Tuesday, March 3, 2009

UPDATED!

Hey all, i updated the blog with all the lectures for exam #2. Sorry its a bit late. If you find ANY problems (something pretty likely) please either just comment on the post with the appropriate corrections, or email me and ill throw them up as posts. Thanks, and good luck!

.derek
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Lecture 19

Vascular Regulation: (what regulates blood flow)

  • To a certain extent, a tissue can regulate its own blood flow – this is called Autoregulation. (Autoregulation is found in the kidney too) Autoregulation has several mechanisms:
    • Myogenic Mechanism – (has to do with the blood vessels) the greater the blood pressure out on the arteriole smooth muscle, the more it stretches. The smooth muscle will contract to resist the stretch. This keeps blood flow more constant.
    • Metabolic Mechanism – decreases the oxygen level (decreases the partial pressure of oxygen (PO2)) in a tissue.  This will cause Vasodilation of the blood vessel and will allow more blood to go to the tissues with low amount of oxygen.
    • Things that cause Vasodilation:
      • Decrease the Oxygen Level (decreasing the partial pressure of oxygen)
      • Increase the Carbon Dioxide Level (increasing in Partial pressure of carbon dioxide)
      • Decrease the pH.
      • Increase the Temperature (more active tissue will generate more head – so if we increase the temperature we will increase the blood going to that tissue)
      • In Skeletal muscle – if we increase the Potassium level or if we increase the Lactate level (lactate builds up when we are doing a great deal of anaerobic activity of the muscle) it will increase the amount of blood going to the muscle.
      • In Cardiac muscle – increase in Adenosine
      • The more active the tissue, the more blood it will receive.
  • Endothelial Factors:
    • Endothelin – is a vasoconstrictor that is created by endothelial tissue.  It is found in arterioles and arteries. Endothelin is secreted in response to stretching of blood vessels, causing smooth muscle to contract, and it will be secreted with other stimuli
    • Nitroic Oxide (NO) – is a Vasodialator released in response to the stretching of blood vessels plus other stimuli (it is released the same way Endothelin was released)
      • We don't find NO in every blood vessel.  If we push on the walls of the endothelial cells, this will constrict to fight that, but if we have NO in the system, the more you push on it the bigger it gets.  It will dilate and the pressure drops in the vessel itself.
      • The Arcuate Artery and Interlobar Artery (are the last 2 arteries in the kidney (that go to the cortex of the kidney) prior to the blood going to the afferent arterioles going to the nephrons) will stretch with the presence of NO.  The afferent arterioles and the arteries prior to the Arcuate artery do not have this ability to stretch in the presence of NO.
        • It helps to be part of the Myogenic system of the kidney, as you increase the blood pressure, it will expand, and the blood pressure will drop. It maintains the blood pressure to the kidney. 
    • The roles vary from tissue to tissue.
    • Sympathetic effects can change the circulation
  • Sympathetic effects can change the Circulation, such as:
    • 1.) Vasomotor Tone
    • 2.) Fight or Flight
    • 3.) Baroreceptors – are stretch receptors in heart and surrounding vessels, which are monitoring blood pressure. Baroreceptors tell the brain lots of information.  The higher the pressure, the higher the firing rate will be.  There are 2 types of Baroreceptors:
      • 1.) High Pressure Baroreceptors –they are located in the Aortic arch (how much pressure is going out to the body), and are in the Carotid Sinus (how much pressure is going out to the brain) (located at the base of the internal carotid artery – regulating pressure to brain, at split of common carotid to the internal and external).  These High Pressure Receptors are monitoring blood pressure.  They monitor Atrial blood pressure, which is the pressure going out into the brain and out of the heart. These receptors increase their firing rates when the blood pressure increases.
      • 2.) Low Pressure Baroreceptors – they increase their firing rate when blood pressure goes up. They are located in the walls of both atria of the heart.
        • In right atrium they are very near the openings for the Superior vena cava and Inferior vena cava – in the walls of the atrium.
        • In left atrium they are near the Pulmonary veins – in the walls of the atrium.
        • There are 2 Types of Low Pressure Baroreceptors:
          • Type A – they discharge their electrical activity during Atrial Systole – how high pressure goes during contraction
          • Type B – they discharge their electrical activity late in Diastole – how high and low it goes during the Relaxation stage.
        • Because of this discharge system, the brain can tell pressure differences due to contraction, and due to over filling.
        • With these 2 types of firing mechanisms, the brain can monitor the blood volume in the venous and arteriole systems (it know the volume of the blood in the body), and it also does this with the pulmonary system (how much blood is going in)
          • They will lower their firing rate in response to lower blood volume even though artial pressure stays high – we are not quite sure how this works, but we think veins give input.
  • Chemoreceptors (Chemical Receptors) – are called Bodies. They are actually made for regulating breathing, but as a secondary function they are used for blood input changes.
    • Carotid Bodies (sit on the back of the carotid sinus, and monitor things going specifically what is going to the brain) and Aortic Bodies (monitor things going to the rest of the body) – the bodies are much smaller
    • These chemical receptors respond to:
      • 1.) Changes in the amount of Oxygen
      • 2.) Changes in the amount of Carbon Dioxide
      • 3.) Change in the pH levels
      • These receptors are mainly involved in regulating breathing
      • The chemical receptors can also affect blood pressure.
      • The following increase heart rate and increase blood pressure:
        • A decrease in oxygen levels increase heart rate and blood pressure.
        • An increase in carbon dioxide levels increase heart rate and blood pressure.
        • A decrease the pH increase the heart rate and blood pressure.
      • Anything that regulates fluid volume can directly or indirectly effect heart rate or blood pressure:
        • ADH (Anti-diuretic hormone) will increase blood pressure
        • Angiotension II will increase blood pressure.
        • ANP - Atrial Natrauretic Protein/Factor will decrease the blood pressure (it is the hormone produced by the atria of the heart in response to high blood pressure in the atria)
        • VIP – Vasoactive Intestinal Peptide will decrease the blood pressure.  It throws electrolytes into GI tract lumen, causing water to come out, and you lose water/fluid this way.
        • ETC.
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Lecture 18

