be calculated as fluid out - fluid in if the calculation favors fluid out -> forces act to move fluid out of the capillary, the reverse is true for fluid in •see figure for a standard values in arteriole vs. venule •this is a dynamic relationship, think of the sphincters if they shut off sections they increase in net filtration forces -> increase in fluid out through the action of starling forces, plasma and interstitial fluid are continuously interchanged •approx. 85-90% of filtrate is returned directly to the blood •10-15% is returned by blood by the lymphatic system -> about 1-2 L of interstitial fluid per day -> enters lymphatic capillaries -> lymphatic vessels -> venous system

Diaphragm

soft latex cup that lodges in pubic bone and fits over cervix -> must be properly fitted and put in 2 hours before intercourse •must be used with spermicidal jelly or cream and should be left in place for 6 hours after the cervical cap is a mini diaphragm that fits over just the cervix and should also be used with spermicidal cream these barrier methods of birth control also offer some protection against STDs -> other example include male and female condoms

Fertilization, Pregnancy, and Parturition

sperm are stored in the epididymis where they are fully developed yet incapable of fertilization ->kept in a acidic state at a pH of 6.5 •during sexual intercourse, a male ejaculates 300,000 sperm into the vagina -> only 100 will survive to enter each fallopian tube -> only 10% of sperm gain the ability to fertilize an ovum "capacitation" capacitation requires seveal hours in female reproductive tract and a number of chemical changes in the sperm including an increase in pH, Ca++ concentration, and cAMP •swimming ability of sperm is suppressed by low pH until they enter the alkaline female reproductive tract (pH 9) -> together with extrusion of H+ (in exchange for Na+) from the sperm raises the pH of sperm cytoplasm, and the increased pH activates dynein in the flagellum -> dynein proteins are ATPase molecular motors in the flagellum that produce beating movements allowing for movemtn due to action of progesterone flagellar movements increase near oocyte -> progesterone is contained in follicular fluid released with the oocyte by the ovary and is supplemented by additional secretion from the granulosa cells surrounding the ooctyte -> progesteron activates unique Ca++ channels located in flagellum's principal piece using a quick, nongenomic mechanism •opening of these channels known as CatSper (cationic channel of sperm) requires both progesterone and the alkalinization of sperm -> increase in sperm Ca++ that results in hyperactivation -> flagellum beats in higher amplitude, asymmetrical, more whiplike motions to produce more forceful swimming •capacitated sperm are guided by chemotaxis and thermotaxis (attraction warmer temp) higher in the oviduct (only occurs in close proximity to the ovum) a women usually ovulates only one ovum/month for a total of less than 450 ova during her reproductive years ->each ovulation releases by a secondary oocytes arrested at metaphse of second meiotic division -> enters the uterine tube surroundedby its zona pellucida and corona radiata of granulosa cells

Local inflammation

inflammation caused by microbial infection -> stimulates innate, nonspecific immune system due to toll-like pathogen recognition receptors -> macrophages and mast cells residing in tissue release cytokines and chemikines -> attract neutrophils and promote phagocytosis and complement activation -> activated complement further increases innate (nonspecific) responses during an inflammation by attracting new phagocytes and mast cells to the area and stimulating their activity mast cells -> are concentrated in the skin, bronchioles, and intestinal mucosa and contain heparin, an anticoagulant, they also produce histamine, which produces a number of symptoms in allergy as well is a neurotransmitter -> histamine binds to H1 histamine receptors in smooth muscle of bronchioles -> bronchiolar constriction (in asthma) but produces relaxation of the smooth muscles in blood vessels (vasodilation) •in addition histamine, serotonin, and other chemicals are released by mast cells and others during inflammation to cause the endothelial cells of capillaries and postcapillary venules to contract from eachother creating gaps -> increase permeability of capillaries to allow escape of fluid and plasma protein form extracellular space -> localized edma as well as increased extravasation of leukocytes into inflamed area histamine and heparin together with protease enzymes are important in inflammation and are stored in granules within the mast cells -> allergic reaction and other responses to pathogens stimulate degranulation -> release of histamine into extracellular fluid and slowly release the protease enzymes -> with time delay mast cells produce prostaglandins and leukotrienes as well as other pro-inflammatory cytokines (ex. tumor necrosis factor -> recruit neutrophils to infected site) Leukocytes stick to endothelial cells in vessels through adhesion molecules on the two surfaced -> through chemokines undergo chemotaxis to move along cell toward the site of infection leukocytes squeeze between adjacent cells by extravasation "diapedesis" and enter the subendothelial connective tissue most phagocytic leukocytes (neutrophils and monocytes) die in the course of infection, however lymphocytes can travel through the lympathatic system and re-enter cirucation resident macrophages and mast cells in infected tissues are activated by the binding of their pathogen recognition receptors (PRRs) to the PAMPs of invading bacteria -> release chemicals that attract neutrophils to the site of infection -> neutrophils release molecules that recruit monocytes, lymphocytes, and other immune cells neutrophils kill microorganisms through phagocytosis and release enzymes and a variety of antimicrobial peptides -> also release neutrophil extracellular traps composed of extracellular fibers to trap pathogens -> immobolize bacteria and activate blood clotting factor XII the start of intrinsic clotting -> through the action of proteases tissues is liquified -> producing a viscous, protein-rich fluid that together with dead neutrophils forms pus -> produces pressure that closes lymphatic and blood capillaries blocking the spread of bacteria away from the site of battle (hinders antibiotics) •neutrophils also release granule protein -> recognzied by monocytes -> promote recruitment of monocytes to site where they adhere to the ECM (extracelluar matrix) -> release NO -> aiding in destruction of bacteria •to prevent damage to organs, neutrophils must be cleared from the infected site after the pathogens have been destroyed -> doneby reverse migration adn apoptosis of neutrophils with remains removed by macrophages -> macrophages release growth factors and other agents to end inflammation and promote repair after a time time B lymphocytes are stimulated to make antibodies for the invading bacteria -> binding of antibodies amplifies the previously nonspecific response -> occurs by activation of complement -> together with antibodies the complement promotes phagocytic actvity -> the ability of antibodies to promote phagocytosis is called opsonization -> produce the redness and warmth of inflammation by increasing amount of blood due to histamin stimulated vasodilation, we also see edema (swelling), pus, and pain due to prostaglandin E2 and pressure •symptoms were first described by celsius around 40A.D. as "rubor, calor, dolor, and tumor" (redness, heat, pain, and swelling) -> pain threshold is lowered by prostaglandin E2 (PGE2) released as a cytokine during inflammation •note - think of opsonization as the way a cell can hold onto a slippery bacteria through the help of antibodies providing handles •pain can be reduced by aspirin and other NSAIDs(nonsteroidal anti-inflammatory drugs) -> inhibit cyclooxygenase enzymes COX-1 & COX-2 that produce prostaglandins •if infection continues the release endogenous pyrogen from leukocytes and macrophages may also produce fever although helpful inflammation can be destructive to the body -> Alzheimer's disease, multiple sclerosis, atherosclerosis, asthma, rheumatoid, arthritis, system lupus erythematosus, and type 1 diabetes mellitus

Intrinsic regulation of blood flow

"Built-in" mechanisms within individual organs that provide a localized regulation of vascular resistance and blood flow. •autoregulation -> ability of some organs (brain & kidney) to utilize intrinsic control mechanisms to maintain a constant blood flow despite fluctuations •these mechanism are classified as either myogenic or metabolic myogenic control mechanisms •if arterial blood pressure and flow through an organ are inadequate (inadequately "perfused" with blood) -> metabolism of the organ cannot be maintained •high blood pressure can be dangerous especially in the brain -> can lead to a cerebrovascular accident (CVA "stroke) -> autoregulation helps mitigate this •changes iin arterial pressure are compensated for in the brain and other organs by vascular smooth muscle -> decrease in pressure leads to dilation of vessels to maintain adequate flow while the opposite is true during high blood pressure to obtain a finer flow •therefor response that are myogenic -> direct responses of vascular smooth muscle in response to pressure a promotion of intracellular Ca++ induced by an alkalotic state can lead to hyperventilation induction of a coronary vasospasm -> stimulates vascular contractile process leading to coronary vasospasm •Ca++ and H+ ions compete for active transmembrane transport -> if excess H+ are removed during hyperventilation then more Ca++ enters smooth muscle -> elicit vasopastic constriction of a susceptible portion of a coronary artery •treatment for vasospasm includes Ca++ channel blockers that target the dihydropyridine (DHP) channels on the outer membrane of vascular smooth muscles -> other types of Ca++ channel blockers can also be used Metabolic control mechanism •local vasocilation within an organ can occur as a result of the chemical environment created by an organ's metabolism -> localized chemical conditions that promote vasodilation include; •decreased oxygen concentrations -> caused by increased metabolic rate •increased CO2 concentrations •decreased tissue pH (due to CO2, lactic acid and other metabolic prodcuts) •release of K+ and paracrine regulators (adenosine, NO, etc.) from other cells •through these changes the organ signals its blood vessles that it needs increased O2 delivery vasodilation that occurs in response to tissue metabolism can be seen by constricting the blood supply to an area for some time -> metabolic products accumulate -> when constriction is removed metabolic products produce vasodilations -> tissue appears red "reactive hyperemia" •similar response occurs in skeletal muscles and other organs in response to increased metabolism "active hyperemia" -> increased blood flow washes out vasodilator metabolites causing a return to pre-exercise levels

Regulation of Coronary Blood Flow

- *Norepinephrine* from sympathetic nerve fibers (alpha-adrenergic) stimulates *vasoconstriction*, raising vascular resistance *at rest.* - Adrenal *epinephrine *(beta-adrenergic) stimulates *vasodilation* and thus decreases vascular resistance *during exercise.* - Vasodilation is enhanced by intrinsic metabolic control mechanisms - increased *CO2, K+, paracrine regulators (NO, adenosine, and Prostaglandins)* exercise training can result in •increased density of coronary arterioles and capillaries •increased production of NO -> vasodilation •decreases the compression of the coronary vessels in systole -> lower cardiac rate (frequency of systoles)

Pressure changes during the cardiac cycle

120/80 (systole/diastole) -> measured based off of left ventricle events of the cardiac cycle •ventricles begin their contraction -> intraventricular pressure rises -> AV valves close producing S1 ---during this time venticles are neither being filled with blood or ejecting blood (has not reached sufficient pressure to open semilunar valves) -> phase is known as isovolumetric contraction -> characterized by contraction of papillary muscles, pressure in the ventricles higher than atria, closed semilunar valves, and constant volume in ventricles •when pressure of left ventricle becomes greater than pressure in aorta the ejection phase begins as semilunar valves open -> pressure in left ventricle and aorta rise to about 120mmHg -> pressure falls below arterial pressure and semilunar valves close producing S2 ---the pressure in the aorta falls to 80mmHg, while pressure in left ventricle falls to 0mmHg "isovolumetric relaxation -> both AV and semilunar valves are closed -> phase lasts until the pressure in the ventricles falls below the pressure in the atria -> rapid filling of ventricle •atrial contraction (atrial systole) delevers the 20% end of end-diastolic volume -> can now proceed to the next phase of isovolumetric contraction of the ventricles similar events happen in the right ventricle but the pressure is lower (25/8 vs. 120/80) a pulse is felt when the arterial pressure rises from the diastolic to systolic levels and pushes against the examiner's finger Arterial pressure graph •infelction -> dicrotic notch "two beat" and is produced by closing the elastic aortic and pulmonic semilunar vales •the closed semilunar valves are stretched by blood pressure generated by inward recoil of elastic aorta and pulmonary arteries -> slight drop in low blood pressure •elastic semilunar valves then recoil -> quick and slight upsurge in blood pressure in the pulmonary trunk and aorta -> continued inward recoil of pulmonary trunk and aorta also contribute to upsurge closing of these valves produces the second heart sound (S2) and the dicrotic notch during the phase of isovolumetric relaxation at the beginning of diastole an electrocardiogram (ECG) allows you to follow the cardiac cycle of systole and diastole •occurs due to myocardial contraction occurring in response to the depolarization stimulus of an action potential -> relaxation occurs during repolarization

Vital Signs: a women battles with a disease so diverse it avoid diagnosis

28 yrs old -> patches on sides of face and scalp -> bones ache suspected the patient was suffering from system lupus erythematosus a widespread attack on her immune system on her own body •signs of this are diagnosed when antinuclear antibodies that cause an autoimmune response to prescription drugs do not turn up and activation of WBC on the skin's superficial layer in systemic lupus, triggered by environmental viruses that lead to the B cells produce antinuclearantibodies that attack healthy cells and vital organs, especially the brain and kidneys varied symptoms include arthritis, facial rash, hairloss, kidney damage, lung inflammation, and paralysis -> mimics diseases such as MS, scleroderma, and rheumatoid arthritis •due to diversity a patient must show at least 4/11 symptoms since onset of disease -> she met this and had the characteristic "butterfly" mark on her face, eroded red patches of skin in other areas, pain in the joints, and a postive ANA test -> like 90% of lupis patients she was female and had developed the disease in child-bearing years treatment options are limited -> cortisone and antimalarial drugs combat inflammation by impeding immune-cell responses, and chemotherapy drugs like methotrexate and cyclophosphamide can curb attacking WBCs, and writtenexumabob -> kills B cells two cancer-related drugs have been used as well, mycophenolate mofetil that interferes with WBCs metabolism and rituximab an antibody that kills B cells -> side effects such as cortisone thinning bones mycophenolate causes anemia, and methotrexate can irritate the liver to suppress the immunologic skin flare ups she was given a topical corticosteroids as well as steroids injected into lesions -> also given oral steroids

Clinical Application: Acquired immune Deficiency Syndrome (AIDS)

AIDS is caused by human immunodeficiency virus "HIV" -> infects and destroys helper T cells, particularly in gastro intestinal mucosa where up to 30% of helper T cells reside -> leads to decreased immunological protection and greater susceptibility to opportunistic infections and cancer HIV is a retrovirus due to its genetic code being carried on its RNA -> the enzyme reverse transcriptase is needed to transcribe this viral RNA into DNA for replication antiretroviral therapy (ART) involves drugs that inhbit this enzyme -> two different Reverse transcriptase (RT) inhibitors have been combined with an inhibitor protease (needed to make virus coat) cna be used to suppres HIV replication indefinitely -> effective treatment -> not a cure -> when you stop taking the medication the virus reappears due to being part of your genome early and continual treatment and reduce the chance of spreading the disease by 96% •vaginal gels with antiretroviral drugs reduce transmission •circumcision reduces risk •methods to stimlulat passive immunity show promise either by injecting neutralizing antibodies or by injecting genes for these antibodies within a virus vector that is injected into skeletal muscle •possible vaccines for stimulating active immunity against HIV are in development -> tricky due to crucial epitopes of the virus being hidden within the virus as well as high mutation rate of the HIV antigens -> however contant epitopes offer some hope

conducting tissues of the heart

Action potentials originate from SA node spread through gap junctions -> fibrous skeleton prevents spreading signal to ventricle -> specialized conducting tissue composed of modified myocardial cells (AV node, bundle of His, and Purkinje fibers) action potentials that have spread from the SA node through the atria pass into the atrioventricular node (AV node) located on the inferior portion of the interatrial septum ->action potentials continue through the atrioventricular bundle "bundle of His" where the signal is delayed -> conducting tissue pierces the fibrous skeleton -> descends along the interventricular septum -> splits into right and left bundle branches, continuous with Purkinje fibers within ventricular walls -> within the myocardium of ventricles the action potential spreads form the endocardium to the epicardium side -> ventricles contract, ejecting blood into the pulmonary and systemic circulations

Regulation by aldosterone

Aldosterone, a steroid hormone secreted by the adrenal cortex stimulates the reabsorption of salt by the kidneys "salt-retaining hormone" -> promotes retention of water indirectly •produces in increase in blood volume, however unlike ADH it does not change plasma osmolality -> done by reabsorption of salt and water in proportionate amount, where ADH only stimulates reabsorption of water secretion of aldosterone is stimulated during salt deprivation when blood volume and pressure are reduced -> adrenal cortex is not directly stimulated to secrete aldosterone but rather is stimulated by an intermediate mechanism in response to decrease in blood volume and pressure -> renin-Angiotensin-Aldosterone system Renin-Angiotensin-Aldosteron system •salt deprivation results in low blood volume and pressure -> low pressure in renal artery reduces amount of NaCl and water in renal filtrate -> juxtaglomerular apparatus in kidneys senses this change -> secretes the enzyme renin into the blood •Renin in blood cleaves a ten AA polypeptide called angiotensin I from the plasma protein angiotensinogen -> angiotensin I passes through capillaries into the lungs where an angiotensin-converting enzyme (ACE) removes two AAs -> leaving the 8 AA polypeptide angiotensin II salt deprivation, low blood volume/pressure -> increase production of angiotensin II •high blood pressure -> reduced production of angiotensin II angiotensin II leads to an increase in blood pressure -> stimulates contraction of smooth muscle layers of the small arteries and arterioles -> powerful vasoconstrictor resulting in an increase in total peripheral resistance •also promotees a rise in blood volume -> done so by stimulate the thirst center in hypothalamus and the adrenal cortex to secrete aldosterone from the zona glomerulosa of the adrenal cortex the relationship between the kidneys, angiotensin II, and aldosterone is called the renin-angiotensin-aldosterone system -> as a result of thirst and activation of this system -> we drink more, retain more NaCl and urinate less -> increase in blood volume and pressure -> increased secretion by juxtaglomerular apparatus of the kidneys a high salt intake -> raise blood volume and pressure -> inhibits Renin secretion -> less angiotensin II formation -> less aldosterone secretion •many people with high blood pressure may have normal or even elevated levels of renin secretion -> must reduce salt intake

opsonization

An immune response in which the binding of antibodies to the surface of a microbe facilitates phagocytosis of the the microbe by a macrophage

Clinical Application: Angiotensin converting enzyme inhibitors (ACE inhibitors)

Angiotensin converting enzyme inhibitors (ACE inhibitors) are drugs that prevent the conversion of angiotensin I to angiotensin II -> reducing the ability angiotensin II to stimulate vasoconstriction -> promotes vasodilation •captopril, enalapril, and lisinopril all ACE inhibitors help treate hypertension, heart failure, stroke, and potential kidney failure angiotensin receptor blockers (ARBs) -> inhibit the binding of angiotensin II to its receptors on vascular smooth muscles -> reduce vasoconstriction -> produce vasodilation •telmisartan, losartan, and valsartan

Dissolution of clots

As a damaged blood vessel is repaired, activated factor XII promotes conversion of inactive molecule in plasma to active form "Kallikrein" •Kallikrein -> conversion of inactive plasminogen into active molecule plasmin (inactive plasminogen can't cleave fibrin, but does have an affinity for it -> incorporated into clot when formed) -> active plasmin can breakdown clots Plasmin is an enzyme -> digests fibrin -> dissolution of the clot •in addition to kallikrein, tissue plasminogen activator (TPA), urokinase, and streptokinase ( bacterial enzyme) all can convert plasminogen to active plasmin •most common pathway is TPA (used after a MI to help prevent tissue damage) TPA is released into blood very slowly by the damaged endothelium of blood vessels -> several days after clot has formed it breaks down (this can be incorporated synthetically) •occurs as plasminogen becomes trapped within clot during its formation -> slowly activates and breaks down fibrin mesh

Inflammation and Atherosclerosis

Atherosclerosis is believed to be an inflammatory disease -> evidence due to measurement of blood C-reactive protein, a marker for inflammation -> a stronger predictor of atherosclerotic heart disease than the blood LDL cholesterol level inflammatory process is instigated by oxidative damage to the artery wall when endothelial cells engulf LDL -> oxidize it to oxidized LDL -> evidence of contribution to endothelial cell injury and spurring migration of monocytes and lymphocytes into the tunica intima antioxidant compounds are important in hindering the progression of atherosclerosis •probucol (drug), Vitamin C, Vitamin E, and veta-carotene, all antioxidants have decreased the formation of oxidized LDL in vitro but have limited success in curing atherosclerosis -> not a cure, but a preventative measure (start early)