Heart, cont.

  • Heart beat is half of the cardiac output
  • Stroke Volume (the other half of cardiac output) – depends on 2 variables:
    • 1.) End Diastolic Volume – how much blood is going into the ventricles; how the ventricle chambers will fill during Diastoli
    • Factors the increase End Diastolic Volume:
      • Stronger Atrial contractions
      • Increased total blood volume
      • Increased venous tone (blood is also stored in the veins) – contracting smooth muscle of the veins increases the amount of blood going back to the heart (thus reducing the available storage area)
      • Increase Pumping of Limb Veins – the veins in your arms and legs have semi-lunar valves in them, and when you are running you are increasing amount of blood going back to the heart.
      • A drop in Interthoracic Pressure – allowing ventricles to expand a bit; a drop means more negative, you drop the Interthoracic Pressure every time you inhale.
      • Increased Peripheral Resistance – it is harder to push the blood out, then more of the blood will remain in the ventricle and get a bigger beat the next beat; there is greater pressure in aorta, and more blood is in the heart because you cannot get as much blood out.
    • Factors that decrease End Diastolic Volume:
      • Standing up rapidly – get dizzy and feel faint – you get dizzy very quickly b/c you decreased the End Diastolic Volume, and it reacts quickly on your brain, so you get a change in blood pressure that caused the brain to get this dizzy message
      • Decreased Ventricular Compliance (Elasticity – the more elastic, the harder it pulls back)(Compliance – is how far something stretches – if we lose compliance we lose the ability to stretch).
        • Lose of compliance: When you have a heart attack, a section of your heart dies (it is like dead skin, it can easily burst open), but the damaged area that dies is replaced with Scar Tissue.  Scar Tissue is stronger than the original cardiac tissue, but it does not beat, contract, or expand, therefore you lose compliance.
      • Weaker Atrial contraction
      • Decreased total blood volume
      • Decreased venous tone
      • Decrease Pumping of Limb Veins
      • An increase in Interthoracic Pressure
      • Decreased Peripheral Resistance

      2.) Contractility – how much blood is coming out of the ventricle.  Contractility is essentially the Ejection Fraction.

      • It is best reflected/measured by the ejection fraction – how much is coming out
      • Refer to Chart from Notes – it reflects changes in contractility.
      • Graphs:
        • Stroke Volume vs. End Diastolic Volume
        • When you are under parasympathetic control the curve you get is a log-like graph
        • When you get sympathetic stimulation and we are working out heart the curve you get is a higher log-like graph
        • This difference is due to a change in contractility and we get a greater ejection fraction.