Fitness application: A-fib

Atrial fibrillation -> atria fail to contract blood that fills the ventricles and what the ventricles eject can often by sufficient to allow a person to live without obvious symptoms -> will experience fatigue and difficulty exercising due to inability to sufficiently increase cardiac output pooling of blood in atra can increase chance of clot formation by 5x -> high chance of stroke -> need to take anticoagulants such as aspirin, warfaring, and rivaroxaban (inhibits factor X activity)

Blood vessels

Blood leaving the heart passes through vessels that gradually get smaller Arteries -> arterioles -> capillaries -> venules -> veins , blood entering heart goes through vessels that gradually get bigger walls of arteries and veins are composed of three coats or "tunics" •Tunica externa -> outermost layer •Tunica Media •Tunica intima/interna -> inner layer the tunica externa is composed of connective tissue, while the tunica media is composed of smooth muscle the Tunica interna consists of three parts •the innermost simple squamous epithelium, the endothelium, which lines with lumina of all blood vessels and is continuous with inner lining of the heart •the basement membrane -> a layer of glycoproteins-> overlies some connective tissue fibers •a layer of elastic fibers, or elastin, forming an internal elastic lamina differences between arteries and veins •arteris have more muscle for their diameters (tunica media) -> bigger •as a results arteries appear more rounded in cross sections while veins appear partially collapsed •veins have many valves, while arteries do not

Vital Signs: No surrender

Cardiac arrest -> heart stopped -> most often caused by ventricullar fibrillation -> irregular electrical misfiring setting off the heart's carefully synchronized rhythm off-kilter •can be caused by a heart attack, K+ imbalance, scarred heart muscle, etc. whatever the cause a heart in V-fib no longer pumps blood -> unless rhythm is restored within four minutes by shocking the heart and reimposing normal electrical activity, the brain will begin to die -> CPR can hold off death for a few minutes (in busy cities only 15-35% of people will live, with only 5% in New York) in the story the lady survived, but her V-fib was likely related to scarring and artificial heart valves -> Endocarditis addicts who use drugs have a high rate of getting endocarditis (infections of the heart valves) •she had developed rheumatic fever as an infant a few years before penicillin could have cleared the infection with ease -> her own antibodies attacked the proteins of the heart tissue although the heart usually heals following the infection the valves do not, and with repeated infections this can build up scar tissue and encrusted choke points -> damage is most common in the Mitral valve in the left ventricle her K+ were very low -> likely cause of the V-fib in the first place -> She (Diane) stopped moving -> possible clot?? -> ran an CT -> no hemorrhage or clot -> fluid build up in brain had temporarily stunned it -> problems persisted through the night until she eventually passed away

Blood Flow to the Brain and Skin

Cerebral: regulated by intrinsic mechanisms, relatively constant, and is least tolerant of low rates of blood flow. Skin (cutaneous): Extrinsic mechanisms, more variation than in any other organ, most tolerant to low rates of blood flow

Vital Signs: a twitch of the heart

Denise age 31 was haviing heart pains -> angina? a condition of a heart starved for oxygen due to narrowed arteries -> patients typically clench their fist against their chest •pains were not regular like typical angina, but rather were periodic and random •Denis was overweight Coronary artery disease (CAD)? -> typically over 50 years old -> seen in diabetics, and those with kidney failure as well as genetic metabolic disorders •she did smoke a half pack a day put her on a cardiac stress test •at stage 2 the increase of speed lead to a plummeting of her heart rate from 80 to 40 -> she had entered distress -> severe bradycardia -> went unresponsive w/ no palpable pulse -> urinated -> convulsion her heart rate quickly began to recover -> went to the hospital where an angiogram was performed -> no obstruction was found Prinzmetal's -> variant angina -> although not well-studied smoking is a provoker -> given a Ca++ channel blocker (group 4) -> this angina develops due to temporary spasm of coronary arteries during hyperventilation

Clinical Application: Digitalis

Digitalis, or digoxin (Lanoxin) •from foxglove plant -> cardiac glycoside drug used to treat those with congestive heart failure or A-fib -> inactivates the Na+/K+ ATPase pumps in the myocardial cell plasma membrane -> interferes with ability to pump Na+ out of the cell this leads to an increase of Na+ in the cell -> increase activity of Na+/Ca++ exchange pump in plasma membrane -> more Na+ goes out with more Ca++ entering -> increase in intracellular Ca++ concentration and stored concentration in sarcoplasmic reticulum -> increased contractility of myocardium -> helps treat congestive heart failure and slows conduction of the impulses through the AV node to treat A-fib

Vital Sign: Night of broken hearts

Elaine, 41, had extreme abdominal pain -> drenched in sweat, could not speak with pain -> blood pressure was normal -> fast pulse at 140 beats/min -> gall bladder stone? •not likely do to having pain all over the abdominal region and not only in the region of the gall bladder hand over the chest is known as Levine's sign named after the cardiologist Samuel Levine -> suggests chest pain •pain of a heart attack can mimick someone who is in need of abdominal surgery husband cheated on her -> thinking of divorce her heat was moving abnormally -> left ventricle pumping in a balloon pattern "takotsubo cardiomyopathy (broken heart syndrome)" -> stress induced heart failure -> extreme emotional stress can change the way the heart pumps -> possibly due to adrenaline caused by emotion

Fever

Fever is a component of the nonspecific defense mechanism -> body temp is regulated by the hypothalamus which contains a thermoregulatory control center -> coordinates shivering and activity of the sympathoadrenal system to maintain body temp at 37˚C thermostat is reset upward by endogenous pyrogen -> in some infections this pyrogen is interluekin-1ß -> leads to increased heat production by brown adipose tissue and decreased heat loss by vessel vasoconstriction •therefor fever is caused by the body in response to infection, not by the infection itself endotoxins from the LPS of gram negative cells stimulates monocytes and macrophages to release various cytokines -> cytokines include interleukin-1, interleukin-6, and tumor necrosis factor -> act to produce fever, increase sleepiness, and a fall in plasma iron concentration a fall in plasma iron concentrations that accompany fever inhibit bacterial activity (benefit of fever) -> other benfits of fever include increased activity of neutrophiles and increased production of interferon

Clinical Application: Filariasis

Filariasis is a tropical disease caused by a parasitic nematode worm in elephantiasis these worms take up residence in the lymphatic system where their larvae blcok the lymphatic drainage -> Edema -> swelling and thickening/cracking of skin can be treated by drug therapy that targets the filariasis parasite -> one a novel prize in physiology -> has successfully treated millions and will likely eradicate the disease

effect of pheromones, stress, and body fat

GnRH stimulates anterior pituitary -> FSH, LH, and GnRH releasing neurons -> master regulators of reproductive system •release of GnRH is regulated by feedback effects of ovarian hormones and higher brain centers •because of GnRH neurons input in olfactory system pheromonees can cause menstrual cycles to synchronize "dormitory effect" -> in specific the nasal mucosa region "vomeronasal organ or VNO" limibic system of brain includes regions involved in emotion -> axons extend from limibc system to GnRH neurons of hypothalamus -> secretion of GnRH in response to emotions such as stress -> therefore stress can cause a cessation of menstruation, or amenorrhea girls who are thin have delayed menarche, and women with low body fat have irregular cycles or amenorrhea •Hypothalamic/functional amenorrhea is the cessation of menstruation caused by inadequate release of GnRH from hypothalamus -> seen in women who are thin or stressed •intense exercise can suppress GhRH •Leptin, secreted by adipocytes regulates hunger and metabolism and indirectly affect the GnRH-secreting neurons of the hypothalamus -> due to this a sufficient amount of adipose tissues and leptin secretion is required for ovulation and reproduction -> inadequate adiposity and leptin secretion can produce functional amenorrhea

Vital Signs: A longed pregnancy threatens a woman's life

Janetha Richards -> finally got pregnant after trying for months -> also got a chlamydial infection from a cheating boyfriend -> she had worsening cramps over the last three weeks -> started to have pelvic pain -> loss consciousness -> pulse was racing and had 70/40 blood pressure -> pain in abdomen due to peritoneal lining pain -> ruptured ectopic pregnancy? ->occur when fertilized egg implants outside the lining of the womb, usually in the fallopian tube -> caused by endometriosis or infections like chlamydia/gonorrhea -> tubal wall is not elastic -> bursts after 6-10 weeks •can be diagnosed earlier by spotting or pain and pelvic pain -> if ultrasound isn't clear then you can measure pregnancy hormone levels due to them not rising to normal levels allowing for diagnoses in the first 8 weeks -> early pregnancy is terminated using methotrexate a chemotherapy drug highly toxic to fetal tissue, or a laparoscopy in equivocal cases to open the fallopian tube she was further along and required a culdocentesis to measure blood pooled in pelvis -> opened her up and found tons of clots -> her egg had almost reached the interior of the uterus but instead had implanted in the muscular wall -> destroyed muscle tissue -> damaging uterine artery -> cut out torn muscle and embryonic tissue/placenta and sewed it all back up -> surgery sealed that side of the fallopian tube and the side was scarred shut due to chlamydial infection -> she can no longer conceive •given nafarelin (synarel) -> downregulation of GnRH receptors -> decrease in FSH and LH •chlamydia when in relation to bilateral scarring results in infertility which is what happened here along with narrowing

Lymphocytes and Lymphoid organs

Leukocytes, erythrocytes, and blood platelets are all ultimately derived from unspecialized cells in the bone marrow •stem cells produce specialized blood cells and replace themselves by cell division -> lymphocytes produced seed in thymus, spleen, and lymph nodes to produce self-replacing lymphocyte colonies in these organs lymphocytes that seed the thymus become T lymphocytes, "T cells" (T = thymus dependent) lymphocytes that are not T lymphocytes are called B lymphocytes "B cells" (bursa-equivalent cells) named after the bursa of fabricius organ in chicken that produces B cells -> these cells are processed in the bone marrow •together the bone marrow and thymus are considered the primary lymphoid organs both B and T lymphocytes function in specific immunity • B lymphocytes -> secrete antibodies into blood and lymph which are both humor fluids -> humoral immunity "antibody-mediated immunity" •T lymphocytes -> directly attack host cells that have become infected with viruses or fungi, transplanted cells, and cancerous cells -> makes physical contact with target cells and destroys it -> cell-mediated immunity "CMI" see chart -> failure in one side of immunity causes you to produce those disease that are associated

Vital Signs: A stress case or a serious disease?

Mary, had neurodermatitis (scratched at skin until it blead) recently got buises all over and itching... -> stress??? also had petechiae -> can be caused by thrombocytopenia also had purpura -> small purple bruises on her arms and legs she was diagnosed with iodipathic thrombocytopenic purpura (ITP) -> those affected that have platelet counts below 30,000 can have bleeding from nostrils, gums, and into urine/stools• if beneath 10,000 -> hematomas, and possibly brain hemorrhages, gastrointestinal bleeding and other internal bleeding•if beneather 1,000 -> medical emergency treatment -> removal of spleen -> increase of platelet levels to normal amounts

Clinical application: Polycysic ovarian syndrome (PCOS)

PCOS is a common endocrine disorder in women during reproductive years -> genetic disorder -> ovaries contain follicles that become fluid filled cysts visible to ultrasound -> amenorrhea, dysmenorrhea (painful menstruation), reduced fertility, excessive growth of body hair, male pattern baldness, and acne ovaries secrete an excessive amount of androgens that produce some of these smptoms -> elevated secretion of insulin from the pancreatic islets coupled with an increased insulin resistance -> increased danger of developing type II diabetes and metabolic syndrome sustained weight loss can improve ovarian function and fertility, lower androgen levels, and improve cardiovascular risk

Parasympathetic control of blood flow

Parasympathetic endings in arterioles are always cholinergic and always promote vasodilation, but it is limited to digestive tract, external genitalia and salivary glands. -> due to this the parasympathetic system is less important than the sympathetic system in the control of total peripheral resistance

Clinical Application: Preeclampsia

Preeclampsia formally known as toxemia or pregnancy occurs in 8% of women who are pregnant beyond their 20th weeks -> onset of hypertension differs from gestational hypetension by evidence of damage to organs such as the liver and kidneys thrombocytopenia may occur and abnormally large amount of protein in the urine (proteinuria) may be present -> indicates damage to kidney's filtering units (glomeruli) into the urine -> lowers oncotic pressure -> edemia and swelling of feet, legs, or hands preeclampsia although not fully understood is believed to be caused by a dysfunction of the placenta with increased risk in those that are obese -> if severe it can lead to seizures and CVA -> only cure is delivery of baby

Vital Signs: Under Pressure

Scott -> chest and abdominal pain, as well as being pale and sweaty -> high blood pressure but otherwise was healthy -> had an upset stomach and pain in the upper part of his abdomen -> gallstones? -> upon probing he observed the aorta undergo acute aortic dissection in aortic dissection the flap is the innermost of the aorta's three layers -> due to high blood pressure, atherosclerosis, or genetics causes the tearing of this flap from the outer portion -> createa a high pressure flow between the layers -> loosens them and eventually splits the aorta along the path that can trael from the aortic valve through the chest and abdomen very rare, and deadly -> often missed jonathan larson -> complaints of severe chest pain and shortness of breath -> written off twice as food poisioning or viral syndrome -> died soon after where they then saw the aortic dissection mortality rate increases by 1% every hour that passes upon inital tearing surgeons replaced most of his ascending aorta and arch with a synthetic graft due to the unusable nature of scott's valve

Vital signs: a past infection haunts a women's health

Sela Miller -> milky urine sample -> full of microorganisms and WBCs and RBCs -> given an antibiotic urine culture grew typical E. coli strain -> ideal situation for the prescription of the antibiotic -> ran additional samples just in case -> urine was loaded with fat "chyluria -> caused by a fistula or microscopic leak between lymphatic vessels and the kidney -> cause? -> a nematode wuchereria bancrofti -> transmitted by tropical mosquitos -> adults worms of these nematodes are famous for blocking lymphatic vessles patients can develop elephantiasis -> swollen limbs and genitalia -> she had grown up in the S. pacific before moving to the US -> she was given an anti-parasite drug "diethylcarbamazine" -> symptoms resolved within a few weeks

Clinical Application: Sepsis

Sepsis is a complication of infction involving whole-body inflammation, multi organ failure, and shock and is involved in 1/3 of all hospital deaths symptoms include high fever, rapid pulse and repiratory rate, hypotension, hypoxemia, and oliguria (low urine) and acidosis due to lactic acid sepsis is triggerd by bacterial infection and is treated with antibiotics, IV fluids, and more aggressive measures when needed the danger is septic shock when blood pressure is so low that organs are not adequately perfused Endotoxin "LPS" is a component of several bacteria (gram negative) and is a instigator for sepsis -> in localalized infection LPS triggers innate immunity through toll-like receptors •in massive amounts of LPS -> enters circulation -> widespread release of inflammatory cytokines -> development of drugs to block these effects of LPS and other gram-negative molecules with similar responses

Clinical Application: Statins

Statins are drugs to help lower LDL-cholesterol concentration -> reduce risk of atherosclerosis statins are inhibitors of HMG-coenzyme A reductase -> an enzyme that catalyzes the rate-limiting step in cholesterol synthesis -> through inhibition reduces the ability of liver cells to produce cholesterol -> low cholesterol concentration stimulates the production of more LDL receptors in plasma membranes of liver cells -> lower blood LDL-cholesterol Statins are also linked to increasing HDL levels and reducing inflammation

Vital Signs: Low Note

Sydney -> recently had began to have facial hair and had a deeper voice and acne and hadn't had a period in months higher insulin and testosterone than normal -> Polycystic ovarian syndrome (PCOS)? -> causes hormonal imbalances leading to enlarged dysfunctional ovaries -> irregular menstruation, infertility, and excess body hair and acne -> treatment requires a diet change and metformin drug -> helps correct bodies insulin levels •prescribed this and saw an opposite effect she was now hairier, more hair, and no periods at all ran another blood test -> testosterone levels were sky high, higher than a patient with PCOS and 4x higher than in a man -> ran a CT -> she had a tumor on her left ovary -> upon removal found a tumor of cells normally found in sertoli cells and leydig cells

Functions of T lymphocytes

T lymphocytes "thymus dependent lymphocytes -> processed to have by thymus to have unique functions -> provide specific immune protection without secreting antibodies, accomplished by three subpopulations of T lymphocytes •Cytotoxic •helper •regulatory T lymphocytes

Capillaries

The arterial system branches extensively to deliver blood to over 40 billion capillaries -> amount of blood flowing through a capillary bed depends on resistance to blood flow in the small arteries and arterioles •vasoconstriction -> decrease blood flow to capillary bed while vasodilation increases blood flow •in some blood flow may also be regulated by circular muscular bands called precapillary sphincters at the origin of the capillaries -> cuts down blood flow to the regions connected -> does not cut it off completely unlike vessels of the arterial and venous systems, capillaries are composed of just one cell layer, a simple squamous epithelium, or endothelium •absence of smooth muscle and connective tissues permits a more rapid exchange between the blood and tissues

Regulation of blood volume by the Kidneys

The formation of urine begins with filtration of fluid through capillaries in the kidneys called glomeruli. *180 L of filtrate is moved across the glomeruli per day*, yet only about *1.5 L is actually removed as urine*. The *rest is reabsorbed into the blood (99%, therefore 1% is removed as urine -> if you alter the reabsorption to 98% you just doubled your urinary output to 2% -> how hormones control output)*. The amount of fluid reabsorbed is controlled by several hormones and the sympathetic nervous system in response to the body's needs. thes sympathetic nervous system is involved in the homeostasis of blood volume -> increase in blood volume -> detected by atria stretch receptors -> increases receptor activity -> sympathetic activity to kidnesy is reduced -> vasodilation of renal arteries -> increased urine production -> lowered blood volume

Intrinsic Control of Contraction Strength

The intrinsic control of contraction strength and stroke volume is due to variations of how much the myocardium is stretched during end-diastolic volume -> increase in EDV -> increase in stretched myocardium -> more forceful contraction •prior to filling the heart the sarcomere lengths in myocardial cells are 1.5 µm -> weak contraction -> the more stretched the heart is the more overlap of actin and myosin giving more force to be developed •stretching during diastole increases sensitivity to Ca++ release channels (ryanodine receptors RyR2 type) in the sarcoplasmic reticulum (SR) promoting their release of Ca++ from stimulation -> greater release of Ca++ -> stronger contraction Frank-starling mechanism results in an initial rapid increase in contractility when ventricles are stretched -> force of myocardial contraction gradually increases over the next 10-15 minutes (anrep effect) -> due to increased Ca++ entering the cytoplasm through the Na+/Ca++ exchanger therefore the degree of myocardial stretching depends on the end-diastolic volume and the 3 mechanisms that ensure an increase in EDV -> intrinsically producing and increasing the contraction strength and stroke volume 1. Frank-Starling mechanism 2. increased sensitivity to RyR2 3. Anrep effect note - these mechanisms occur on both ventricles

Clinical Application: Thrombolytic Agents

Thrombolytic drugs -> protease enzymes that convert plasminogen to plasmin -> promotes clot dissolution of blood clots recombinant DNA tech has allowed synthetic production of plasminogen activator (t-PA, or alteplase as well as r-PA, or reteplase) products derived from streptococcus bacteria urokinase and streptokinase -> produce plasmin ->dissolution of clots these treatments are important in conditions such as deep vein thrombosis, stroke, coronary thrombosis and pulmonary embolism note - must be used carefully to prevent risk of hemorrhage