 
 

  • Circulation: (we have the blood out of the heart, now where is it going?)
    • Blood exhibits Laminar flow – refer to diagram – the blood moves faster in the center of the vessel, and as we go to the outside edges, the blood moves slower.  This keeps on going until we get to a theoretical layer of blood that isn't moving at all (it is theoretical b/c it is infinitely thin layer of blood (which is impossible) and it goes against the wall where it is not moving at all – it is theoretical because it is not there). The most important thing is that blood flow is slower towards the outside edges.
      • The RBC's bend to get into the arterial end of the capillary and it stays bent even at the larger venous end of the capillary because of Laminar Flow (even though the RBC diameter is 8.6um and the venous end is 10um). This shape is also ideal for Gas Exchange.
      • The capillary is 5um at the arteriole end and 10um at the venous end
      • The RBC's tend to go towards the faster flow
      • The cells start to get more concentrated as you get towards the center.
      • The hematocrit at the edge will be lower the hematorcrit at the center.
        • If we split the capillary, then you will get an equal Hematocrit going in both directions
        • If we have a capillary coming off of this at a right angle, then that capillary will get a lower Hematocirt b/c it is taking from the blood where there are fewer cells – this  is due to laminar flow and is known as Plasma Skimming.
        • The Capillary Hematocrit is 25% lower then the rest of the body
      • Laminar flow is smooth (soundless) and exists up to a certain Critical Velocity. Then the flow becomes Turbulent – Turbulent Flow is noisy, swirling, and is going no place. Laminar Flow is silent and efficient.
        • Turbulence is used to help take blood pressure, you can hear the sounds. You are listening to the turbulence created when you cut off the circulation of the brachial artery.
          • There is a unitless number that we measure that tells us the chances/probability of Turbulence called a Reynolds Number – the higher the number, the higher the probability of having turbulent flow.
          • Turbulence usually exists in the human body only under pathological conditions.
          • You hear turbulence when you are listening to a person's blood pressure, you are going to squeeze the brachial artery completely and then we reduce the pressure. Initially you are going to heart beats (caused by turbulence) – and those are called Korotkow Sounds.
          • Exception - ascending aorta at peak systole
            • Usually means accluded artery
  • Flow is going to equal ∆pressure / resistance
    • ∆pressure = mean arterial pressure – mean venous pressure.
    • Resistance = (8 x fluid viscosity x tube length) / (π x radius of tube^4).
      • The biggest input is the radius – the changes in the radius are the variable that is going into the resistance.
      • Blood viscosity is mainly hematocrit
      • 19% increase in radius doubles flow

       
       

  • Blood Pressure
    • Look at Pressure vs. Volume charts for arteries and veins.
      • For Arteries – we see a positive straight increasing linear graph
      • For Veins – we see a low pressure first, then suddenly we get a quick rise.
    • Arteries are thought of as Resistance vessels (pressure regulators)
    • Veins are thought of as Capacitance Vessels (a storage area for blood).
    • The pressure in aorta = 120/80mmHg (Systolic over Diastolic) – normal blood pressure
      • The blood pressure will drop when it moves into arteries and then into arterioles
      • The Pulse Pressure in the Aorta is 40mmHg
        • If you subtract the numbers (120-80) you get a Pulse Pressure
        • By the time you get to the end of the arterioles, the Pulse Pressure is 5mmHg.
        • In the Capillaries the Pulse Pressure is 0mmHg (non-existent)
        • Further away from heart = lower pulse pressure
    • If we look at a recording of a blood pressure going up and down, and we are possibly recording it on a polygraph, we will see a little notch, and that is called the Dicrotic Notch – this little notch is due to the closure of the Aortic Semi-lunar Valve
    • The blood pressure in Capillaries at the Arteriole end it is approximately 32mmHg.
    • The blood pressure in Capillaries at the Venous end it is approximately 15mmHg.
      • In the venules (when it gets into the venules), it will be between 12 to 18mmHg.
      • When it gets back to the large veins (outside of the thorax) it will be approximately 5.5mmHg.
      • At the entrance to Vena Cava (at the entrance of the Right Atrium) it is approximately 4.6mmHg
        • This 4.6mmHg will fluctuate due to 2 things: (it will go to 2mmHg and then it will go to 6mmHg cycling back and forth)
          • 1.) Part of this is due to the action of the heart contracting
          • 2.) It is mainly due to breathing
            • During Inspiration it drops to 2mmHg.
            • During Expiration it rises to 6mmHg.
    • (We are still looking at the capillary picture) The filtration pressure of a capillary is determined by Starling Forces.
    • Starling Forces – are:
      • Hydrostatic pressure – the measurable pressure (can be measured with a gauge); that is what we are looking at here, the 15mmHg and the 32mmHg
      • Osmotic Gradient – osmosis is the flow of water from a greater concentration to a lesser concentration. It is a gradient b/c we will stated in terms of mmHg
        • The membrane will only allow water to cross (salt cannot get though). Think of a two chamber system with a permeable membrane between them.
          • If one side is diluted with salt, water will flow to that side.
          • The level of water stops because the weight of the water equals the draw of the gradient (this is how we determine where the gradient is) – it is how much pressure is needed to offset them
          • The Osmotic gradient at the Arteriole end is 25mmHg
          • The osmotic gradient at the Venule end is approximate the same at 25mmHg
      • At the Arterial end the Hydrostatic Pressure in the capillary is 32mmHg – pushing out, and the Osmotic Gradient will be about 25mmHg pushing in (trying to draw the fluid towards it/inward).
      • At the Venule end Hydrostatic Pressure of 15mmHg out, but Osmotic Gradient is still about 25mmHg still inward.
      • The area outside the capillary but not inside a cell is called the Interstitium.
        • In the Interstitum, we consider the pressure to be about 0mmHg. 
        • There is 3mmHg Osmotic Gradient – it is drawing fluid out.
      • Calculations:
        • Arterial end (we have 32 out, 3 out, and 25 in) = 32 + 3 – 25 = 10mmHG outward – this is the Filtration Pressure
        • Venule end (we have 15 out, 3 out, and 25 in) = 15 + 3 – 25 = 7mmHg in (the Filtration Pressure is never a negative values – it just changes inward or outward flow)
      • The Filtration pressure is outward at the arterial end and inward at the venous end. The Filtration pressure will change from a 10mmHg out to a 7mmHg get inward (there is a change in direction)