Regulatory "supressor" T lymphocytes

Treg lymphocytes provide a "brake on specific immune responses -> inhibit activity of cytotoxic T lymphocytes and B lymphocytes -> those with a deficiency of these cells have severe autoimmune disease and allergy •these cells can be distinguished due to FOXP3 -> codes for a transcription factor required for the development and maintenance of regulator T lymphocytes mechanisms for how they suppress immune responses are not fully understood -> requires close proximity -> release of cytokines including interluekin-10 and TGFß (a transforming growth factor) -> immune suppression •often promote destruction of their target cells by releasing granzymes and perforins much like cytotoxic T cells •due to suppression when they fail or don't function properly we see allergies and autoimmune disease -> seen in mutations in FOXP3 gene resulting in autoimmune diseases

Vital Signs: Aretha Franklin Test

Tumor in young women's chest (mrs. henley) she had come into the hospital after she had a collapsed lung and fluid in cavity -> mass at the bottom of the lung, although cancer alone won't collapse a lung lab results -> mix of strange glands and blood in lung cavity -> caused by adenocarcinoma a glandular cancer in determining if it was malignant or not they looked at the nucleus of the cells -> in malignant cells the rapid growth causes distorted nuclei, however as long as they don't impact surround cells they can be considered benign -> her cells were orderly and benign what about the glands in the sample -> the surface of the lungs contain glands that secrete fluid to prevent the lungs from drying out -> should not be seen outside of the lungs stromal cells -> support cells of many organs such as endometriosis endometriosis -> thin coating of gland and stromal cells that lines the uterus -> can migrate but will still response to hormonal cycles •the start of the cycle signaled to the endometrial lining to decay and sluff off -> damged surrounding tissue which in this case was the lung -> her pain only went away when she was pregnant there is no cure for endometriosis

Frank-Starling Law of the Heart

Two physiologists Otto Frank & Ernest Starling -> demonstrated that the strength of ventricular contraction varies directly with the end-diastolic volume even in hearts separated from nerves and increase in EDV results in increased contraction strength -> increased stroke volume the relationship between EDV, contraction strength, and stroke volume is a built-in "intrinsic" property of heart muscle and is known as the Frank-Starling Law explains how the heart can adjust to a rise in total peripheral distance -> rise in peripheral resistance -> decrease in stroke volume of ventricle -> more blood remains in the ventricle -> more stretching of EDV the following cycle -> stronger contraction (ex. jumping into a freezing lake after sitting in a hot tub) •this mechanism allows for the left ventricle to match the output of the right ventricle due to the need to be equal to prevent fluid accumulation

Clinical Application: Vericose Veins

Varicose veins are enlarged surface veins -> generally in lower limbs -> occur when venous congestion stretches the veins to the point that enous valves no longer close effectively Genetic susceptibility, as well as occupations that require standing for long periods of time, obesity, age, and preganancy are all risk factors -> walking helps treat this and relieve some issues surgical treatment -> Sclerotherapy -> chemicals are injected into the veins to scar them, while laser therapy, ligation, and stripping are other techniques inadequate venous flow -> deep vein thrombis risk -> venous thromboembolism (travelling blood clot) -> walking as soon as possible after surgery helps prevent this as well as compression stockings anticoagulant drugs or thrombolytic agents may be necessary to prevent or treat thromboembolisms to prevent pulmonary embolisms

Blood Volume

a person weight 70kg (154 lb) has an average blood volume of 5.5 L •blood volume is one part of the total body water •2/3 of total body water is within the cells in the intracellular compartment •remaining 1/3 is in extracellular compartments -> 80% of this is in tissues as interstitial fluid, the remaining 20% is plasma distribution of water between interstitial fluid and blood plasma is determined by opposing forces acting on capillaries -> blood pressure promotes formation of interstitial fluid from plasma, while osmotic forces draw water from the tissues into the plasma -> mechanism that affect drinking, urine volume, and distribution of water between plasma and interstitial fluid thus help to regulate blood flow volume -> regulate cardiac output and blood flow

Pulse pressure and mean arterial pressure

a pulse is the feeling of the expansion of the artery caused by beating of the heart -> measure of cardiac rate -> caused by expulsion of left ventricle into systemic circulation •pulse is produced by the rise in pressure from diastolic to systolic levels -> difference is known as pulse pressure -> a person with 120/80 mmHg would have a pulse pressure of 40 mmHg (pulse pressure = systolic pressure - diastolic pressure) the mean arterial pressure represents the average arterial pressure during the cardiac cycle

Ischemic Heart Disease

a tissue is said to ischemic when its oxygen supply is deficient due to inadequate blood flow, most commonly from atherosclerosis of coronary arteries, which is also the most common cause of myocardial ischedmia •adequacy of blood flow is relative -> a obstruction in a coronary artery may be sufficient to allow blood flow during rest but not when stressed •in these cases the increased activity of sympathadrenal system causes the heart rate and blood pressure to rise, increasing the work of the heart -> raising oxygen requirements mental stress can cause constriction of atherosclerotic coronary arteries -> leads to ischemia of the heart muscle myocardial ischemia is also associated with increased concentration of blood lactic acid produced by anaerobic metabolism in the ischemic tissue -> causes substernal (chest) pain "angina pectoris" and may also lead to referred pain to the left should and arm as well as other areas such as the jaw -> those impacted take nitroglycerin to relieve ischemia and pain -> produce vasodilation -> decreases workload on heart myocardial cells are adapted for aerobic respiration and cannot metabolize anaerobically for more than a few minutes -> if ischemia and anaerobic metabolism is prolonged, necrosis will occur in areas deprived of O2 -> called an myocardial infarction "MI" -> leading cause of death in the western world -> called a "heart attack" although that is a broad term •area of dead cells cannot be replaced due to myocardial cells limited division ability -> rather they produce non contractile scar tissue -> can lead to congestive heart failure over time •the reperfusion injury can be a greater threat than the initial event caused by apoptosis -> accumulation of Ca++ and production of superoxide radicals by mitochondria -> increase infarct and weaken the wall of the ventricle the infarct may cause the ventriclar wall to thin and distend under pressure •stem cell therapies -> from bone marrow can possibly differentiate into myocardial cells (other options include fibroblasts, and pluripotent stem cells) •another approach is to stimlulate myocardial divison -> has been done in rodents but more research needs to be done in humans acute chest pain caused by myocardial ischemia is a common reason people seek aid •myocardial ischemia can be detected by changes, either elevation or depression in the S-T segment of the electrocardiogram -> sustained blockage of a coronary artery that produces a myocardial infarction (MI) is accompanied by an elevation of the S-T segment diagnosis of an MI is based mainly on rising blood troponin levels, primarily troponin I, as well as the enzyme creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)

Arrhythmias

abnormal heart rhythms, can be detected by abnormal ECG tracing they produce cardiac rate below 60 beats -> Bradycardia cardiac rate above 100 beats -> tachycardia •both can occur naturally -> athlete's bradycardia result from higher levels of parasympathetic inhibition of the SA node and is beneficial abnormal tachycardia occurs if the heart rate icnreases when the person is at rest •may be due to abnormal fast pacing of atria, caused by drugs, or the development of abnormally fast ectopic pacemakers -> cells located outside of SA node that assume pacemaker function -> abnormal atrial tachycardia differs from normal sinus, (SA node) tachycardia •ventricular tachycardia -> result of fast ectopic pacemakers in the ventricles -> beat independently of the atria -> can quickly lead to ventricular fibrillation -> deadly

Heart Murmurs

abnormal heart sounds produced by abnormal patterns of blood flow in the heart •can be caused by defective heart valves -> aortic valve stenosis (narrowing) -> due to Ca++ deposits on aortic side of the valve -> produces a mid-systolic heart murmur •defective heart valves may be congenital, or as a result of rheumatic endocarditis, caused by rheumatic fever -> damaged is caused by antibodies produces by streptococcus bacteria -> Rheumatic fever is an autoimmune disease where a cross-reaction with heart tissue occurs leading to damaged valves and heart murmurs •can also be caused by small defects that produce detectable murmurs but not serious enough to compromise the ability of the heart -> large issues may require surgery in mitral stenosis -> thickening and Ca++ deposits -> impairs blood flow from left atrium to left ventricle -> causes a backup/traffic jam -> increase atrial pressure and pulmonary vein pressure results in pulmonary hypertension -> leads to right ventricle growth (bad) mitral valve prolapse (in 2.5% of people) -> most common cause of chronic mitral regurgitation where the blood flows back into left atrium •congenital and acquired forms -> in younger people it is usually caused by excess valve leaflet material •most don't have symptoms -> but the disease can progress leading to lengthening and rupturing of the chordae tendineae -> need for repair or replacement of mitral valve with a mechanical or biological (pig or cow) valve Murmurs can also be produced by flow of blood through septal defects -> holes in the septum between the right and left sides (very bad with clots due to ability to travel everywhere) •due to high pressure from left side, blood will travel from left side to right when no other defects are present -> buildup of tension on right side may lead to pulmonary hypertension and edema in the lungs

Clinical Application: Arrhythmias

abnormal patterns of electrical activity that result in abnormalities of the heart beat drugs used to treat this affect the nature and conduction of cardiac action potentials and classified into 4 groups •group 1 drugs -> block the fast Na+ channels (quinidine, procainamide, lidocaine) •Group 2 drugs -> beta-blockers -> interfere with catecholamines to stimulate beta-adrenergic receptors (propranolol, atenolol) •Group 3 drugs -> block the K+ channel (amiodarone) slowing repolarization group 4 drugs -> block teh slow Ca++ channels (verapamil, diltiazem) •nobody kicks cats different arrhythmias are best treated by the specific action of each drug

Excitation-contraction coupling in Heart muscle

action potentials conducted by sarcolemma -> open voltage-gated Ca++ channels in plasma membrane (dihydropyridine receptors) -> small amount of Ca++ diffuses into cytoplasm from extracellular fluid -> stimulates Ca++ release channels in sarcoplasmic reticulum (ryanodine receptors RyR2 type) -> large of amount of Ca++ released -> binds to troponin and stimulates contraction occurs during plateau phase these events occur at signaling complexes -> regions where the sarcolemma come in very close proximity to the sarcoplasmic reticulum (20,000 signaling complexes in a myocardial cell -> all activate at same time by depolarization) -> this results in myocardial contraction that develops during the depolarization phase of the action potential during the repolarization phase concentration of Ca++ in cytoplasm must be lowered to allow for relaxation and diastole (done by three means) •1. done by sarcoplasmic reticulum Ca++ ATPase "SERCE pump" -> transports Ca++ into the lumen of the SR •2. Na+/Ca++ exchanger (NCX) -> functions by secondary active transport where downhill movement of Na+ into the cell powers the uphill extrusion of Ca++ •3. Ca++ ATPase pump -> primary active transport the heart cannot sustain contraction -> due to the atrai and ventricles behaving as if they were only composed of one muscle cell "functional syncytium" -> single unit •contraction to to the long action potential for myocardial cells can be thought of as a muscle twitch (although that only lasts .02-.1 s compared to .3s) •heart normally cannot be stimulated while in a refractory period -> by preventing summations of contractions the myocardium must relax -> creates the rhythmic pumping action of the heart

conduction of the impulse

action potentials from the SA node are fast -> .8-1.0 m/s across myocardial cells of both atria in the AV node this slows to .03-.05 m/s -> accounting for the delay between excitation of the atria and ventricles conduction rate increases greatly in the atrioventricular bundle and reaches 5 m/s in the Purkinje fibers overall this is what allows for the .1-.2 second delay in lub-dub

Destruction of T lymphocytes

activated T lymphocytes must be destroyed after the infection has been cleared -> done as T cells produce surface receptor FAS -> after a few day T cells begin to produce another surface molecule called FAS ligand -> binding of the two causes apoptosis of the two -> used in eye and testis to create immunologically privileged sites sertoli cells protect the developing sperm from immune attack through two mechanisms •tight junctions between adjacent sertoli cells forming a barrier that normally prevents •sertoli cells produce FAS ligand -> triggers apoptosis of any T cells that enter the area the anterior chamber of the eye is also a immunologically privileged site -> if not present the eye could not see when inflammation is present -> neurological layers of the retina cannot regenerate -> the interior lining of the eye is coated with FAS ligand -> promotes apoptosis, and secretion of different cytokines that inhibit inflammation some tumor cells have been found to produce FAS ligand -> defends tumor from attack by triggering apoptosis of lymphocyte

Luteal phase

after ovulation, the empty follicle is stimulate by LH to become the corpus luteum -> change in function -> progesterone increase and hit peak levels during the luteal phase -> one week ovulation and lasts from day 14 to day 28 -> more stable in its length than the follicular phase high levels of progesterone combined with estradiol during luteal phase -> inhibitory negative feedback effect on FSH and LH secretion •corpus luteum -> produces inhibin during luteal phase -> suppress FSH secretion -> retards new follicle development so that further ovulation does not occur follicles start to develop toward the end of one cycle in preparation for the next -> due to decreased production of inhibin -> estrogen and progesterone levels also fall during late luteal phase starting around day 22 as corpus luteum regresses and stop functioning caused by the hormone luteolysin (in mammals) secreted by the uterus •luteolysin in human may be prostaglandin F2a although not fully understood -> breakdown of corpus lutem "lutolysis" can be prevented by high levels of LH -> normally keep low during the luteal phase as a result of negative feedback by ovarian steroids (estradiol and progesterone) declining function of corpus luteum -> estrogen and progesterone fall to very low levels by day 28 of the cycle -> withdrawal of ovarian steroid causes menstruation ->permits new cycle of follicle development

Vital Signs: Bird flu leaves tracks in brain

after surviving a bout of virulen bird flu and mouse's brain shows short-term lreudction of key chemicals and long-lasting signs of infection •studies show that these lasting effects in people could lead to parkinsons H5N1 bird flu kills 50% of people it infects -> takes resident in the brain -> dopamine production gets shut down or hindered -> after 60 days dopamine functions normal again but signs of inflammation remain may enter by the nose or vagus nerve into the brain

Histocompatibility antigens

all tissue cells with the exception of mature RBCs are genetically marked with a characteristic combination of histocompatibility antigens on the cell surface -> the greater the variance in these antigens between a donor and recipient leads to greater chance of rejection -> why tissue type is matched prior •since WBCs are use for this purpose histocompatibility antigens in humans are also called human leukocyte antigens (HLAs) or MHC molecules after the genes that code for them -> coded by a group of genes called the major histocompatibility complex (MHC) located on chromosome 6

Clinical Application: Auscultatory chest positions

allows for the closing of separate valves to be heard so that the first and second heart sounds may be heard to "split" into their components closing of the tricuspid valve is best heard when the stethoscope is placed to either side of teh lower sternum just above the xiphoid process closing of the mitral valve is best heard at the apex of the heart in the fifth left intercostal space closing of the pulmonary and aortic semilunar valves is heard best at the second left and right intercostal spaces these positions can be impacted by obesity, pregnancy and other conditions

Clinical Application: Angiogram

an Angiogram is an X-ray picture taken after a catheter is inserted into a brachial or femoral artery -> threaded by a fluoroscope to the desired site at the coronary arteries where an iodine contrast dye is injected -> standard method for assessing coronary artery disease due to its ability to reveal narrowing caused by atherosclerotic plaques coronary angioplasty -> technique of inserting a catheter with a balloon into the occluded site of a coronary artery and then inflating the ballon to push the artery open -> following this "balloon angioplasty" a stent is often inserted to support the section and if required a coronary artery bypass grafting (CABG) may be performed -> most common open-heart surgery involving grafting of a vessel taken from the patient onto the aorta so that is bypasses the narrowed coronary artery

Electrocardiogram

an Electrocardiogram "ECG/EKG" is a recording of the device known as a electrocardiograph -> done by placing surface electrodes -> each cycle produces three distinct ECG waves, designated as P, QRS, and T ECG is not a recording of action potentials but rather results from production and conduction of action potentials in the heart -> figure corresponds to the action potential and contraction of the ventricles The spread of depolarization through the atria causes a potential difference that is indicated by an upward deflection of the ECG when half the mass of atria is depolarized the upward deflection reaches its max value due to the potential difference between the depolarized and unstimulated portions is at a max -> when the entire mass is stimulated the ECG returns to baseline since all the regions of teh atria have the same polarity -> spread of atrial depolarization creates the P wave -> repolarization is not visualized because it occurs during depolarization of the venctricles conduction of the impulse in the ventricles creates a similar structure -> represented by QRS wave the S-T segment is the plateau phase of the ECG repolarization of the ventricles occurs at the T wave •also an upward deflection due to spreading in opposite direction from epicardium to endocardium compared to the other conduction pathways that occured from endocardium to epicardium -> allows for the hyperpolarization of the T Wave to appear as an upward deflection

Clinical application: Angiogenesis

angiogenesis is the formation of new blood vessels from preexisting vessels, usually venules -> needed due to cells needing to be within 100µm of capillaries to survive angiogenesis is required for the growth of neoplasms (tumors) and is involved in the development of neovascular age-related macular degneration "wet macular degeneration -> inhibition of angiogenesis aids in this condition two paracrine regulators, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) bind to tyrosine kinase receptors to stimulate angiogenesis •monoclonal antibody bevacizumab (Avastin) binds and inactivates VEGF -> treatment for colon, lung, breast, cervix, ovary, and kidney cancers •Ranibizumab (Lucentis) also a monoclonal antibody preparation -> injected into the vitreous humor of the eye to inhibit the angiogenesis of wet macular degeneration •mab "monoclonal antibody"

The complement system

antibodies don't destroy pathogens -> identify targets for immunological attack and activate nonspecific immune processes -> bacteria are "buttered" (tagged) with antibodies -> improved phagocytosis by neutrophils and macrophages "opsonization" •immune destruction of bacteria is also promoted by antibody-induced activation of a system of serum proteins known as complement in 20th century scientists realized that antibodies alone don't lyse cells unless they added certain protein components of the serum "complement -> constitute a nonspecific defense mechanism activated by bonding of antibodies to antigens, thus it is a directed against specific invaders that have been identified -> called a complement due to how it complements the antimicrobial activity of antibodies •complement proteins are designated C1 through C9 -> proteins are present in an inactive state -> activated by attachment of antibodies to antigens function of the complement system can be subdivided into three components; 1. recognition (C1) 2. activation (C4, C2, and C3, in that order) 3. attack (C5 through C9) -> attack phase consists of complement fixation where complement proteins attach to the cell membrane and destroy it there are two pathways of complement activation •the classic pathway -> initated by IgG and IgM and is more rapid than the alternative pathway initiated by unique LPS "endotoxins" classic pathay of complement-dependent cytotoxicity -> initiated by binding of IgG to their cell surface receptors -> activates C1 which catalyzes the hydrolysis of C4 into two fragments C4a and C4b -> C4b binds to cell membrane and is fixed and becomes active -> through an intermediate step involving the splitting of C2, C3 is cleaved in C3a and C3b (conversion point of both pathways) -> C3b converts C5 into C5a and C5b -> C5a stimulates mast cells to release histamine -> C3a and C5a serve as chemokines and attract macrophages neutrophils, monocyte, and eosinophils to site -> C5 through C9 are inserted into the bacterial cell membrane to form the membrane attack complex membrane attack complex -> large pore that can kill the bacterial cell through osmotic influx of water -> this pathway is what causes hemolysis in incompatible transfusion reactions and in fetus and infants impacted by hemolytic disease of the newborn (HDN) complement fragments that are liberated into the surrounding fluid rather than becoming fixed have a number of effects; •Chemotaxis -> attract phagocytic cells to site of complement activation •opsonization -> phagocytic cells have receptors for C3b -> form bridges between phagocyte and the victime cell facilitating phagocytosis •stimulation of histamine release -> stimulates mast cells and basophils by fragments of C3a and C5a -> vasodilation and increased capillary permeability -> brings more phagocytic cells to site of infection -> can also lead to edema through leakage of plasma proteins into the surrounding tissue fluid

Regulation by Antidiuretic hormone (ADH)

antidiuretic hormone (ADH) also known as arginine vasopressin •produced by neurons in the hypothalamus (supraoptic and paraventricular nuclei) -> transported by hypothalamo-hypophyseal tract to posterior pituitary -> released in response to hypothalamic stimulation ->stimulation occurs by osmoreceptors in hypothalamus when plasma osmolality increases •can be caused due to dehydration and/or salt intake -> sensation of thirst and increase in ADH released -> ADH stimulates water reabsorption from the filtrate •drinking more and urinates less due to ADH -> dilutes the plasma lowering osmalality and raising the blood volume (important in those with dehydration) -> drinking excessive amounts of water w/o salt does not result in prolonged increase in blood volume and pressure -> there is a momentary increase in blood volume however it dilutes the blood resulting in a decrease in osmalality, inhibiting the release of ADH -> more urine excreted/formed (water is a diuretic) •dilutioin of blood lowers of ADH secretion, however a rise in blood volume (even in absence of dilution) can also reduce ADH secretion -> possible by mechanical stimulation of stretch receptors in the left atrium, and carotid sinus -> cause increase firing of sensory neurons (IX & X) -> ADH secretion is inhibited and more water is eliminated from the blood by the kidneys lowering the blood volume by 10% reduces stimulation of stretch receptors -> reduce firing -> increase in ADH secretion -> water retention by kidneys •stimulation of stretch receptors have an additional affect -> secretion of the hormone atrial natriuretic peptide -> increases secretion of salt and water in the urine -> works like ADH to lower blood volume

T cell receptor proteins

antigens recognized by B cells can be either proteins or carbohydrates, but only protein antigens can be recognized by T lymphocytes -> T cells do not make antibodies and do not have antibodies on their surface to serve as receptors for antigens -> they do have antigen receptors on their surface closely related to immunoglobulins but they cannot bind free antigens -> require the need of antigen presenting cells -> allows for a more broad response dendritic cells are the chief presenting cells but we also see it in B cells and macrophages -> both dendritic cells and macrophages come from monocytes which are formed in bone marrow and migrate to almost every organ -> very concentrated in potential sites where antigen-bearing microorganisms may enter such as skin, intestinal mucosa, and lungs the epidermis contains dendritic cells known as langerhans cells derived from bone marrow and make up 3-5% of cells in the epidermis and occupy spaces between the keratinocytes -> cells engulf protein antigens via pinocytosis -> digest proteins into shorter polypeptides and move them to cell surface -> on surface become polypeptides associated with histocompatibility antigens -> allows the antigen-presenting cells to activate T cells in order to interact with correct T cells (with specific antigen) -> dendritic cells migrate to secondary lymphoid organs where they secrete chemokines to attract T cells (a non activated T cell will reside in this tissue for 24 hours, an activated one will reside for 3-4 days) -> activated T cells divide to first produce effector T cells (those that perform a specific function) and then produce memory T cells

Regulation of Cardiac Rate

as long as the myocardial cells are alive the heart will beat, even without neural influences •caused by depolarization of the SA node both sympathetic and parasympathetic (vagus) nerve fibers are continuously active to a greater or less degree -> if one increases the other will decrease and vice versa •Norepinephrine from sympathetic axons and epinephrine from the adrenal medulla bind to ß1-adrenergic receptors in the heart to stimulate production of cyclic AMP -> acts on HCN and Ca++ channels -> increase rate of depolarization -> faster cardiac rate Acetycholine release dby vagus nerve endsing binds to muscarinic Ach receptors -> open K+ channels -> outward diffusion of K+ counters inward diffusion of Na+ channels through HCN channels -> slowing of cardiac rate •vagus nerve (X) is tonically active to a degree and the ACh effects generally keep the resting rate slower than 90-100 beats/min, which it would be if the muscarinic receptors were not active pace of the SA node depends on net effect of antagonistic influences -> mechanisms that affect the rate as said to have a chronotropic effect (chrono - time) •increase in rate -> positive chronotropic effect •decrease in rate -> negative chronotropic effect autonomic innervation of SA node is a major means by which the SA node is regulated -> sympathetic endings in the musculature of the atria and ventricles increase the strength of contraction and cause a decrease in time spent in systole (quicker and more powerful contraction resting bradycardia of endurance athletes is due high vagus nerve activity •during exercise vagus nerve inhibition decreases and sympathetic nerve stimulation occurs activity of the autonomic innervation of the heart is coordinated by the cardiac control center in the medulla oblongata of the brain stem •cardiac control center is affected by higher brain areas due to sensory feedback from pressure receptors "baroreceptors" in the aorta and carotid arteries •this way a fall in blood pressure -> produces a reflex to increase heart rate

Atherosclerosis and cardiac arrhythmias

atherosclerosis -> most common form of arteriosclerosis (hardening of arteries) -> cause of 50% of deaths in US, Europe, and Japan •localized plaques "atheromas" protrude into the lumen of the artery and reduce blood flow -> serve as sites for thrombus formation process of atherosclerosis begins as a result of damage or "insult" to endothelium -> insults are produced by smoking, hypertension, high cholesterol, and diabetes •fir anatomical change is the appearnace of fatty streaks -> grey-white areas that protrude into the lumen of arteries, particulary at arterial branch points -> aggregations of lipid-filled macrophages and lymphocytes within the tunica intima (tunica internal) in the intermediate stage -> area contains layers of macrophages and smooth muscle cells in advanced stages -> fibrous plaques that consist of a cap of connective tissue with smooth muscles cells over accumulated lipid and debris, and macrophages derived from monocytes and lymphocytes •the fibrous cap becomes thin and prone to rupture, promoting the formation of a thrombus although instigated by damage to the endothelium, its progression is promoted by inflmmation stimualted by cytokines and other paracrine regulators secreted by endothelium and other cells including platelets, macrophages, and lymphocytes •some of these regulators attract monocytes and lymphocytes and cause them to penetrate the tunica interna where monocytes become macrophages, engulf lipids and gain the foam cell appearance •smoth muscle takes on a synthetic state appearance in which they produce and secrete connective tissue matrix proteins •cytokines released during inflammation can reduce smooth muscle collagen synthesis -> stimulate production of collagenase enzymes in macrophages weaking the plaque's collagen cap -> when it ruptures and exposes the undelrying tissue to the blod -> clot forms endothelial cells prevent progression by presenting a physical barrier barrier to penetration of monocytes and lymphocytes (macrophages) by producing regulators such as nitric oxide, a vasodilator -> counters vasoconstrictor effects of another paracrine regulator, endothelin-1, increased during atherosclerosis •hypertension, smoking, and high cholesterol interfere with the protective function of the endothelium -> aerobic excercise improves it

Atrioventricular and Semilunar valves

atria and ventricles are separated into two functional units by a sheet of non-conductive tissue •embedded in this sheet of tissue are one-way atrioventricular (AV) valves -> on the right side between the atrium and venticle there are 3 flaps "tricuspid valve", while on the left side there are only 2 flaps and is thus called a mitral, bicuspid valve The AV valves allow blood to enter the ventricles from the atrium, but prevent backflow •when the ventricles are relaxed venous return of blood creates pressure in the atrium exceeding the pressure in the ventricle -> flap opens and blood enters -> once the ventricle contracts the pressure rises above the pressure of the atrium and the AV valves close •if there is too much pressure from the ventricles it can lead to everting the flaps, this is normally prevented by contraction of papillary muscles aided by strong tendinous cords called chordae tendineae (like strings on a parachute) one-way semilunar vales are located at the origin of the pulmonary artery (pulmonary semilunar valve) and aorta (aortic semilunar valve) •not supported by chordae tendineae due to less pressure present -> these valves open during ventricular contraction, and during relaxation when pressure in the arteries is greater than the ventricles the semilunar valves are shut -> prevents backflow why are there no one-way valves at the inlets of the atria (you don't want it) •allows for venous inflow of the heart to be continous and non-pulsatile -> in a nonfuntioning atria venous flow becomes pulsatile and circulation rate is decreased Atria have 4 essential characteristics that cause them to promotore continuous blood flow 1. no atrial inlet valves to interupt blood flow during atrial systole 2. atrial systole contractions are incomplete and thus do not contract to the point that would block venous flow through the atria to the heart -> during atrial sytole, blood only empties from the atria into the ventricles, but blood continues to flow uninterrupted from the veins right through the atria -> ventricles 3. atrial contracts must be gentle enough so that the force of contraction does not exert significant back pressure that would impede venous flow 4. relaxation of atria must be timed so that they relax before the start of ventricular contraction to be able to accept venous flow without interruption By preventing the inertia of interrupted venous, nearly 70% of of ventricular possible occurs, while only 20% of blood is added by atrial contraction •key benefit of the atria is in preventing circulatory inertia and allowing uninterrupted venous flow to the heart -> you can survive with a non-functioning atria -> higher risk of clots/stroke (ex. A-fib)

baroreceptor reflex

baroreceptors are stretch receptors in the aorta arch and carotid sinuses (where the carotid splits) •constantly (tonically) active -> baseline action potential during rest -> an increase in blood pressure results in an increased frequency of action potentials along sensory nerve fibers -> a fall in blood pressure leads to a decrease in action potentials sensory activity from baroreceptors ascends via the vagus (X) and glossopharyngeal (IX) nerves to medulla oblongata -> directs autonomic system to respond appropriately •vasomotor control center -> in the medulla regulates the degree of vasoconstriction/dilation -> regulates total peripheral resistance •cardiac control center -> in the medulla -> regulates the cardiac rate the varoreceptor reflex consists of; • sensors -> aortic arch and carotid sinus •integrators -> vasomotor and cardiac control centers •effectors -> parasympathetic and sympathetic axons to the heart and blood vessels a fall in blood pressure -> increase in sympathetic nerve activity, with a decrease in parasympathetic division -> compensatory increase in cardiac output and total peripheral resistance •on the other side a rise in pressure -> decline ini sympathetic activty with an increase in parasympathetic division activitiy -> reduction in cardiac output and total peripheral resistance the reflex of raising or lowering of blood pressure is mainly due to sympathetic nerve regulation of total peripheral resistance, secondarily the reflex of raising or lowering the cardiac output •varoreceptor reflex is the most important regulator of arterial blood pressure on a beat to beat basis (long term regulation is done by the kidneys) when a person goes from a lying to standing position there is a shift of 500 -> 700 ml of blood from veins of the thoracic cavity to veins in lower extremities -> expansion of capacitance vessels -> fall in blood pressure is compensated immediately by the varoreceptor reflex •decrease in varoreceptor sensory information to medulla oblongata inhibits parasympathetic activity and promote sympathetic nerve activity -> increase in cardiac rate and vasoconstriction -> increase in blood pressure -> opposite can occur when blood pressure rises above the normal range -> slowing of heart beat and vasodilation •varoreceptor sensitivity is reset during exercise where a rise in blood pressure is beneficial -> cardiac rate and output still high but also restrained by baroreceptor reflex manual massage of carotid sinus can lead to lower blood pressure and reduction of tachycardia -> can lead to loss of consciousness and even cardiac arrest if you massage both sinus

Clinical Application: Valsalva Maneuver

bearing down and forceful exhalation -> raise intrathoracic pressure -> compresses thoracic veins and reducing venous return to the heart briefly raises the aortic pressure causing a slowing of the heart by the baroreceptor reflex -> fall in venous return decreases the cardiac output -> fall in return stimulates the baroreceptor -> increase in heart rate when the person again breathes the thoracic pressure falls and the aortic pressure briefly falls -> increase in heart rate before venous return raises the aortic pressure and slows the cardiac rate we see this maneuver in weightlifters and those with constipation -> can be dangerous in those with coronary heart disease

Pulmonary and Systemic circulations

blood with low oxygen content -> right atrium -> right ventricle -> pumped into pulmonary trunk and pulmonary arteries -> transport blood to lungs, where gas exchange occurs (O2 to blood, CO2 to lungs) -> blood returns to left atrium by pulmonary veins -> this results in one pulmonary circulation •pulmonary arteries carry blood low in oxygen, and pulmonary veins carry oxygen rich blood (reverse of what is "normal" •due to proximity of lungs to the heart this is a low pressure system •continuing -> from left atrium -> enters left venticle and is pumped into the largest artery the aorta -> arterial branches supply O2 rich blood to all organs systems -> system circulation •higher pressure system due to distance travelled due to cellular respiration O2 is low and CO2 is high in tissues compared to blood •O2 depleted blood has a maroon color (darker) -> upon return from organ sytems it ultimately empty into two large veins -> superior and inferior venae cavae -> return of blood to right atrium -> completes systemic circulation small muscular arteries and arterioles of the system circulation lead to greater resistance to blood flow -> pressure can reach near 0 by the time it reaches the capillaries •despite the amount of work needed the rate of blood flow through the systemic circulation must be equal to pulmonary circulation -> compensated by the difference in size between the two (left ventricle ~8-10mm, while the right is ~2-3mm)

Circulatory changes during exercise

breathing and pulse rate increases within a second of exercising -> suggest that motor cortex is also responsible for influencing cardiovascular adjustments -> also impacted by sensory feedback and baroreceptor -> together increase the activity of the sympathoadrenal system and reduce parasympathetic nerve activity -> results in an increase in cardiac rate, stroke volume, and cardiac output vascular resistance through muscles decreases during dynamic exercise but increases during static (isometric exercise) -> resistance to flow through visceral organs and skins increases in both types -> increased resistance through viscera and skin is produced by vasoconstriction of adrenergic sympathetic fibers caused by sensory stimulation blood flow through dynamically exercising muscles increases due to: •increased blood flow (cardiac output) •metabolic vasodilation in the exercising muscles •diversion of blood away from the viscera, due to vasoconstriction in these organs all these effects result in skeletal muscles and the heart receiving 85%-95% of the cardiac output during maximal exercise total blood flow to brain may increase slightly from rest to mild exercise but thereafter remains constant as exercise intensity increases •despite the constant total blood flow the areas of the brain responsible for motor activity and related somatosensory function receive more blood because of local vasodilation in response to increased metabolism •at heavier exercise (more than 60% of Vo2 max) -> cerebral blood flow decreases somewhat due to hyperventilation which lowers the blood CO2 producing cerebral vasoconstriction -> contributes to central fatigue caused by the brain during exercise cardiac output increase by 5x -> can only increase to a maximum value which is determined by age -> athletes have higher stroke volumes -> cardiac output can reach 6-7x resting values -> increased oxygen delivery to muscles •within only a few weeks of endurance training you can increase your cardiac output and VO2max -> genetics still play a large part •young adults can increase their stroke volume from 70mL/beat to 100 mL/beat from rest to VO2 max •EDV is not significantly changed during exercise the proportion of the EDV ejected per stroke can increase from 60% at rest to 90% during heavy exercise -> the increased ejection fraction is produced by increased contractility that results in sympathoadrenal stimulation (pacemaker cells) •must also be a decrease in total peripheral resistance as a result of vasodilation -> decreases the afterload and further augments the increase in stroke volume endurance training results in lowering the cardiac rate and increasing stroke volume -> caused by greater inhibition of the SA node -> increased stroke volume caused by an increase in blood volume (500 mL) -> improved oxygen delivery to skeletal muscles that occur as a result of endurance training

ovulation

by the 10-14th day after the first day of menstruation only one follicle has continued its growth to become a fully mature graafian follicle -> other follicles during that cycle regress and become atretic "without an opening" in reference to failure to rupture -> follicle atresia or degeneration is a type of apoptosis that results from a complex interplay of hormones and paracrine regulators •gonadotropins (FSH and LH) as well as various paracrine regulators and estrogen act to protect follicles from atresia •paracrine regulators that include androgens and FAS ligand promote atresia of the follicles follicle that is protected from atresia => develops into graafian follicle and becomes so large that it forms a bulge on the surface of the ovary -> ruptures during ovulation -> extrudes into peritoneal cavity "ovulation" the released cell is a secondary oocyte surrounded by the zona pellucida and corona radiate -> if not fertilized the cell will degenerate in a couple of days or less •sperm passes through corona radiate and zona pellucida entering the cytoplasm of the oocyte -> oocyte will undergo its second meiotic division -> once again this division is not equal -> zygote (fertilized egg) & a polar body that is discarded changes continue following ovulation •the empty follicle through luteinizing hormone from anterior pituitary becomes a corpus luteum -> secretes not just estradiol like other follicles but also progesterone -> towards end of cycle this structure regresses to become a nonfunctional corpus albicans

Cardiac Cycle

cardiac cycle refers to the repeating pattern of contraction and relaxation of the heart •contraction -> sytole •relaxation -> diastole •if you don't specific what region these terms apply to the contraction and relaxation of the ventricles atrial contraction occurs towards the end of diastole, when ventricles relax, when the ventricles contract during systole, the atria are relaxed there is a quiescent period (relaxation phase) when all four chambers of the heart are in diastole -> this is what is changed in heart rate the heart thus has a two-step pumping action •the left and right atria contract almost simultaneously, following by the contraction of the ventricles .1-.2 seconds after •when relaxed venous return fills the atria -> builds up pressure causes AV vales to open and blood flow from the atrium to ventricles (ventricles have 80% blood before atria contract -> add last 20% to the end-diastolic volume -> total volume of blood in the ventricles at the end of diastole) contraction of the ventricles in systole ejects about 2/3 (ejection fraction) of the blood they contain, the amount ejected is the stroke volume -> leaves 1/3 still in ventricles known as end-systolic volume •ventricles once again fill with blood and the cycle repeats on average the cardia rate is 75 beats/min -> each cycle lasts .8 seconds (.5 in diastole and .3 in systole)

Cardiac Output

cardiac output is the volume of blooc pumped/min by either ventricle •on average the cardaic rate = 70beats/min, while the average stroke volume is 70-80mL/beat of one ventricle -> combine these variables and you get an average cardiac output of 5,500 mL or 5.5 L total blood volume also averages about 5.5 L -> each ventricle pumps the total blood volume each minute under resting condition

Heart Sounds

closing of the AV and semilunar valves produces a sound -> heard by auscultation (listening with a stethoscope) These sounds are verbalized as "lub-dub" •the Lub or first sound (S1) is produced by closing of the AV valves during isovolumetric contraction of the ventricles •the Dub or second sound (S2) is produced by closing of the semilunar valves when the pressure of arteries exceeds the ventricles thus the first sound is heard when ventricles contract at systole, and the second sound is heard when the ventricles relax at the beginning of diastole