      • We will be taking less fluid in then we will be putting out.  This is due to both Filtration Pressure and Starling Forces
      • THERE WILL BE FORCES LIKE THIS ON THE TEST (WE WILL HAVE TO CALCULATE A FILTRATINO PRESSURE ON THE TEST) HE WILL GIVE US BLANKS TO FILL IN DURING THE SHORT ANSWER SECTION
    • The design of the capillary is a very good explanation of the Starling Forces.
    • You never get negative numbers when adding the Starling Forces, you just reverse the flow. It is possible to get zero.  There was a point where zero was reached.
  • More fluid will be leaving the capillary then will be retrieved by the capillary.
  • 85% of the fluid/filtrate returns through the Capillaries and Pericytic Venules.
  • 15% of the fluid/filtrate will return as Lymph (in the Lymphatic System)
  • Starling Forces will vary from tissue to tissue (ex. The Kidney – filtration and reabsorption)
    • This picture that we drew is the drawing that Starling drew when he first talked about Filtration Pressure, but it didn't give a good idea of how the system was working.
    • In the Renal Glomerulus, the flow is outward for the entire length of the capillary – this is in humans. In rats and other experimental mammals, there filtration pressure will drop to zero but it never reverses and comes back in. It is all outward flow.
    • Intestinal villi is inward flow almost always over its entire length.
    • Peritubular capillaries in the kidney – 100% inward flow.
  • We have an Arteriole coming down and then we have a Through Channel, and they come down the other side, and we have a Venule there
  • Coming off of this is a Capillary, and that will go into a Capillary Bed
  • Capillary Beds – consist of a Through Channel with an arteriole end and a venule end.
    • This can drain back directly into the Venule or it can go on and connect back on into the Through Cannel.
    • Sitting around this is a Capillary Sphincter, it is not innervated by anything, but it is just regulated by local prostaglandins in the tissue
  • Skeletal muscle doesn't have capillary sphincters
    • The Capillary sphincter will wink open and close (they are not innervated) – there is an outward and inward flow. When they are open the fluid is basically going out into the tissue, and when they are closed the fluid is going back into the capillary bed.  There are a series of capillary beds functioning like this, and there is even another set of capillaries coming off too.
      • Capillary sphincters aren't opening or closing at the same time, so we are getting a steady flow of blood in and out of the tissue at the same time.
    • If we drop the pressure inside the blood vessel, then the Hydrostatic pressure of the Interstiutium/outside will be enough to collapse the capillary, stopping the blood flow through – this is called the Critical Closing Pressure.
      • Once it collapses, there is nothing going back into it, it is not absorbing anything.
      • There are some other ways that the capillaries get things out (besides Starling Forces and Hydrostatic Pressure) such as through little Vacuoles. 
    • Capillaries mainly in the CNS will use Starling Forces and Transcytosis.
    • Transcytosis (CSF, aqueous humor, endolymph of ear) – are all leaving in this direction, all being returned to the venous system. This is the main system for the CNS.
      • How Transcytosis works is that a cell that has Vacuoles will open up, which pick up fluid at one end, then travel to the other end and let the fluid out. The vacuole will then travel back to the beginning to where it can pick up more fluid.
        • Sometimes the vacuoles are stacked together (taking stuff in or letting stuff out).  Sometimes a vacuole comes between them and makes a channel between them.
      • We see Transcytosis associated with the Central Nervous System.  Some examples are:
        • When the Cerebral Spinal Fluid is being returned to the blood stream (if we increase the Hydrostatic Pressure behind the CSF it will increase the flow of the CSF in the Dura Sinus)
        • When we are returning Aqueous Humor in our eye into the Canal of Schlemm.
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Lecture 17