Veins

contain most of the blood volume •expand as they accumulate additional blood amounts •average pressure is 2mmHg, compared to arterial pressure average of 100mmHg •due to low pressure the return of blood is aded by two mechanisms -> massaging action of skeletal muscles, and one-way flow to the heart by venous valves discovered by William Harvey when he saw that vein don't allow backflow of blood the massaging action of skeletal muscles is known as the skeletal muscle pump •during exercise blood is returned quicker due to increased muscle use •when a person is less active such as standing or bed ridden veins bulge with accumulated blood •critical in movement of venous blood from the lower limbs to the large abdominal veins movement of blood from the abdominal to thoracic veins is aided by breathing "respiratory pump" -> done by diaphragm, which when inhaling this muscular sheet separating the thoracic and abdominal cavities contracts -> flattens and descends into the abdomen -> increases pressure in abdomen -> squeezes veins, and decreasing pressure in the thoracic cavity -> pressure difference of this inspiratory movement forces the blood into the thoracic veins and return the venous blood to the heart

cyclic changes of the endometrium

cycle can also be described in terms of changes in the endometrium of the uterus -> occur due to cyclic changes in the secretion of estradiol and progesterone from ovaries three phases can be identified •proliferative phase •secretary phase •menstrual phase proliferative phase •occurs while ovary is in follicular phase •increase amounts of estradiol -> stimulate growth (proliferation) of the stratum functionale of the endometrium -> growth of spiral arteries -> estradiol also stimulates the production of receptor proteins for progesterone secretory phase •occurs when ovary is in the luteal phase -> increased progesterone secretion by corpus luteum stimulates development of uterine glands -> gives endometrium a thick spongy appearance as the uterine glands become engored with glycogen -> grows in thickness from 2mm to 12-13mm -> can now accept and nourish an embryo if fertilization occurs menstrual phase •occurs as a result of the fall in ovarian hormone secretion during the late luteal phase •necrosis and sloughing of the stratum functionale is caused by constriction of the spiral arteries -> lead to menstrual bleeding -> note - animals don't contain these arteries and don't bleed •hormone changes can also cause system symptoms -> Nausea, vomiting, headache, and water retention (caused by estrogen promoting an influx of Na+ into tissues) and menstrual cramps (contractions of smooth muscle) cyclic changes in ovarian secretion -> cyclic changes in female reproductive tract •high levels of estradiol secretion -> cornification of the vaginal epithelium (upper cells die and become filled with keratin), also leads to production of a thin watery cervical mucus that can be easily pentrated by spermatozoa -> fertile mucus "spinnbarkeit" presence indicates high estrogen level and shows that a women's fertility is at its peak (mucus has guiding channels for sperm) during the luteal phase of the cycle high levels of progesteron cause the cervical mucus to thicken and become sticky after ovulation has occurred -> cloudy and thick -> protective barrier against sperm or bacteria entry

Lymphokines

cytokines of the lymphocytes, and are all known as interkeukin to indicate a cytokine once its amino acid sequence has been determined •interluekin-1 -> first interleukin discovered -> secreted by macrophages and other cells of innate immune system in response to toll-like receptors (usually) -> activate the T cell system and promote other effects such as IL-1ß (endogenous pyrogen) which promotes fever •interleukin-2 -> produced by helper T lymphocytes residing in lymph nodes -> critical for development of helper, cytotoxic, and regulatory T lymphocytes •interluekin-4 -> required for proliferation and clone development of B cells •interleukin-5 -> central role in eosinophil differentiation, proliferation, and activation

septic shock (1 of 3 shocks)

dangerously low blood pressure (hypotension) that may result from sepsis, or infection -> result of a bacterial lipopolysaccharide "endotoxin" (endogenous pyrogen -> stimulates fever in the supraoptic region of the hypothalamus) mortality is high at 50-70% endotoxin results in activation of the nitric oxide synthase within macrophages -> NO production -> vasodilation -> fall in blood pressure •treatments for this shock involve inhibition of the nitric oxide production •septic shock is caused by the mass spread of endotoxin/LPS -> drugs are made to reduce response to LPS

Circulatory Shock ( 1 of three forms of shock)

defined as inadequate profusion of your tissues •occurs when there is adequate blood flow and/or O2 utilization by the tissues signs of shock are a result of inadequate tissue perfusion, as well as cardiovascular responses that help compensate for the poor tissue perfusion ->when these compensations are effective, they with medical care restablish adequate tissue perfusion -> however for many unknown reason the shock may progress to an irreversible state and cause death

correlation of the ECG with Heart sounds

depolarization of the ventricles indicated by the QRS wave -> stimulates contraction by promoting the diffusion of Ca++ into regions of the sarcomeres -> thus the QRS wave is the beginning of systole •the rise in intraventricular pressure that results cause the AV valves to close producing the S1 sound is immediately after the QRS wave repolarization of the ventricles as indicated by the T wave occurs as the same time that the ventricles relax at the beginning of diastole -> resulting fall in intraventricular pressure causes the semilunar valves to close producing the S2 sound -> sound produced shorlty after the T wave begins

Types of Capillaries

different organs have different types of capillaries, distinguished in their structure -> Continuous, fenestrated, and discontinuous Continuous capillaires •adjacent endothelial cells are closely joined together •found in muscles, lungs, adipose tissues, and CNS •lack of intercellular channels in the CNS contributes to blood-brain barrier -> evidence of pinocytotic vesicles which are the only type of transport involved in capillary exchange -> contributes to selectivity of blood-brain barrier •in other organs these capillaries have narrow intercellular channels that permit passage of molecules other than protein Fenestrated capillaries •occurs in kidneys, endocrine glands, and intestines •characterized by wide pores that are covered in mucoprotein, which serves as a basement membrane over the capillary endothelium •the mucoprotein serves to restrict the passage of certain molecules (particularly protein) that would otherwise pass through discontinuous capillaries •found in bone marrow, liver, and spleen •distance between endothelial cells is so great the capillaries look like little cavities (sinusoids) in the organ in a tissue that is hypoxic (low O2), new capillaries are stimulated to grow •growth is promoted by vascular endothelial growth factor (VEGF) as well as adenosine (from AMP) -> stimulates vasodilation of arterioles, increasing blood flow to hypoxic tissue

Adaptive (specific) immunity

discovered by Emil Adolf Von Behring through the use of guinea pig showed that small amounts of diphtheria toxin could result in immunity to large doses after time -> called the chemicals in its serum antibodies -> shoed that they were specific only to diphtheria infection and were specific in their actions -> later found these antibodies were produced by a particular lymphocytes •also found that you can share immunity (plasma donation/vaccines) antigens -> molecules that sitmulate the production of specific antibodies •usually large with a molecular weight greater than 10,000 (exceptions) •foreign to blood and other body fluids typically (blood types) -> due to the immune system being able to distinguish itself from other organisms -> mounts an immune response only against nonself antigens •ability of a molecule to function as antigen depends not only on size but also complexity of its structure (ex. implants -> not very antigenic due to simple repeating structure) -> a large complex molecule can have many different antigens "antigenic determinant sites" (epitopes) which are areas of the molecule that stimulate the production of different antibodies (natural for this to occur most of the time)

Aerobic requirements of the heart

due to the density of capillaries each myocardial cell is within only 10µm of a capillary compared to the average of 70µm seen in other organs -> allows for quick exchange contraction of the myocardium squeezes the coronary arteries -> for this reason blood flow in the coronary artery is less during systole than diastole •myocardium contains large amounts of myoglobin (pigment related to hemoglobin) -> stores oxygen during diastole and releases it during systole -> allows for a continuous supply of oxygen even when blood flow is reduced during systole •myocardium contains large amounts of mitochondria and aerobic respiratory enzymes -> very specialized in aerobic respiration (moreso then type I fibers) -> almost all ATP produced in heart is a result of aerobic respiration and oxidative phosphorylation within the mitrochondria -> so effective that ATP within myocardial cells is completely turned over every 10 seconds -> 50% of ATP comes from acetyl CoA produced by ß-oxidation of FAs, with the other 50% from glucose (hence it is a balance of glucose and lactate) a normal heart always respires aerobically even at heavy excercise (oxygen requirement can increase from 80mL/min to 400 mL/min per 100 g tissue)

Rhythm Method

employed as part of family planning -> liklihood of pregnancy is close to 0 more than six days prior to ovulation or a day following ("honeymoon phase") •liklihood of pregnancy is highest one to two days prior to ovulation cyclic changes in ovarian hormone secretion also causes cyclic changes in basal body temp •in rhythm method of birth control a women measures her body temp upon waking -> on day of LH peak body temp is lower -> one day following the LH peak the body temp sharply rises as a result of progesterone secretion contraceptive pill is statistically more effective means of birth control

Clinical Investigation: Jessica

experienced heavy menstruation -> caused by iron loss -> anemia -> low RBC count mitral valve proplapse -> blood leaking past the mitral valve and producing a murmur -> heard by placing stethoscope at apex position of the heart A-fib -> lack of P wave in ECG -> fatigue if cadiac output cannot increase sufficiently when she is active -> tendency to form clots in heart -> ischemic stroke -> damage to neurons due to ischemia-induced lack of oxygen and nutrients and excitotoxicity physician prescribed a drug that inactivates factor X -> inhibts formation of thrombin by both clotting pathways smoking -> risk for atherosclerosis -> promotes coronary heart disease and thrombus formation

Functions of B lymphocytes

exposure of a lymphocyte to the appropriate antigen activates the B cells and causes it to enter a germinal center of a secondary lymphoid organ where it undergoes cell division -> some progeny become memory cells, while others become plasma cells, which produce 2,000 antibodies/second and have a 2 week lifespan -> antibody bonding serves to identify the enemy and to activate defense mechanisms antibodies are plasma proteins that can be divided into five major classes by electrophoresis •albumin -> most plentiful and smallest •alpha-1 globulin •alpha-2 globulin •beta globulin •gamma globulin -> largest and contains antibodies (synonymous with antibodies and immunoglobulins) antibodies are structurally related and form only a few classes (five Immunoglobulin (Ig) subclasses) •IgG (Y) -> most antibodies •IgA (Y2) -> most abundant in mucosal membranes, saliva, and breast milk •IgM (Y5) •IgD (Y) •IgE (Y) -> involved in allergy (hypersensitivity rxns) Antibody Structure •all molecules consist of four interconnected polypeptide chains -> two long heavy chains (H chains) and two shorter lighter (L) chains -> form a Y •the stalk/constant region has been called the crystallizable fragment (Fc) whereas the top is called the antigen-binding fragment (Fab) AA seq. of antibodies has been determined by analyzing myelomas (cancer of B cells) -> showed that the Fc region is constant while the Fab regions are variable and allows for specific site for bonding on particular antigens B lymphocytes have antibodies on their plasma membrane that serve as receptors -> have all the variations when you are born -> provides active immunity

Flutter and Fibrillation

extremely rapid rates of electrical excitation and contraction of either the atria or ventricles may produce flutter or fibrillation • flutter -> contractions are rapid (200-300 beats/min) but are coordinated •fibrillation -> contraction of different groups of myocardial cells occur at different times -> coordination is impossible Atrial flutter -> degernates quickly into A-fib -> disorganized production of impulses ( 600 beats/min) -> contraction of atrai is ineffectual •AV node does not respond to impulses but enough impulses get through to stimulate the ventricles to beat at a rapid rate -> 150-180 beats/min •atrial fibrillation only reduces cardiac output by 15% -> although livable this conduction increases mortality due to stroke and heart failure -> 20-25% of all strokes occur from thrombi promoted by A-fib •most common heart arrhythmia and is uaully treated with antithrombotic and antiarrhythmia drugs -> alternative is percutaneous catheter ablation -> destroys SA node area Ventricular fibrillation -> deadly within a few minute -> can be extended by cardipulmonary resuscitation (CPR) or fibrillation being ended by electrical defibrillation •fibrillation -> caused by continuous recycling of electrical waves known as circus rhythms through the myocardium -> normally prevented by refractory period -> caused by a variety of mechanisms that disrupt this •focal excitation -> region of myocardium outside the SA node that is damaged by ischemia or fibrosis spontaneously depolarized, generating action potentials propogatd by surrounding cells •reentry -> action potential is regenerated and conducted along a pathway (scar tissue) that is not in refractory phase •external shock at the middle of the T wave when different myocardial cells are in different stages of recovery (danger of shocking yourself) whatever the means V-fib is caused by uncoordinatd contraction and an impotent pumping action sudden death from cardiac arrhythmia usually progresses form ventricular tachycardia through V-fib, culminating in asystole (beating stopping -> straight line on ECG) -> usually caused by acute myocardial ischemia -> insufficient blood to heart, or by atherosclerosis of the coronary arteries fibrillation can sometimes be stopped by a strong electric shock delivered to the chest "electrical defibrillation" -> depolarizes all myocardial cells at the same time causing them to enter a refractory state -> hopes that SA node can begin to stimulate normal contraction -> does not correct initial cause but provides time to find out what is going on •there are now implantable converter-defribrillator for high risk patients -> implanted iinto a subcutaneous pocket in the pectoral region with a lead going into the heart -> delivers defibrillating shocks if V-fib is detected

other causes of circulatory shock (besides hypovolemic, circulatory, and septic shock)

fall in blood pressure in anaphylactic shock, caused by the direct insertion of a foreign compound into blood stream that results in a severe allergic reaction -> widespread release of histamine -> vasodilation and decrease in total peripheral resistance rapid fall in blood pressure also occurs in neurogenic shock -> decrease in sympathetic tone, usually from upper spinal cord damage or spinal anesthesia Cardiogenic shock -> results from cardiac failure resulting in lack of O2 to heart •cardiac output is inadequate to maintain perfusion •occurs during MI leading to a loss of a significant proportion of the myocardium -> may result from severe cardiac arrhythmias or valve damage

Clinical Application: Female Athlete Triad

female athlete triad refers to •energy deficiency due to inadequate food intake •menstrual disturbances and amenorrhea •osteoporosis young female athletes are vulnerable due to excessive focus on thinnes; the eating disorders of anorexia and bulimia may or may not be present exercise and low body fact acting through the suppression of hypothalamic-pituitary ovarian axis and reduced estradiol secretion -> osteoclast activity -> reduces bone density -> increased risk of fractures a healthy athlete without the triad, bone mineral density improves as a result of phsyical stresses on the bone

Measurement of blood pressure

first done by Stephen Hales in 1677-1761 an English clergyman by inserting a tube into the artery of a horse and seeing how the blood column bounced between systolic and diastolic pressure Nikolai Korotkoff discovered the indirect, or auscultatory method based off pressure and arterial sounds • cuff is placed on the upper arm around the brachial artery •the artery is silent before inflation of the cuff -> laminar flow, occurs when all parts of fluid moves in same direction parallel to the axis of the vessel -> moves fastest in central axial stream and more slowly by the walls of the vessel •turbulent flow -> occurs when some parts of the fluid move in different direction leading ot churning and mixing of the blood -> vibrations and possibly sound -> Korotkoff sounds when the artery is pinched blood flow through constriction becomes turbulent •pressure above systolic pressure will have no sound, -> between systolic pressure and diastolic pressure we will hear korotkoff sounds • these sounds are not "lub-dub" which are produced by closing of the heart valves •korotkoff sounds are heard during every systole as long as the pressure cuff and attached meter (together known as a sphygmomanometer) are between diastolic and systolic pressure first korotkoff sound is heard as blood passes in a turbulent flow through a constricted opening of the artery last korotkoff sound -> occurs when the cuff pressure is equal to the diastolic pressure -> in some individuals this does not occur, in this dase we take diastolic pressure when the appearance of sound muffling occurs average systemic circulation -> 120/80 mmHg •average pulmonary arterial blood pressure -> 22/8 mmHg • due to frank-starling relationship the cardiac output from the right ventricle into the pulmonary circulation is matched to that of the left ventricle into the system circulation •since the cardiac outputs are the same the lower pulmonary blood pressure is caused by the lower peripheral resistance in the pulmonary circulation -> the lighter workload of the R ventricle results in thinner walls •accomplished by low resistance, low pressure, and high blood flow

Contraceptive pill

first sold in 1960, oral contraceptives are used by 10 million women in US and 60 million women worldwide •consist of synthetic estrogen combined synthetic progesterone -> taken once each day after the last day of the menstrual cycle -> causes immediate increase in blood levels of ovarian steroids and maintained -> results in negative feedback inhibition of gonadotropin secretion (ovulation never stops) -> entire cycle is like a false luteal phase, with high levels of progesterone and estrogens with low levels of gonadotropins due to containing ovarian steroid hormones the endometrium proliferates and becomes secretory just like in a normal cycle -> in order to stop abnormal growth women stop taking the steroid pills after three weeks (sugar pills on fourth week) -> hormone levels fall permitting menstruation to occur "mini-menstruation" -> new contraceptive pills are very effective have a number of beneficial side effects, including reduced risk for endometrial and ovarian cancers and reduction in osteoporosis -> increases risk for breast and cervical cancer •all oral drugs pass through hepatic portal vein to liver before being delivered vaginal ring and contraceptive patch deliver contraceptive steroids through mucous membrane or skin -> allows for lower doses of hormones to be delivered over 3 weeks long-acting reversible contraceptive devices (LARC) which include intrauterine devices (IUDs) and subdermal hormonal implants •the LARC devices are approved for use over 3-10 years are safe for most women and have a lower failure rate than contraceptive pills -> subdermal hormonal implants have a progestin and inhibits ovulation and thicens cervical mucus (IUDs contain a hormone that has a similar effect) -> some IUDs contains copper which release copper ions that are toxic to sperm preventing fertilization (do not destroy embryos)

Clinical Application: Glucocorticoid drugs

glucocorticoid drugs including hyrocortisone (cortisol), cortisone, prednisone, prednisolone, and dexamethasone -> suppress immune system for treatment of various inflammatory conditions, aautoimmune diseases, and allergy can also enhance cytokines secreted from Th1 cells -> promote a shift form cell-mediated to humoral immunity immunosuppressive effects of these drugs result form their ability to suppress pro-inflammatory cytokines including IL-1 and other interluekins, gamma interferon, and TNFa -> these cytokines released by microglia in the brain activate the pituitary adrenal axis -> which stimulates the hypothalamus to secrete CRH -> stimulates anterior pituitary ACTH secretion -> stimulate adrenals to secrete cortisol glucocorticoids suppress the pro-inflammatory cytokines which stimulates increases secretion of cortisol -> negative feedback loope -> nervous, endocrine, and immune systems interact to maintain homeostasis

Clinical Investigation: Mark

had crohn's disease -> loss of proteins through the intestine -> loss of plasma protein concentration (hypoproteinemia) and fall in oncotic pressure lead to edema his prolonged running made him dehydrated -> gave him orthostatic hypotension making him dizzy upon standing -> advised to drink more and switch to sports drinks to replenish Na+, K+, and Cl- lost in sweat -> maintain blood volume and pressure so help his baroreceptor during orthostatic hypotension later had essential hypertension -> took an ACE inhibitor -> inhibted angiotensin-converting enzyme -> reduced angiotensin II induced vasoconstriction lowering total peripheral resistance advised not to perform valsalva maneuver when lifting weights to avoid heart fluctuations and blood pressure this produces due to how hypertension is a risk factor for atherosclerosis and coronary heart disease

Vital Signs: Why is Covid-19 bad for the heart?

heart patients are particularly susceptible to COVID-19 -> fatality rate of 10% -> due to how COVID enters cells -> latches onto angiotensin-converting enzyme 2 (ACE2), an enzyme that lines heart cells and lung ACE2 does more than offer the virus an entry point, it is also a part of a system of hormones -> the renin-angiotensin-aldosterone system -> regulates blood pressure and cardiovascular/kidney function drugs that target other proteins in this sytem are used to lower blood pressure (two classes ACE inhibitors and ARBs) inflammation caused by the infection can lead to plaque rupture in arteries narrowed by plaques -> rupture induces blood clotting and can lead to a heart attack

Cholesterol and plasma lipoproteins

high blood cholesterol increases risk of atherosclerosis •can be obtained by diet or an inherited condition known as familial hypercholesterolemia -> a rare single dominant gene -> if you inherit two of these genes you have extremely high cholesterol and suffer heart attacks in childhood due to having a low amount of LDL receptors lipids, including cholesterols are carried in blood attached to protein carriers •cholesterol is carried to the arteries by plasma proteins called low-density lipoproteins (LDLs) -> derived from very low-density lipoproteins (VLDLs) -> small protein-coated droplets produced by the liver composed of cholesterol, TGAs, FAs, and phospholipids -> after enzymes remove most of the TAGs, the VLDLs become LDLs that transport cholesterol to the organs cells in different organs contain receptors for the proteins "apolipoproteins" in LDLs -> when apolipoproteins bind to their receptors, the cell engulfs the LDL particles by receptor-mediated endocytosis -> most LDLs are removed this way by the liver •uptake and accumulation of the apolipoprotein B into the subendothelial connective tissue of an artery -> initatiates formation of of an atherosclerotic plaque •Apo. B enhanced by oxidation acts on the endothelium to promote entry of monocytes into the lesion and conversion of monocytes into macrophages -> macrophages ingest lipoproteins -> become foam cells -> progression of the disease High-Density Lipoproteins (HDLs) •offers protection against atherosclerosis by carrying cholesterol away from arterial wall •in development of atherosclerosis, monocytes mirate through the arterial endothelium to the intima, where they become macrophages that can engulf oxidized LDLs. becoming foam cells -> progress is hindered by HDL which accepts cholesterol from foam cells and carrry it to the liver for metabolism •HDL levels are determined by genetics -> higher in women prior to menopause, and in people who excercise regularly

Structure of the Heart

hollow, cone-shaped, muscular pump about the size of a fist •the right and left atria (atrium) receive blood from the venous system; the right and left ventricles pump blood into the arterial system •The left and right sides of the heart are separated by a muscular wall "septum" that prevents mixture of blood from the two sides of the heart between the atria and ventricles there is a laye rof dense, non-conductive connective tissue known as the fibrous skeleton •bundles of myocardial cells in the atria attach to the upper margin of the fibrous skeleton and form a single functional unit -> myocardium, the same concept happens in the ventricles in the lower margin to form a different myocardium •due to this the myocardia are structurally separateed and a special conductive tissue is needed to carry action potentials •connective tissue of the fibrous skeleton also forms rings "annuli fibrosis" around the four heart valves -> foundation for the support of the valve flaps

Clinical application: Hydration

hydration during excercise becomes increasingly important the longer the duration -> 900mL loss to sweating/hour lowered blood volume -> lower cardiac output and blood flow -> reduces ability to dissipate heat and limits excercise during long strenuous exercise water may not be sufficient -> use of electrolytes (Na+, K+, Cl-) -> sports drinks containing electrolytes and sugars taken predetermined intervals (1.5-4 cups/hour) can improve performance when exercise is greater than 1 hour

Pituitary-Ovarian Axis

hypothalamic-pituitary-ovarian axis -> interactions of the hypothalamus, anterior pituitary and ovaries •anterior pituitary secretes FSH & LH -> promote cyclic changes in structure and function of ovaries -> release of hormones is controlled by gonado-tropin releasing hormone (GnRH) in the hypothalamus and feedback effect •ovarian steroid hormones include estradiol, which is secreted cyclically changing the concentration thorughout the cycle -> progesteron is only secreted after ovulation and a corpus luteum has formed in adition to the effects of estradiol secretion from the ovaries on the female sex accessory sex organs is can also lead to iincrease amount of NO produced in endothelial cells -> vasodilation -> lower vascular resistance in women •it also increases HDLs, smooth muscle & platelet function, and reduces the risk of atherosclerosis and cardiovascular disease in premenopausal women -> following menopause the decline in estradiol secretion increases risk for cardiovascular disease

Hypovolemic shock (1 of 3 forms of shock)

hypovolemic shock refers to circulatory shock that is due to low blood volume due to hemorrhage, dehydration or burns -> decrease in blood pressure and cardiac output -> activation of baroreceptor -> tachycardia and vasconstriction in the skin, digestive tract, kidneys, and muscles •decreased blood flow in the kidneys stimulates renin secretion and activation of the renin-angiotensin-aldoesteorone system •a person with this type of shock therefore has low blood pressure, rapid pulse, cold clammy skin, and reduced urine output due to resistance in the coronary and cerebral circulations not being increased -> blood is diverted to these areas •vasoconstriction in organs other than the brain and heart raises the total peripheral resistance to compensate for the drop in blood pressure due to low blood volume •due to drop of capillary blood flow less filtrate is formed -> osmotic return of fluid to the capillaries is either unchanged or increased -> blood volume is increased at expense of interstitial fluid •vasoconstriction of kidneys leads to water-conseving affects of ADH and aldosterone which are secreted in increase damonts during shock

Helper T lymphocytes

identified by their surface molecule CD4 -> these cell enhance the immune response -> improve ability of B lymphocytes to form plasma cells and secrete specific antibodies •also enhance ability of cytotoxic T lymphocytes to mount a cell mediated immune response -> done so by lymphokines, a type of cytokine specific to lymphocytes such as interleukin-2 which aids in cytotoxic T lymphocyte response two subtypes of helper T lymphocytes are designated as Th1 & Th2

Cytotoxic/killer T lymphocytes

identified in the lab by a cell surface molecule known as CD8 -> coined CD8+ cytotoxic T lymphocytes due to this connection ( CD = clusters of differentation) •function is to destroy body cells that harbor foreign molecules -> can also be from cell's genome during malignant transformation, or simply because the body hasn't seen the before (testes and eyes) in contract to the B cells humoral immunity, cytotoxic T cells kill their victim cells by cell-mediated immunity -> requries physical contact -> T cells secrete perforins and granzymes -> perforin molecules enter the plasma mebrane of the target and polymerize forming a pore in the membrane similar to the complement system, Granzyme enzymes on the other hand activate the caspase cascade -> leads to apoptosis •cytotoxic T lymphocytes defends against viral and fungal infections and are responsible for transplant rejection and immunological surveillance against cancer •most bacterial infections are handled by B lymphocytes, but some targets are attacked by cytotoxic T lymphocytes such as tubercle bacilli "tuberculosis" •tests for this include tuberculin time test and and mantoux skin text which after 48-72 hours if inflammed will tell you if you've had contact with TB -> delayed hypersensitivity reaction is a cell-mediated rather than humoral shown by an infusion of lymphocytes, but not serum

Interferons

in 1957 they found that cells infected with a virus produced polypeptides that interfered with the ability of a second, unrelated strain of virus to infect other cells in the same culture -> these interferons produced nonspecific, short-acting resistance to viral infection •now known that nuclei acids that enter the host cell cytoplasm from viruses/bacteria stimulate the production of proteins known as STING "stimulator of interferon genes" -> stimulates transcription of of host cell genes which includes interferons and pro-inflammatory cytokines required in innate immunity alpha and beta interferons are produced by almost any cell in body (alpha seen predominantly in hematopoietic cells) in response to microbial infections •polypeptides act as messengers that protect other cells in the vicinity from viral infection -> viruses can still penetrate these cells but the ability of the viruses to replicate is inhibited •HIV which leads to AIDS as well as other STDs including HPV (leads to cervical cancer and genital warts), HSV (causes genital herpes), and hepatitis B virus are all viruses that are hindered by these gamma interferon -> produced by only particular lymphocytes and natural killer cells -> immunological defense against infection and cancer FDA has approved the use of interferons to treat a number of diseases such as multiple sclerosis (M.S.) •alpha interferon -> treat hepatitis B & C, hairy-cell leukemia, genital warts, and Kaposi's sarcoma beta interferon -> relapsing-remitting MS •Gamma interferon -> treat chronic granulomatous disease •current tests to see effectiveness on cancer

Excessive clotting disorders

in some inappropriate clotting can occur and obstruct the flow of blood in circulatory system a blood clot that obstructs of blood vessel is called a thrombus •When a clot blocks a blood vessel the tissue that has block blood flow and is impacted is known as an infarction •Thrombi can occur for various reasons -> abnormal tendencies "hypercoagulable state", birth control pills, smoking, genetic defects (factor V Leiden -> in 5% of caucasian women -> greatly increases risk of thrombus formation) •bed rest -> reduce rate of blood flow particularly in legs -> production of clots vessel abnormalities can also serve to stimulate clot formation •atherosclerosis -> develop in walls of vessels and works its way into lumen -> narrowing of walls and damage to endothelium •Varicose veins -> veins are diseased and twisted •phlebitis -> inflammed veins -> intrinsic pathway activated •infection -> caused by endotoxins when a thrombus is moved by blood from its origin it is called an embolus, a mass of undissolved material (air, fat, amniotic fluid, clot, etc) •thrombi frequently form in the veins in legs -> travel to lungs as emboli due to it being the first capillary bed they hit leaving the veins (emboli get stuck on capillary beds) •emboli can cause damaging obstructions (infarcts), or death, as they block blood flow -> primary reason elderly can't live alone after falling (the area of tissue necrosis that results for lack of blood is called an infarct infarction of brain tissue due to the blood-brain barrier does not occur from clots but rather damage to on the left side of the heart (A-fib)

Arteries

in the aorta and other large arteries -> numerous layers of elastin fibers between the smooth muscle cells and the tunica media -> elastic arteries expand when blood pressure rises during contraction -> recoil once pressure falls -> this elastic recoil is what drives the blood during the diastolic phase (the longest phase of the cardiac cycle) the small arteries and arterioles are less elastic and have a thicker layer of smooth muscle for their diameter -> unlike the large arteries the smaller muscular arteries don't change the diameter near as much as the larger counterparts -> due to this the arterioles and small muscular arteries have narrow lumina and provide the greatest resistance to blood flow in arterial system arteries that are 100µm or less in diameter branch to form smaller arterioles (20-30µm) •in some tissues such as the fingertips blood from arterioles can enter the venules directly through arteriovenous anastomoses •in most cases arterioles -> capillaries (7-10µm) -> serve as the business end of the system where gas and waste exchange occurs (remember a RBC is 7µm) resistance to blood flow is increased by vasoconstriction by arterioles -> occurs in tunica media -> decreases the blood flow downstream to capillaries -> opposite occurs during vasodilation due to less resistance •norepinephrine vasoconstrictor effect, and the acetylcholine vasodilation effect may be propagated for some distance along the arteriole wall by depolarization and hyperpolarization through gap junctions

Vital Signs: Stents aren't always necessary

in their time stents and bypass surgery were the way to go with time new studies have shown that statins, aspirin and other drugs work just as well the way to manage those with stable ischemic heart disease is by medication -> requires commitment and diet clinical study ISCHEMIA is the largest clinical trial to examine whether drugs alone reduce death or heart attacks in a certain group of patients however those that had stents and medication had a better living w/o chest pain than those that were only on drugs (50% vs. 20%) plaques in arteries perform different in men vs. women, in men they tend to rupture causing a blockage at the site while in women plaques contribute to heart attacks in a few different ways such as through erosion where small pieces break off producing clots further along-> women are more likely than men to have heart disease that doesn't arise from a block at all but from a condition called microvascular dysfunction where the small blood vessels don't feed the heart properly

Clinical Application: In vitro fertilization

in vitro fertilization -> women undergoes ovarian hyperstimulation->injection of gonadotropin (FSH) over the course of a few days to stimulate follicle development -> other treatments with GnRH analogues prevent normal ovulation from occuring so that she will have a number of follicles that develop at the same time for harvesting of her oocyte tubes are then guided by vaginal ultrasound then aspirate the follicular fluid and the oocytes from her ovary fertilization may be produced by intracytoplasmic sperm injection (ICSI) a technique in which a single, capacitated sperm is injected through the zona pellucida and into the cytoplasm of an isolated secondary oocyte a number of embryos are growth this way and are growth for 3-5 days before they are transferred to the uterus using a small tube -> usually 3 or more of these are transferred at the same time (raise risk of multiple births) and any remaining embryos are preserved in nitrogen

Secondary lymphoid organs

include lymph nodes, spleen, tonsils, and peyer's patches under the mucosa of the intestine which act as guard stations •organs are strategically located where antigens could gain entry to the blood or lymph •spleen filters blood, while other secondary lymphoid organs filter lymph received by lymphatic vessels secondary lymphoid organs capture and concentrate pathogens presenting them to macrophages and other cells -> serve as sites for where circulating lymphocytes can come into contact with foreign antigens •process is aided particularly in T lymphocytes by other cells that are known as antigen-presenting cells (APCs), chiefly dendritic cells these migrate from lymph node to lymph node until they encounter pathogens and lymphocytes specific for that antigen

Innate (nonspecific) immunity

includes the external physical and chemical barriers provided by the skin and mucous membranes. also includes the internal defenses these defenses are always present and are the first line of defenese against invasion invading pathogens, or chemicals called toxins secreted from them may enter the blood or lymphatic capillareis and be carried to other areas of the body innate immunological defenses are the first employed to counter the invasion and spread of infection -> if not sufficient, lymphocytes may be recruited and their specific actions used to reinforce the nonspecific immune defense activation of innate immunity the innate immune system distinguishes between the body's own cells and pathogens through the use of the pathogen-associated molecular patterns (PAMPs) that are unique to invaders (ex. lipopolysaccharides "endotoxins") •some cells of the innate system have receptor proteins "pathogen recognition receptors" that recognize PAMPs -> genes for these receptor proteins are inherited through germ cells -> distinguishing feature of the innate immune system •adaptive immune system has a greater diversity because of postnatal mutation and recombination of the DNA coding for these receptors an important group of pathogen recognition receptors (PRRs) are toll-like receptors -> named after fruit flies ->are specific for a different type of molecule that is characterisitc of iinvading pathogens but not of human cells •we have ten different discovered toll-like receptors •won a nobel prize in 2011 in medicine exposure to LPS from bacteria -> stimulates toll-like receptor on certain cells (dendritic cells and macrophages) -> stimulated to secrete chemokines (cell attractant) -> recruits other immune cells and cytokines (cell growth and regulatory molecules) -> promotion of different aspects of immune responses (ex. innate -> phagocytosis and fever & adaptive -> B & T lymphocytes) Another group of pathogen receptors are NOD-like receptors -> located in cytoplasm -> recognize intracellular molecules derived from bacteria -> form inflammasomes (multimolecular protein complexes) -> activate caspase -> apoptosis •mutated NOD genes contibute to crohn's disease, where normal bacterial population of the gut cause intestinal inflammation The complement system integrates innate and adaptive immune responses •consists of protein in plasam and other body fluids that become activated when antibodies (adaptive immunity) bind to their molecular targets "antigens" (antigen refers to a substance that is capable of antibody generation •when this occurs complement proteins of the innate immune system promote phagocytosis, lysis of target cells, and other aspects of local inflammation inflammation can also be produced in absense of infection when tissue damage leads to necrosis -> immune system is exposed to DAMPs "danger-associated molecular patterns" which like PAMPs in invading microorganisms stimulate the innate immune responses and inflammation •when cells die by apoptosis they generally do not express DAMPs and thus do not provoke inflammation

T lymphocyte response to a virus

infection virus stimulates innate immune mechanisms at beginning antigen-presenting cells (mainly dendritic and macrophages) have pathogen-recognition receptors (PRRs) that cause the cells to engulf viruses and migrate to secondary lymphatic organs -> with MHC class-2 molecules present them to helper T cells -> activation of helper T cells to viral antigens and changes them into effective Th1, and Th2 and other specialized helper T cells -> stimulate B cells to form memory cells and antibody-producing plasma cells -> aid in proliferation of cytotoxic T lymphocytes •therefore activation of helper T cells is needed for optimal response of both B and T cells to viral infection cytotoxic T cells can only destroy infected cells if they display the foreign antigen with class-1 MHC molcules -> interaction between the two also stimulates proliferation of cytotoxic T cells -> proliferation also stimulated by interleukin-2 secreted by helper T cells that were activated by macrophages or dendritic cells the network of interactions allows for spread outward -> Helper T cells promote humor immunes response of B cells -> B cell genes for antibodies undergo somatic hypermutation and class switch recombination (switch between antibody subclasses) within the germinal centers of lymph nodes -> ability of B cells to produce class switched antibodies is dependens on helper T cells -> these helper T cells home to germinal centers of lymph nodes where they are activated by antigen-presenting cells -> aid B cells to divide and develop into plasma cells and memory B cells -> interaction between helper T cells and B cells help promote long term humoral immunity and ability of vaccines to evolke active immunity

Lymphatic system

interstitial space, or "interstitium is the space between blood vessels and the tissue cell of an organ •contains interstitial fluid and the extracellular matrix •interstitial fluid -> aqueous solution containing salts, nutrients, waste products of metabolism and proteins from plasma-> formed by filtration of blood capillaries extracellular matrix -> consists of fiber scaffolding formed from collagen proteins and a gel formed of glycosaminoglycans lymphatic system has three basic functions 1. transports interstitial fluid, initially formed as a blood filtrate, back to the blood 2. transports absorbed fats from the small intestine to the blood 3. its cells, called lymphocytes, provide immunological defenses against disease causing agents (pathogens) the smallest vessels of the lymphatic system, lymphatic capillaries form the vast networks in intercellular spaces within most organs -> very porous allowing whatever needs to enter and leave easily -> fluid in lymphatic capillaries is referred to as lymph merging lymphatic capillaries occurs as lymph is carried into larger lymphatic vessels called lymph ducts •walls of ducts are similar to those of veins -> same three layers and valves to prevent backflow -> fluid movement occurs by peristaltic contraction, valves, skeletal muscle movement, and arterial pulsation smooth muscle within the lymph ducts contains pacemaker cells that initiates the contraction potentials associated with Ca++ entry -> lymph ducts empty into one of two principal vessels, the thoracic duct and right lymphatic duct -> they then drain the lymph into the left and right subclavian veins -> interstitial fluid which is formed by filtration of the plasma out of the blood capillaries is ultimately returned to the cardiovascular system before the return the lymph is filtered through lymph nodes •the nodes contain phagocytic cells -> remove pathogens, and germinal centers which are sites of new lymphocyte production •tonsils, thymus, and spleen together are called lymphoid organs and likewise contain germinal centers for lymphocyte production lymphatic system may also transport cancer cells that can enter and later leave through the porous capillaries -> seeding other organs -> leading to the spread of cancer "metastasize" -> metastasis to the regional lymph nodes is the first step in the dissemination of tumors for cancers of the breast, colon prostate, and others

severe combined immunodeficiency disease (SCID)

lack both antibody-mediated immunity and cell-mediated immunity and typically die in infancy -> inherited disease that causes stem cells of WBCs to lack an enzyme adenosine deaminase -> body cannot fight infection about 100 children are born with this each year but the most famous was David Vetter, who lived 12 years in a bubble -> died in 1984 when given a bone marrow transplant from his sister that contained Epstein-Barr virus "EBV" -> caused David to develop cancer of his B-cells -> B cell lymphoma Gene therapy has been tried to cure these patients but so far it has only resulted in leukemia

Clinical Application: orthostatic (postural) hypotension

lowering of blood pressure upon standing that causes a person to feel dizzy and weak and in extreme cases even fainting normally the varoreceptor reflex compensates for the fall in pressure when a person stands -> caused as 700 mL of blood pool in the lowe rlimbs if an individual has low blood pressure because of dehydration medication (ex. beta-adrenergic receptor blockers) or any other cause including postprandial hypotension (among elderly) -> pressure falls after eating leading to orthostatic hypotension

Clinical Application: Lymphedema

lymphedema -> swelling of an arm or leg due to excessive amounts of fluid and protein in the interstitial fluid -> results form a blockage or destruction of the lymphatic drainage usually due to surgery or radiation treatments for cancers no cure and can trigger inflammation that leads to degenerative changes in the surrounding tissues can also be caused by a nematode worm which can block lymphatic vessels and cause enormous swelling or a leg or scrotum in the disease elephantiasis

Interactions between Antigen-Presenting Cells and T lymphocytes

major histocompatibility complex of genes produces two classes of MHC molcles •Class-1 MHC molecules -> on all cells except mature RBCs and present polypeptides derivd from proteins in the cell's cytoplasm and nucleus -> present "self" antigens normally, but can also present viruses •Class-2 MHC molecules -> produced only by antigen-presenting cells -> take foreign proteins through endocytosis, process them, and move the foreign polypeptide antigens to the surface -> with MHC class-2 moleculess present them to helper T lymphocytes, which can only be activated when antigens are associated to the class 2 MHC cytotoxic T lymphocytes can be activated to destroy a victim cell only if the cell presents antigens to them in association with the class-1 MHC molcules -> different between receptors results in coreceptors which are proteins associated with the T cell receptors •coreceptor known as CD8 is associated with cytotoxic T cells interacts only with class 1 MHC •coreceptor CD4 of helper T cells associates only with class-2 MHC molecules