The Heart

  • The Electrical Event of a Heart Beat
    • First, the SA Node fires – the excitation sweeps across the atria but it will be moving the fastest through Bachmann's Bundle (the Preferential Pathway).
    • Bachmann's Bundle carries excitation to the left atrium.
    • Bachmann's Bundle carries excitation 3x faster than other parts of the atria.
    • Electrical activity sweeps down Inter-Atrial septum, it got there via Bachmann's Bundle. There is no connection to the AV node, it just sweeps slowly down there.
    • The AV node then fires
    • The AV node is connected to Bundle of His and the impulse is carried through the skeleton of the heart (this goes through the only hole in the heart which is insulating the 2 atria from the ventricles) through the Bundle of His – this is the beginning of the Perkinji system
    • The Bundle of His only conducts in one direction (that is down into the ventricles) – and is the only electrical connection between the atria and the ventricles. Anything that starts in the ventricles will not go up to the atria.
    • The electrical excitation branches into bundle branches.  Coming off the bundle branches are Perkinji Fibers, which moves the excitation quickly into the ventricle so that we get a uniformcontraction of the ventricle.
    • Bundle Branches and Perkinje Fibers are all sub-endocardial – They are under the endocardium layer and they are lining the inner parts of the ventricles.
    • When the electrical activity fires in the ventricles, it is going to move from the endocardium towards the epicardium. It will be firing from the inside out.
    • Repolarization of the ventricles will start at the apex and sweep back towards the base of the heart (look at a picture of the heart to see this)
  • EKG or ECG – The Electrocardiogram: (monitors electrical activity of the heart)
    • The EKG was developed by Einthoven, he was the first one able to monitor the electrical event and name the waves. He invented the machine that we use today to monitor them (he won the Noble Prize).
    • Einthoven determined and used 3 leads – I, II, III
    • A professor at the University of Michigan, named Wilson, developed Unipolar Leads.
      • Wilson called the Unipolar leads VR, VL, and VF
      • Wilson also did Chest Leads but he never standardized them (he was always changing V1)
    • Standard EKG uses 12 Leads – called a 12 Lead EKG.
      • These are Bipolar Readings
      • We have Limb Leads, which are I, II, and III that Einthoven worked with, and they are termed Bipolar Limb Leads. We term them as positive or negative electrodes.
        • Now the pen is moving up and down – when it sees a positive charge it moves up (upward deflection) – this is referred to as the Positive electrode. The left arm does not have a physically positive charge.
          • The pen doesn't move left and right
        • I – is monitoring the Right Arm vs. the Left Arm – and the left arm is positive.
        • II – is monitoring the Right Arm vs. the Left Leg – and the left leg is positive
        • III – is monitoring the Left Arm vs. the Left Leg – and the left leg is positive
    • Einthoven said that if we take an equilateral triangle and put an electrical event in the center of the triangle, and we monitor the corners of the triangle for an electrical event, they will sum to zero.
      • Zero electrical activity means that would be a ground said Wilson
    • Wilson said if that is true, we can do Unipolar Reading if we add all the readings (heart in center of triangle) and compare them to a probe that is positive.
      • Anything with a V is a Unipolar reading (V leads = Unipolar leads). The probe would always be the positive one.
      • VR (Right Arm) – the positive probe is on the Right Arm, and that was compared to the other 3 – Left Arm, Left Leg, Right Arm – you get a reading wherever the probe is put.
      • VL (Left Arm) –the positive probe is on the Left arm, that is vs. Left Leg, Right Arm, Left Arm
      • VF (Femoral) – the positive probe is on the Left Leg and that is vs. the Right Arm, Left Arm, Left Leg – all these will be positive in this case, they are the probe which is always positive.
        • The probe is always positive.
      • When Wilson did chest leads he would do these 3 vs. wherever he put the positive probe on the leg.
      • Think of what a Bipolar recordings is -  if we saw a po sitive we move the pen in one direction, and if the other one sees that same positive it is saying move the pen in the other direction
      • If we put a probe on the right arm and if we put another probe on the right arm, they are seeing the same thing.  One is saying go in this direction in some amount, and the other one on the arm is saying the same thing but to go in the other direction with the same amount.  But that means that the pen doesn't move.
      • 1/3 of all of all of these trials are going to be 1/3 smaller than they could be. 
      • 1/3 of the input into the recording machine is saying don't move and it does not move. The other probes are the ones causing the movement.  So people in the 1930's and 1940's thought that they should augment the Leads (change the system).  Now we are just comparing Right Arm to the Left Arm and the Left leg.  We will do the same with the Left Arm, where we take out the comparison to the Left Arm, and compare it to the Right Arm and Left Leg.  Then we will do the same thing with the Left Leg, where we take out the comparison to the Left Leg, and compare it to the Right Arm and Left Arm.
      • These will give identical recordings but now we will get a larger blip and it will be easier to read.
        • The machine switches by comparing this aV one to the other two.
      • These are called Augmented Leads (a = augmented lead): these are called Unipolar Limb Leads (b/c you don't need a probe, they are called Limb Leads)
        • aVR (Augmented Unipolar Right Arm) – compared to Left Arm, Left Leg
        • aVL (Augmented Unipolar Left Arm) – compared to Left Leg, Right Arm
        • aVF (Augmented Unipolar Femoral – Left Leg) – compared to Right Arm, Left Arm
    • Wilson added Chest Leads:
    • V1 – in the 4th intercostal space to the Right of the sternum.
    • V2 – in the 4th intercostal space to the Left of the sternum.
    • V3 – is halfway between V2 and V4. You have to find V4 first but you never run V4 first, always V3 first
    • V4 – in the 5th intercostal space and it is Mid-clavicular line (if you go to your clavicle to the manubrium to the Mid-clavicular line down to the 5th intercostals space)
    • V5 – anterior axillary line (armpit) at the corner of the chest, and it is at the same level as V4.
    • V6 – is the mid-axillary line, directly under the arm, and it is at the same level as V4 (the same level as V4 doesn't mean that it is in the 5th intercostals space – the same level as V4 means (when someone is lying down) it is going straight down the side of their chest in a straight line, like you have a plum line)
    • V5 and V6 are not in the 5th intercostal space, because the 5th intercostal space rises up – you want to be at a plum level, straight down to the ground.
      • Most books will say that V4, V5, V6 are in 5th intercostals space, but that's NOT true, V5 & V6 are not in 5th intercostals space, it's a plum bob level.  The 5th intercostals space rises up, but V4 and V5 don't (THIS WILL BE ON THE TEST)
        • Read the American Heart Journal – Volume 15, page 277 (1935 Journal).  The announcement in the journal said that the American Heart Association and the Cardiac Society of Great Britain and Ireland were the ones who set the definition for V1 through V6.  When they did the setting for V4, they said "V4 is at the outer boarder of the Apex beat" – you were supposed to listen for the Apex beat with a stethoscope.  V5 and V6 were said to be at the same level as the Apex beat, the Apex beat doesn't rise up (the 5th intercostals space does), but the Apex beat stays at the same level all the way done. It went on to say that if the Apex beat cannot detected, then we V4 should be considered  mid-clavicular line 5th intercostal space, (but they didn't correct V5 and V6) - So the same line as V4 is a straight line down the side
    • Always record them in proper numerical order, but they are not necessarily found in order.
  • There are Experimental Leads that are used for people with non-normal conditions or different orientation of the heart. Just know that they exist.
    • V7 – Posterior axillary line on the back edge of thorax
    • V8 – Inferior angle of the left scapula – V3R (Right) goes through V8R (went around the right side of the body to get there).
    • V9 – Spinous process of the 8th thoracic vertebrae
    • Don't have to know thesehh
      • There is a man from Russia who did a 12 Lead EKG (in this class) – it was all messed up – he said that his aorta ascends on the right (normal to ascend on the left) – his heart was in backwards essentially – he is someone who you might want to use those leads so you could be able to rotate the leads around to make sense of the EKG
  • Typical EKG Waves:
    • Einthoven (Nobel Prize – 1927) named the waves and invented the machine that could record them.
      • P-Wave, R-Wave, S-Wave, T-Wave, U-Wave
        • P = round and up and small
        • Q = small point and down
        • R = big point and up
        • S = small point and down
        • T = bigger hump up
        • U = tiny little bump up
    • P wave – 1st upward deflection in the normal EKG – represents Atrial Depolarization
    • Q wave – is the downward deflection that occurs prior to the R wave. It is always followed by an R wave
    • R wave – (gets smaller as you move across the chest leads)
    • S wave – is the downward deflection/wave the follows the R wave (picture on the board is this wave)
    • This is called the QRS complex – represents the Depolarization of the Ventricles. The Repolorization of the Atria is probably buried somewhere in this pattern/area (it gets lost in this QRS complex), because it does not appear anywhere else. 
      • Want to write it like this qRs – this means q wave was short, R was tall, and s was short.
    • T wave (very large) – are the Repolarization of the Ventricles, they are massive.
      • Repolorization starts at the apex and sweeps back over to the base.
    • U wave – they think it is the Bundle of His Repolarization or papillary muscle repolarization.
    • Once in a while we see a QRS complex that has the Q the R and the S, and then the S comes up and there is another wave up and that is called an R prime (R'). And then we have another one down and that is called S prime (S'), and then if we have another one up is an R prime prime (R''), and then if we get another one down that is called an S prime prime (S'') (you rarely go beyond a double prime – you will be dead)