Menopause

menopause "pause in menses" refers to the cessation of ovarian activity and menstruation that occurs at about the age of 51 years •the 5-10 years prior to menopause are known as perimenopause -> menstrual cycles become irregular and estradiol secretion fluctuates from cycle to cycle -> decreasing likelihood of pregnancy -> fall in estradiol is due to changes in the ovararies not the pituitary -> FSH an dLH secretion by pituitary is elevated due to lack of negative feedback only estrogen found in blood of postmenopausal women is the weak estrogen estrone found in mesenchymal cells in adipose tissue -> formed from weak androgens such as androstenedione and dehydroepiandrosterone (DHEA) secreted by the adrenal cortex -> due to adipose tissue being the only source of estrogen -> larger women have less chance of getting osteoporosis it is the withdrawal of estradiol secretion from ovaries that is responsible for many symptoms of menopause -> such as vasomotor disturbances and urogenital atrophy -> vasomotor distrubances produce "hot flashes" of menopause where a fall of body temp is followed by feelings of heat and profuse perspiration •atrophy of urethra, vaginal wall, and vaginal glands occurs with loss of lubrication •increased risk of atherosclerotic cardiovascular disease and progression of osteroporosis menopause is not considered complete until menstruation is absent for one year

phases of menstrual cycle: cyclic changes in the ovaries

menstrual cycle is typically 28 days long -> due to being a cycle there is no beginning or end •we call the first day of menstruation "day 1" ->when flow of menstrual blood is the most apparent •you can also divide the cycle into phases based on changes that occur in the ovary and endometrium •ovarie are in the follicular phase from the first day of menstruation until the day after ovulation -> enter luteal phase until first day of menstruation cyclic changs of endometrium are called the menstrual, proliferative, and secretory phase

Follicular phase

menstruation lasts from day 1 to day 4 or 5 •secretions of ovarian steroid hormones are at their lowest and ovaries only contain primordial and primary follicles •follicular phase of ovaries lasts from day 1 to about day 13 (variability due to menstrual cycle lengths) •during follicular phase -> primordial follicles grow, develop vesicles, and become secondary follicles - > one follicle in one ovary reaches maturity and becomes a graafian follicle •as follicles grow, granulosa cells secrete an increasing amount of estradiol -> highest concentration is two days before ovulation around day 12 "estrogen surge" -> increased sex drive growth of follicles and estradiol secretion is stimulated by FSH -> seen in higher amounts during early follicular phase compared to later (varies) -> stimulates FSH receptors in granulosa cells -> follicles become increasingly sensitive to FSH -> sensitivity augemented by estradiol which also stimulates production of new FSH receptors in the follicles -> stimulatory effect of FSH and their secretion of estradiol increases despite not having an increase in FSH levels -> toward end of follicular phase, FSH and estradiol also stimulate the production of LH receptors in graafian follicle •rapid rise in estradiol secretion from granulosa cells during follicular phase -> acts on hypothalamus to icnrease frequency of GnRH pulses -> LH secretion -> stimulates a positive feedback effect of estradiol on pituitary resulting in a LH surge -> occurs 24 hours before ovulation and reaches peak about 16 hours before, it is this surge that trigger ovulation -> there is also a smaller surge in FSH, which is possibly involved in preparing follicles for next month's cycle

Contraceptive methods

most reliable form -> abstinence, also prevents STDs birth control methods vary greatly in their effectiveness •birth control pill -> 98% •natural family planning -> 80% will not get pregnant and 20% will get pregnant within the year -> requires cooperation and planning between partners in a stable arrangement -> higher effectiveness (over 90%) when both people are committed •ovulation is charted by measuring: basal body temp, detecting spinbarkeit, detecting mittelschmerz, rising and lowering of the cervix, and mood changes

Electrical Activity of the Heart

myocardial cells are short, branched, and interconnected by gap junctions, which function as electrical synapses •mass of cells interconnected is known as a myocardium and is a single functioning unit or functional syncytium •impulses generally originate from the atrium so the atrial myocardium is excited before the ventricles if a heart of a frog is removed form all surrounding tissues and nerves the heart will still beat as long as the myocardial cells remain alive -> this automatic nature is known as automaticity, or intrinsic rhythmicity there are 3 regions that can generate action potentials and function as pacemakers (modified myocardial cells) •in a normal heart, only one the Sinoatrial node (SA Node) functions as a pacemaker -> located on R atrium near the opening of the superior vena cava •the two potential, or secondary pacemaker regions the AV node and purkinje fibers are normally suppressed by action potentials originating in the SA node

Fertilization

normally occurs in the uterin tubes and begins when the sperm binds to specific carbohydrates in the glycoproteins of the zona pellucida -> sperm are exposed to progesterone secreted by corona radiate -> progesteron activates the CatSper channels in the sperm head -> permits entry of Ca++ causing hyperactivation, required for the acrosomal reactions each sperm contains a large, enzyme-filled vesicle above its nucleus known as an acrosome •binding of the sperm with the zona pellucida triggers the entry of Ca++ and the acrosome reaction -> involves the progressive fusion of acrosomal membrane with plasma membrane of the sperm -> creates pores through which the acrosomal enzymes can be released by exocytosis -> these enzymes including protein-digesting enzyme and hyaluronidase (digests hyaluronic acid part of extracellular matrix) -> allow sperm to digest a path through the zona pellucida to the oocyte when sperm fuses with oocyte -> sperm release phospholipase C -> oocyte membrane produces second messenger inositol triphosphate -> stimulates the ER to release stored Ca++ -> rise of cytoplasmic Ca++ creates a Ca++ wave (takes a few seconds) -> activates the fertilized egg cell causing metabolic changes -> one such is the exocytosis of cortical granules -> contain chemicals that induce changes surrounding the ooxyte so that other sperm cannot fertilize it preventing polyspermy once fertilized the Ca++ wave allows the oocyte to continued from its arrest at metaphase II -> oocyte is stimulated to continue meitotic division -> produces a mature ovum and one polar body within 12 hours of fertilization the nuclear membrane in ovum disappears and the haploid number of chromosome (23) is joined by haploid chromosomes from the spermatozoon •fertilized egg, zygote, now contains 46 chromosomes •monozygotic twins "identical twins" ->derived from a single zygote that splits and becomes two embryos whereas dizygotic twins "fraternal twins" -> derived from two different zygotes produced by two ovulated oocytes fertilized by two different sperm spermatozoon contributes more than the paternal set of chromosomes it also contributes the centrosome needed for the organization of microtubules into the spindle apparatus,= •also sperm midpiece contributes some mitrochondria although these don't make up the embryo in the end -> quickly eliminated due to autophagy -> as a result all mitochondria in the body come from the mother a secondary oocyte that has been ovulated but not fertilized -> can't complete second meiotic division -> degenerates 12-24 hours after ovulation -> fertilization cannot occur if intercourse takes place later than one day following ovulation •sperm can survive 3-5 days in female reproductive tract -> fertilization can therefore occur within 3-5 days prior to day of ovulation or within a day

Causes of Edema

normally prevented by proper balance between capillary filtration and osmotic uptake of water by lymphatic drainage, Edema is the excessive accumulation of interstitial fluid may arise from a variety of reasons •high arterial blood pressure -> high capillary pressure -> excessive filtration •Venous obstruction -> "phlebitis" -> occurs when a thrombus forms in the veins or a mechanical compression of the veins (ex. pregnancy) -> congestive increase in capillary resistance •leakage of plasma protein into interstitial fluid -> decrease in osmotic flow of water to capillaries -> can occur during inflammation and allergic reactions as a result of increased permeability •myxedema -> excessive production of mucin glycoprotein in extracellular matrix -> caused by hypothyroidism •decreased plasma protein concentration -> caused by liver disease or kidnsey disease -> plasma proteins are excreted in the urine •obstruction of the lymphatic drainage -> due to parasitic larvae in elephantiasis or surgery (ex. breast cancer)

Paracrine regulation of blood flow

paracrine regulators are molecules produced by one tissues to help to regulate another tissue of the same organ (very common with blood vessels) -> particularly important in the endothelium of the tunica interna which produces a number of paracrine regulators allowing for vasoconstriction/dilation

congestive heart failure

occurs when cardiac output is insufficient to maintain the blood flow required by the body -> by MI, congenital defects, or hypertension (increase in afterload) •most commonh cause of left ventricular heart failure are MI, aortic valve stenosis, and incompetence of aortic and bicuspid (mitral) valves -> leads to postive feedback cycle where MI results in heart failure that results in heart remodeling that results in dangerous arrhythmias •failure of the right venticle is usually caused by prior failure of the left ventricle heart failure can occur due to electrolyte distruances -> excessive K+ in plasma decreases membrane potential of myocardial cells, while low blood Ca++ reduces the excitation-coupling process (low blood K+ and high Ca++ can lead to cardiac arrest) •congestive heart failure is caused by increased venous volume and pressure •failure of the left ventricle -> raises the left atrial pressure and produces pulmonary congestion and edema -> shortness of breath/fatigue, and possible death •failure of right ventricle -> increased right atrial pressure -> congestion and edema in circulation compensatory responses in congestive heart failure are similar to those seen in hypovolemic shock •activation of sympathoadrenal system -> increase in cardiac rate, contractility of ventricles, and constriction arterioles •in hypvolemic shock, renin secretion is increased and urin output is reduced -> increased secretion of the renin adn consequent activation of the renin-angiotensin-aldosterone system causes salt and water retention -> occurs despire an increased secretion of atrial natriuretic peptide (which would provide a compensatory effect on promoting salt and water excretion) due to all of this compensations chronically low cardiac output is associated with elevated blood volume and dilation and hypertrophy of the ventricles -> require high metabolic requirement for oxygen CHF (congestive heart failure) is associated with elevated plasma renin activity and angiotensin II production -> elevated activity of the sympathetic nervous system which has been shown to be stimulated by angiotensin II •drugs such as ACEIs and ARBs are usually the first line of treatment •treatment can be aided by beta-adrenergic receptor blockers with digitalis to increase myocardial contractility •vasodilators such as nitroglycerin and diuretics are also often given •we can identify this by overall edema in the body and swelling -> treated with digitalis from foxglove plant

Disseminated Intravascular coagulation (DIC)

often fatal, when a potent stimulant of coagulation enters the blood and stimulates wide-spread diffuse blood clotting which can be so severe it uses up all available platelets and clotting porteins -> leads to consumptive coagulopathy (aka DIC), a disorder of the clotting system -> hemorrhaging will ensue these patients will clot and bleed simultaneously •typically triggered by other conditions (ex. hyperkalemia from ruptured cells following a mismatched blood transfustion) •leads to fragmented blood cells (shishtocytes caused by fibrin nets) and purpura other triggers •obstertrical complications -> amniotic fluid embolisms, or a dead fetus •infection (endotoxins -> produced by gram negative bacteria) •Cancer -> abnormal growth •tranfusion reactions of incompatible blood -> factor VII -> DIC the best treatment is to remove and treat the underlying cause •low dose of heparin may be used -> stops cascade event •give fresh frozen plasma to replace depleted clotting factors -> as well as antibiotics

Vital Signs: Up in the Air

on a plane a man was slumped over -> chalky face with eyes open staring off -> no breathing and no pulse -> started on CPR you should take your own pulse before taking the patients pulse in an emergency to remind yourself to calm down ABC algorithm for handling cardiac arrest -> Airway, breathing, and circulation only 1/3 of patients suffering cardiac arrest in the hospital survive to the 24 hour mark (outside of the hostpital is around 10% and 1/7 on planes) use of defibrillator -> needed the use of a IV kit to give medications to restore his pulse •airplane kit had a variety of medicines but you need to know what caused the cardiac arrest (ex. high K+) coach class syndrome -> cause of a blood clot on a plane due to sitting to long •80% of diagnoses are made off of patient history telephone booth syncope "fainting" -> falling over is the body's way of protecting itself from low blood pressure by allowing remaining blood to work with gravity to the brain -> stuck in plane seat would prevent this mechanism by keeping the body restrained -> correct his posture, lifting his legs, CPR, and IV -> saw movement and a pulse return although he lived this time, long-term survival depends on diagnoses of the causing issue

Myocardial Action Potential

once another myocardial cell has been stimulated by action potentials from the SA node it produces its own action potentials myocardial cells have a resting potential of -85mV -> upon stimulation Na+ gates open -> rapid diffusion of Na+ through fast Na+ channels -> membrane now roughly -15mV ->this level of depolarization is held constant for .2-.3 seconds "plateau phase" -> held constant by slow inward diffusion of Ca++ through slow Ca++ channels (DHP receptors) -> balances out the slow outward diffusion of K+ •rapid repolarization at the end of the plateau phase due to opening voltage-gated K+ channels • (action potential of myocardial cells is most associated with the plateau phase) the plateau phase is accompanied by the entry of Ca++ -> beings excitation-contraction coupling (what allows for delay in heart "lub-dub") summation and tetanus is prevented form occuring in the myocardium by this long refractory period

Clinical application: artificial pacemakers

pacemakers -> implanted under the skin below the clavicle -> contains electrodes that are threaded into the heart and used to correct arrhythmias as a blockage in conduction of the impulse in the AV node or bundle of His many types -> some stimulate one change, while some stimulate both an atrium and ventricle by delivering a shock to cause depolarization and contraction -> most sense if a heartbeat is delayed and stimulate the heart on demane to maintain a good rate -> some can even sense if the person is exercising and adjust the rate

Clinical Application: Salt

salt -> needed to maintain blood volume and pressure •can be used as a food preservative -> ex. salt cakes were used as money in abyssinia, and rome (the word Salary comes from this) Mahatma Gandhi led indians, in their bid for independence, to make their own salt in defiance to the british

Cutaneous Blood Flow

skin acts as the first line of defense against disease-causing organisms -> also maintains the deep-body temp through thermoregulation •the thinness and large area of the skin make it a great radiator of heart amplified through the use of capillary loops near the surface of the skin -> blood flow through the skin is adjusted to maintain deep-body temperature at about 37˚C (98.6˚F) -> done by variation in degree of dilation/constriction by arterioles and unique arteriovenous anastomoses, found predominantly in structures on body (ears, nose, finger tips, etc. ) and shunt blood directly from arterioles to deep venules bypassing capillary loops •both orginary arterioles and arteriovenous anastomoses are innervated by sympathetic nerve fibers -> when temp is low nerves stimulate constriction -> blood flow is decreases so less heat will be loss -> skin may also appear rosy due to arteriovenous anastomoses diverted blood to superficial capillary loops -> lowered blood flow skin can tolerate extreme cold due to its metabolic rate decreasing, however if too restricted we see frostbite form -> vasoconstriction reflex is impaired in older adults making them more prone to hypothermia •blood flow can vary from 20 mL/min at maximal vasoconstriction to 3-4 L/min at vasodilation when warm -> decreased activity of sympathetic vasoconstrictor (adrenergic) axons -> dilation -> increased activity of sympathetic cholinergic axons -> further dilation by ACh -> cholinergic sympathetic axons stimulate sweat glands -> heat loss by evaporation •sweat glands secrete bradykinin, a polypeptide that stimulates vasodilation during excercise, no matter the temperature the need to maintain a deep-body temp takes precedence over the need to maintain an adequate system blood pressure -> vasodilation in cutaneous vessels occurs together with vasodilation in the exercising muscles •in ambient temp,. the cutaneous vascular resitance is high that the blood flow is low when not exercising •if a person exercises n hot weather -> increased skin temp and vasodilation can persist after exercise has ended -> low peripheral resistance with low cardiac output from resting makes the blood pressure fall quickly -> lost consciousness and even death changes in cutaneous blood flow occur as a result of changes in sympathetic nerve activity •emotional states acting through control centers can affect blood flow •fear -> vasoconstriction in the skin along with activation of sweat glands can produce pallor and a "cold sweat" •ex. of vasodilation in blushing

Haptens

small organic molecules too small to be antigens can become antigens if they bind to proteins and become antigenic determinant sites on the protein •discovered by karl landsteiner who also discovered blood typeing (ABO) •Landsteiner called these small molecule haptens ->bonding of haptens to a person's own proteins can occur (ex. penicillin) and can produce a variety of results, such as in penicillin leading to a possibly fatal allergic response •penicillin and other drugs can bind to platelets triggering an auto-immune response to a person's own platelets triggering drug-induced thrombocytopenia purpura

intrauterin device (IUD)

small piece of molded plastic that is inserted into the uterus by a physician •non-copper IUDs alter the environment of the uterus and oviducts so that fertilization will not occur and if it does implantation cannot take place •copper IUDs can kill sperm to prevent fertilization •hormonal IUDs -> have hormones that prevent ovulation whil simultaneously preventing the implantation if ovulation does occur

Menstrual cycle

stemming from old-world monkeys 1 month intervals -> menstrual cycle "menstru=monthly" •periodic shedding of stratum functionale of endometrium which thickens prior to menstruation •most animals don't have bleeding during shedding of endometrium and therefore these cycles are not called menstrual cycles •due to menstrual cycles primates can undergo intercourse at any time, which in contrast in other species females are only sexually receptie "in heat or estrus" at particular times in their cycles -> shortly before or after ovulation -> thus said to have estrous cycles •we see bleeding in dogs and cats shortly before they permit coitus due to high estrogen secretion (not shedding of endometrium) •bleeding in menstruation is caused by a fall in estrogen and progesteron secretion

Regulation of sympathetic nerves

stimulation of sympathoadrenal system -> increase in cardiac output, and peripheral resistance (caused by alpha-adrenergic stimulation of norepinephrine and epinephrine -> vasoconstriction of arterioles in viscera and skin) when a person is calm the sympathoadrenal system is active to a certain degree and sets the "tone" of vascular smooth muscle -> in this case adrenergic sympathetic fibers (release norepinephrine) activate alpha-adrenergic receptors to cause a basal level of vasoconstriction throughout the body -> during fight or flight we see vasoconstriction to digestive tract, kidneys, and skin Arterioles in skeletal muscle receive cholinergic sympathetic fibers -> release ACh as a neurotransmitter -> during fight or flight these cholinergic fibers increase -> vasodilattion (by epinephrine from the adrenal medulla -> stimulates beta-adrenergic receptors) •during fight or flight blood flower is decreased in the viscera and skin due to alpha-adrenergic effects of vasoconstriction , whereas in skeletal muscles it is increased -> gives muscle an extra edge during an emergency • a stimilar response occurs during excercise with increased blood flow to muscles

Regulation of stroke volume

stroke volume is regulated by three variables; 1. the end-diastolic volume 2. total peripheral resistance -> frictional resistance, or impedance to blood flow by arteries 3. contractility -> strength of ventricular contraction end-diastolic volume (EDV) •blood in ventricles immediately before they begin to contract •this is a workload imposed on the ventricles prior to contraction, and thus is sometimes called the preload •stroke volume is thus direclty proportional to the preload -> an increase in EDV results in an increase in stroke volume (frank-starling law of the heart) •stroke volume is also proportion to contractility; when the ventricles contract more forcefully, they pump more blood in order to eject blood the pressure generated in the ventricles must be greater than the pressure in the arteries (blood flows from high to low presure) •the higher the peripheral resistance, the higher the pressure •ejection of blood stops shortly after the aortic pressure becomes equal to the intraventricular pressure •the total peripheral restance thus presents an impedance to the ejection of blood from the ventricles, or an afterload imposed on a ventricle after contraction has begun • high peripheral resistance -> high arterial blood pressure -> high afterload -> hypertension (if enough resistance is present) stroke volume is inversely proportional to peripheral resistance -> ventricles compensate by increasing their contraction strength (ex in the cold causes cutaneous vasconstriction) -> inability to compensate can lead to congestive heart failure the proportion of the end-diastolic volume that is ejected against a given afterload depends on ventricular contraction strength -> normally contraction strength is sufficient to eject 70-80 mL of blood out of a total end-diastolic volume of 110-130 mL -> ejection fraction is thus about 60% (a percentage that remains relatively constant)

Clinical Application: Cerebrovascular accident "stroke"

strokes are the third leading cause of death in the United States and the second worldwide two categories: ischemic stroke, and hemorrhagic stroke ischemic stroke -> blockage of a cerebral artery by thrombus and usually the result of atherosclerosis hemorrhagic stroke -> bleeding of the cerebral artery due to an aneurism hypertension is the major risk factor, as well as A-fib, high blood cholesterol, and diabetes ischemic stroke can be treated with anticoagulants and thrombolytic drugs (TPA drugs "alteplase & metaplase") but are most effective if given quickly after the stroke due to excitotoxicity a process by which neurons die as a result of the ischemia-induced impairment in the removal of glutamate from synaptic clefts -> excessive Ca++ through NMDA receptors -> neuron death (currently there is no way to prevent excitotoxicity and its consequences) •excitotoxicity is the neurologically equivalent of cardiac reperfusion •can be prevented with Rivaroxaban which inactivates factor X

Blood Flow to the heart and skeletal muscles

survival requires that the heart and brain receive an adequate supply of blood at all times -> done by mechanism that increase cardiac output and divert the blood away from the viscera and skin so that the heart, skeletal muscles, and brain receive a greater proportion of the total blood flow

Vascular Resistance to blood flow

the amount of blood the heart pumps/min is equal to the rate of venous return (5.5L/min) -> this cardiac output is distributed unequally to the different organs because of unequal resistances to blood flow through organs the term extrinsic regulation refers to control by the autonomic nervous system and endocrine system •ex. angiotensin II -> stimulates vascular smooth muscle to constrict -> ADH also has a simiilar effect hence its name of vasopressin (this effect it not believed to significant under physiological conditions in humans

Pacemaker Potential

the cells of the SA node exhibits a slow spontaneous depolarization called a pacemaker potential, rather than a resting membrane potential •because the pacemaker potential occurs during diastole, it is also called a diastolic depolarization •SA node develops this depolarization in a clocklife manner through interactions with different membrane ion channels and transporters production of spontaneous depolarization involves ion channels in the plasma membrane and in the sarcoplasmic reticulum •HCN channels unique to pacemaker cells ---The H stands for hyperpolarization -> these channels open in response to hyperpolarization to allow entry of Na+ to produce a depolarization -> to unusual cause this called a "funny current" ---the CN part stands for cyclic nucleotide ->these channels open to cyclic AMP (cAMP) -> response to stimulation of beta-adrenergic receptors by epinephrine and norepinephrine The "funny current" is important, but also the clocklike entry of Ca++ into cytoplasm contributes significantly •once diastolic depolarization reaches the threshold value (-40mV) -> opens voltage gated Ca++ channels (DHP receptors) -> influx of Ca++ -> stimulates ryanodine receptors (RyR2 type) •called a Ca++ induced Ca++ release -> leads to a massive release of Ca++ from the sarcoplasmic reticulum into the cytoplasm causing contraction of myocardial cells •repolzarization is produced by opening the voltage-gated K+ channels that allow outward migration of K+ when repolarization is complete, mechanisms for the next depolarization begin -> next heartbeat •cardica rate can vary depending on the effects of the autonomic nervous system •epinephrine and norepinephrine -> produce cAMP in pacemaker cells -> opens HCN channels to produce a depolarization, as well promotes entry of Ca++ into cytoplasm -> by this means sympathoadrenal stimulation increases the rate of diastolic depolarization to produce a faster heart rate and increasing strength of myocardial contraction Acetylcholine (ACh) released by parasympathetic (vagus nerve) axons that innervate pacemaker cells -> binds to muscarinic receptors -> through G proteins opens K+ channels -> outward diffusion of K+ slows the time for the diastolic depolarization to reach the threshold, slowing the action potentials -> slowed the cardiac rate the SA node is not a uniform structure, but rather different regions that electrically separated from each other within the right atrium -> communicate through the sinoatrial conduction pathway •action potential spreads from this pathway to depolarize both atria and through other conduction pathways (AV node, bundle of His, and Purkinje fibers) to depolarize the ventricles -> paces the heart creating a normal sinus rhythm the AV node and Purkinje fibers are suppressed due to the refraction period produced by the SA node depolarization -> once the cell recovers it will again be stimulated by the SA node to do being faster than the other sites •if the conduction of the SA node is blocked the other regions could depolarize and produce action potentials -> region would serve as an abnormal pacemaker "ectopic pacemaker/ectopic focus" -> due to the SA node being the quickest these regions would produce a lower than normal sinus rhythm

Cerebral Circulation

the cerebral blood flow must be held constant at 750 mL/min -> amounts to 15% of total cardiac output at rest •not impacted much by sympathetic nerve activity under normal conditions -> only when the arterial pressure is about 200 mmHg do we see vasconstriction in the cerebral circulation -> help protect the small, thin-walled arterioles from bursting under the pressure and prevents CVAs (strokes) •in normal range of arterial pressures, the cerebral flow is regulated by intrinsic mechanisms -> autoregulation -> constant flow even during pregnancy when there is increased perfusion in other organs -> autoregulation is achieved by both myogenic and metabolic mechanisms myogenic regulation •occurs when there is variation in system arterial pressure -> pressure falls -> cerebral arteries dilate -> when pressure rises they constrict •cerebral vessels are also sensitive to CO2 concentration of arterial blood -> when high during inadequate (hyperventilation) ventilation -> arterioles dilate -> believed to be caused by pH rather than the effect of CO2 itself -> we see the opposite response when CO2 levels fall by hyperventilation -> constrict -> dizziness (why we feel dizzy with hyperventilation) metabolic regulation •active regions of the brain receive increased blood flow due to metabolic regulation -> active regions are hyperemic -> their blood flow exceeds the aerobic requirements of the active neurons •shunting of different brain regions occur due to changes in metabolic activity such as the production of vasodilation by K+, adenosine, NO, etc. -> astrocytes secrete vasodilator chemicals as well such as prostaglandin E2 and CO when stimulated by glutamate -> cause arterioles to produce vasodilators as well including NO •therefore neurons, astrocytes, and arterioles function together creating the neurovascular coupling process -> so that increased activity in the brain leads to increased blood flow - due to functional hyperemia the active neurons receive more O2 and glucose for their needs

Defense mechanisms

the immune system includes all the strutures and processes that are involved in protection against potential pathogens (disease-causing agents) and can be grouped into 2 categories; 1. Innate (nonspecific) immunity 2. adaptive (specific immunity Innate defense mechanisms are inherited -> epithelial membranes such as skin and mucous in organs cover all body surfaces -> these epithelial membranes secrete a variety of antimicrobial peptides •strong acidity of gastric juice (pH1-2) helps kill many pathogens before they can invade the body •these external defenses are backed by internal defenses such as phagocytosis seen in both a specific and nospecific manner adaptive immune response is function of lymphocytes and allows for defense against specific pathogens by prior exposure •immunological memory where lymphocytes ability is greatly impoved by prior exposure is the hallmark of adaptive immunity and the basis of vaccination •some cell in the innate immune system such as natural killer cells exhibit increased effectiveness during secondary exposure to a pathogen in a process known as trained immunity genes required for innate immunity are inherited -> recogniztion of molecules such as gram-negative bacteria on their surfaced -> molecules are known as lipopolsaccharides or endotoxins in adaptive immunity -> specific features of pathogens are recognized -> large amount of genes are required, far to large to be inherited -> produced by genetic changes in lymphocytes during the life of each person

Phagocytosis

three major groups of phagocytic cells: 1. neutrophils 2. mononuclear phagocyte system (monocytes and macrophages, as well as dendritic cells in connective tissue) 3. organ-specific phagocytes (liver, spleen, lymph nodes, lungs, and brain) -> include langerhans cell (epidermal dendritic cells) of the epidermis and kupffer cells (stellate macrophages) of the liver, and microglia of the brain -> these embryonically and functionally relatd macrophages are considered part of the mononuclear phagocyte system kupffer cells of the liver as well as phagocytic cells of the spleen and lymph nodes are fixed phagocytes -> immobile in walls of sinusoids -> as blood flow through foreign chemicals and debris are removed by phagocytosis and chemically inactivated -> sterilizes blood after a few loops macrophages operate separate of the immune system as they perform clearing of cellular debris -> when they recognize pathogenic signals such as PAMPs they become activated to secrete proinflammatory cytokines -> attract neutrophils and monocytes in connective tissues whcih through chemotaxis move to the site of infection (neutrophils arrive first, monocytes arrive later and transform into macrophages as battle progresses) neutrophils and monocytes interact with vessels in the infected area initiating a multistep process where leukocytes roll along the endothelia wall and activate where they then exit the vessel through extravasation "diapedesis" at postcapillary venules •narrowest venules consist of only endothelial cells and surrounding support cells -> leukocytes can penetrate the endothelial layer within minutes but may be held up by the basement membrane, a highly cross-linked network for up to 30 minutes before entering surrounding tissue phagocytic cells have membrane receptors for microbial molecules as well as for antibodies and complement protein -> trigger phagocytosis -> eaten microbe is contained within a vacuole "phagosome" -> fuses with lysosome which contains a digestive enzyme -> lysosomal enzymes may be released before the fusion is complete killing the cell and contributing to the inflammation of the infected area cells that commit apoptosis signal macrophages to attack by displaying a phospholipid "phosphatidylserine" on the surface that normally is found only on the inner layer of the plasma membrane -> tells macrophages to eat the cell -> suppresses inflammatory processes -> limits collateral damage that would result from the inflammation

Clinical Application: aerobic exercise training

training reduces cardiac rate while increasing stroke volume also increase vagus nerve parasympathetic inhibition of the SA node -> slows heart rate exercise also increases EDV and stroke volume, can see a 500mL increase in volume after only 8 days of training -> more forceful heart contractions -> improved oxygen delivery as a result of aerobic exercise training

Anticoagulants

used to reduce clotting tendencies •anticoagulants are not clot busters, anticoagulants prevent new clots, while clot busters break down existing clots, also anticoagulants are not blood thinners either due to not changing the viscosity of the blood Aspirin (acetylsalicylic acid) acts by permanently damaging the ability of platelets to clump (aggregate) -> effects can last 7-10 days (platelet life cycle) clotting of blood can be prevented by the addition of sodium citrate or ethylenediaminetetraacetic acid -(EDTA) both of which chelate (bind to) Ca++ -> lows Ca++ in the blood that can participate in clotting pathways -> this effect can be reversed by adding excess Ca++ in a test tube or by the metabolism of the sodium citrate in the body a mucoprotein called heparin can also prevent clotting -> activates antithrombin III -> a plasma protein that inactivates thrombin -> Heparin is given by IV (Intravenous) during medical procedures and acts immediately Warefarin "coumadin" -> administered orally, blocks the cellular activation of vitamin K (required in clotting) -> most common used oral anticoagulant •Vitamin K is produced by intestinal bacteria and is found in leafy green veggies •essential factor to hepatic enzyme, gamma-glutamyl carboxylase -> adds a carboxyl group to glutamic acid residues on factors II (prothrombin), VII, IX, and X -> in doing so it oxidizes itself, where it is then reduced by vitamin K epoxide reductase -> active once again (the reductase is important target of warfarin) •drug creates a deficiency of reduced vitamin K by blocking reductase -> inhibiting maturation of clotting factors •vitamin K deficiency from other causes (ex. malabsorption), prolonged antibiotic therapy, or impaired vitamin K metabolism in disease (hepatic failure) -> lead to formation of IVKAs (proteins induced in by vitamin K absence) -> partially, or totally non-gamma carboxylated -> affect coagulation factors' ability to bind to phopholipid •due to the indirect action of this drug It must be given several days before an effect is seen (2-3 days) -> need to use up available platelets •has been used to treat A-fib and venous thromboembolism -> now newer oral anticoagulants such as rivaroxaban (Xarelto) that directly inhibits factor X have become alternatives to warfarin for some patients

Clinical Application: platelet aggregation inhibitors

useful to prevent clot formation and coronary thrombosis -> major cause of MI aspirin irreversibly inhibits the enzyme cyclooxygenase -> required for prostaglandin formation -> inhibits the ability of platelets to produce the prostaglandin thromboxane A2, used in aggregation Clopidogrel (plavix) -> inhibits ability of ADH to promote platelet aggregation dipyridamole -> interferes with production of ADH glycoprotein llb/llla -> monoclonal antibodies that block the platelet plasma membrane receptors needed for platelets to bind to collagen and to von willebrand's factor -> prevent sticking to wound site

contraceptive vaccines

vaccine intended to immunize women against hCG a necessary hormone in implantation of embryo -> also goals of making an anti-sperm vaccine

Blood Pressure

variation in the diameter of arterioles as a result of vasoconstriction and vasodilation affect the blood flow through capillaries and simultaneously the arterial blood pressure "upstream" from the capillaries •how vasoconstriction raises arterial blood pressure -> blood pressure can also be raised by an increase in cardiac output •therefore the most important variables affecting blood prssure are thus the cardiac rate, stroke volume (due to blood volume), and total peripheral resistance -> an increase in any one of these if not compensated by a decrease in another variable will result in increased blood pressure blood pressure can be regulated by the kidneys -> control blood volume -> control of stroke volume •increased action of sympathoadrenal system -> raise blood pressure by vasoconstriction of arterioles -> increase in peripheral resistance -> promoting an increased output •sympathetic stimulation can also affect blood volume indirectly by stimulating constriction of renal blood vessels -> reduce urine output Blood pressure is measured in units of millimeters of mercury (mmHg) ->in a U-shaped column blood pushes on one surface while atmosphere pushes on the other -> is arterial pressure were equal to atm pressure we would see 0 mmHg, a 100 mmHg blood pressure would be 100mmHg higher than atm pressure •instrument used to measure pressure are called sphygmomanometers (cuff and gauge) -> contain either mercury or a spring-loaded equivalent

Vasectomy and tubal ligation

vasectomy was previously discussed tubal ligation -> cutting and sealing of oviducts -> using the method of laparoscopy which requires only two small incisions the surgeon inserts a small lighted endoscope to view the oviducts and cut and tie them •vasectomy or tubal ligation should be considered permanent and not a reversible operation due to 50% success rate

Venous Return

venous return must be balanced with blood leaving the heart •venous pressure serves as the driving force for returning blood to the heart and filling the atria and ventricles veins have a thinner, less muscular wall than arteries -> higher compliance -> pressure gives more expansion •2/3 of blood is held in the veins -> veins are therefore also called "capacitance vessels" (arteries are less compliant and are thus said to be "resistance vessels") •although the veins contain 2/3 of blood volume the mean venous pressure is only 2mmHg compared to the arterial pressure of 90-100mmHg -> pressure drop is due to drop between arteries and capillaries as well as the venous compliance •pressure is higher in the venules (10mmHg) and lowest at the junction of the venae cavae with the right atrium (2-6 mmHg) -> creates a pressure difference that drives the return of blood to the heart •venous return is also aided by sympathetic nerve activity -> stimulates smooth muscle contraction reducing compliance •the skeletal muscle pump -> squeeze veins during muscle contraction •pressure difference in thoracic and abdominal cavities contractions of skeletal muscles function as a "pump" by virtue of its squeezing action on veins -> diaphragm lowers as it contracts -> increases thoracic volume and decreasing abdominal volume -> partial vacuum in the thoracic cavity and high pressure in abdominal cavity -> pressure difference favors blood flow from abdominal to thoracic veins

hypertension

when blood pressure exceeds the normal range, starting at 130 mmHg for systolic, and 80 mmHg for diastolic hypertension caused by disease processes such as renal failure or an adrenal tumor is known as secondary hypertension -> only accounts for 5% of cases hypertension that is a result of a poorly understood process is known as primary, or essential hypertension -> found in 95% of cases ( we see risk of this above 115/75 mmHg) essential hypertension caused by either a change in cardiac output or total peripheral resistance -> possible role of NaCl? •dietary Na+ -> increase in osmolality -> ADH secretion -> increased water reabsorption -> higher blood volume increases cardiac output and pressure •should be prevented by abilityof kidneys to excrete the excess salt and water -> ability declines with age •aldosterone levels may be inappropriately high -> salt and water reabsorption -> if this is the case we should see elevated levels of renin an uncompensated chronic increase in blood volume -> increase in cardiac rate -> increase in blood pressure (hypertension) •baroreceptor reflex is chronically active during these times and should reduce sympathetic nerve activity -> vasodilation -> lowering of peripheral resistance -> lower blood pressure -> removal of excess NaCl and water however the activity of the sympathadrenal system in hypertension is often increased -> vasconstriction -> increase in peripheral resistance possbly by changes of secretion of paracrine regulators from the artery epithelium -> increase in endothelin (vasoconstrictor) and decrease NO -> with time structure of arterial wall may change to narrow the lumen and increase resistance hypetension and obesity -> production of leptin in rats -> increase in sympathetic nerve activity -> increase in cardiac output and peripheral resitance and water secretion due to all these factors the kidney function may be the "final common pathway" in essential hypertension a diet low in potassium -> raises blood pressure -> a diet with higher potassium leads to increased renal flow and acts as diuretic to lower blood volume and pressure -> due to this a salt-restricted diet containing K+ floods is more helpful in controlling blood pressure than one that is only lower in Na+

Immunoassays

when molecules act as antigens and can bind to antibodies, the antigens can be assayed by means of an antigen-antibody reaction (think WESTERN) •if they are attached to the surface of cells, or to artifical particles such as small polystyrene beads the antigen antibody reaction becomes visible because cells or particles agglutinate (clump) -> caused by antigen-antibody bonds, which create bridges between the cells or particles (not coaguation) agglutinated particles can be used to assay antigens and tests that do so are called immunoassays -> blood typing and pregnancy tests are examples -> to increase sensitiviy immunoassays use antibodies that exhibit specificity for just one antigenic determinant site

Vital Signs: Fetal Attraction

women fresh from prenatal yoga walks in at 35 weeks pregnant -> high blood pressure and protein in urine -> preeclampsia -> although the mother often feels fine she will need to be put on bed rest to prevent furthering of the situation to severe swelling, seizures, and even death 8% of women develop this -> possibly caused by placental pieces causing an inflammatory immune response -> women with this disease often have intact fetal cels in their blood streams these cells protect against breast cancer but women with preeclampsia have 8x what is normal "double edge sword"

Vital Sign - When flying can turn fatal

women on birth control started to develop clots was also on prednisone, a steroid, for a cat allergy calf was swollen and sore -> Deep vein thrombosis (DVT) 2/3 top killers are related to our lifestyles (stroke and heart attacks) age and birth control pills, smoking, obesity all increase the odds of getting a clot •there are also genetic factors that impact the parts of the clotting cascade treatment for DVT is anticoagulation -> typically heparin which requires constant IV dosing, newer drugs such as Lovenox can be injected subcutaneously once a day at home they could not see the clot initially on her -> silent pulmonary embolism?? •she did not have cat allergies -> her breathing issues were caused by a pulmonary embolism -> put on blood thinners and clot prevention method

treatment of hypertension

• life style changes if the typically the first form of treatment •Weight reduction • Physical activity • Diet (decrease Na+ intake and increase K+ intake) -Rich in fruits and vegetables -Reduced contents of saturated & total fats -Sodium restriction • Moderate alcohol consumption • Smoking cessation •increase intake of Ca++ • Diuretics -> increase urine volume -> lowering pressure/volume • β-Blockers (atenolol) -> decrease cardiac rate • Calcium channel blockers (CCBs) • ACE inhibitors, Ca++ antagonists, and vasodilators • ARBs -> blocks binding of angiotensin II ACE inhibitors and ARBs are the most commonly prescribed drugs for hypertension -> new drugs may inhibit renin activity in other ways