 
 

  • Mechanical Contractions of the Heart
    • Systole – is the contraction of the heart
    • Diastole – is the relaxation of the heart
    • Highest blood pressure is the systolic, lowest is the diastolic.
    • Late in Diastole – the AV valves are open, and the ventricles are filling passively.  Also, the semi-lunar valves of the pulmonary trunk and aorta are closed.
      • The blood is coming in, but it is going down into the ventricle, it is filling passively.
      • During diastole 70% of all ventricle filling is passive.
    • Atrial Systole starts – it is the contraction of atria
      • This completes the filling of ventricles
      • Emptying auricles – are the ear like appendage on each atria (these auricles are important b/c your blood is a fluid system and you can't stop the flow.  We are shut valves, and that is going to stop the blood from flowing, but you don't want the blood to stop flowing (or else you get tragic results).  We need a place for the blood from the veins to go.  When the valve is closed between the Right Atrium and the Right Ventricle that ear like appendage will fill with blood, and the blood will continue to flow into the atria (this is a place to flow).  When it beats it empties the blood out, and it gets ready to accept blood when the valves close again.  This will keep the blood flowing)
    • Ventricular Systole starts – the AV valves shut (between the atria and the ventricle). The ventricles are kind of full of blood. 
      • We have valves between the aorta and the pulmonary trunk, and they are shut too.  Now we have a chamber with all valves shut, and you can't compress a fluid. The tension builds up in this until finally it creates enough pressure in there to pop open the aortic valve and the pulmonary trunk valve. 
      • The semi-lunar valves have not opened yet and pressure builds up, you cannot compress a fluid (cannot compress blood) – the volume is not changing because there is not place for it to go.  The time that the blood spends here where all 4 valves are shut (in this closed chamber where you are increasing your pressure) is called the Isovolumetric Contraction Phase.
      • Finally the pressure exceeds the pulmonary trunk and the aorta and the semi-lunar valves are forced open (ejecting the blood), and they stay open (the pressure is going to drop), but both of these are expandable b/c they are elastic arteries, so they expand with the pressure.
        • Semi-lunar valves close when pressure drops, but there is a hesitation (especially in aorta) because a small amount of the blood will go into the aorta because it has momentum.
        • The Semi-lunar valves close due to the drop in pressure of the ventricles. The pressure continues to drop and diastole beings.
        • Even though the pressure has dropped, it is not low enough to open the AV valves – this is called the Isovolumetric Relaxation Phase (the heart it is relaxed and all 4 valves are closed.
          • Isovolumetric = all 4 valves are closed
          • Then the pressure drops and passive filling will begin.
    • At rest, at the end of Diastole, the ventricles are each filled with 130ml of blood.
    • At the end of systole, approximately 50ml will remain,
    • 80ml were ejected during the beat – this is 62% of the total blood in the ventricle that was pumped out
      • This percentage is called the Ejection Fraction. The fraction will change with heart rate.
    • The highest pressure that was reached in the aorta at rest was approximately 120mmHG – we call this the Systolic Pressure
    • The lowest pressure that was reached in the aorta at rest was approximately 80mmHg – we call this the Diastolic Pressure
      • 120/80mmHG (Systolic over Diastolic)
      • This is the blood pressure of the aorta.
        • If we had this pressure in the lungs we would be dead (fluid would get into our lungs immediately)
      • A Pulmonary Trunk Pressure would be far lower otherwise we would drown in our own fluids – 25/12mmHg (Systolic over Diastolic). Sometimes this is referred to as the Hidden Blood Pressure (so that you don't drown in your own fluids)

 
 

  • Cardiac Output – the volume of blood pumped per one minute.
    • Cardiac Output is dependent upon 2 variables:
      • Heart rate
      • Stroke volume
    • Heart Rate:
      • If increase heart rate that increases cardiac output
      • This works until you get to 180 beats/minute
      • The heart rate will rarely go over 200.
      • Heart rate peaks at 180 beats per minute because the veins cannot return blood faster than that. They cannot fill the ventricles quick enough.
      • The pacemaker of the heart is the SA node. 
      • The SA node is being stimulated tonally by the sympathetic and parasympathetic fibers firing at the same time. They are both sides of the SA node telling it what to do.
      • The parasympathetic system is saying slow down
      • The sympathetic system is saying speed up. 
      • The normal resting heart beat is about 70 beats per minute.
    • If we cut Vagal stimulation (thereby blocking the sympathetic tonal firing) then the heart rate goes up to 150 to 180 beats per minute – the sympathetic is telling this thing to beat at 150 to 180 beats per minute all the time.
    • If we block both the parasympathetic and the sympathetic system, so the SA node is on its own, then the heart beats at 100 beats per minute.
    • The parasympathetic system is winning b/c your normal heart rate is only 70 beats per minute – this is tonal firing of the parasympathetic system, it adjusts for different activity levels.
      • As the professor walks around he is not in fight or flight, so when stands up his heart rate changes. But it is the Parasympathetic system that changes the firing rate, which then allows the Sympathetic system to win to increase your heart rate (under normal circumstance of non flight or fight the heart rate is controlled by the parasympathetic system)
  • The Vagal Innervation of the SA node (we should immediately think Parasympathetic system b/c it is the Vagus Nerve) is from the Right Vagus – it slows the heart by decreasing cyclic AMP – this slows the opening of the Calcium – L Channels.
    • It also decreases the slope of the Pre-potential by opening potassium channels.
    • The Stellate Ganglion (is Sympathetic) is innervating to the SA node is from the Right Stellate ganglion – it increases cyclic AMP (but it doesn't do anything to the slope of the Pre-potential – if the slope does change it is due to the lack of parasympathetic stimulation).
  • The Vagal Innervation of the AV node is from the left and the Stellate Ganglion of the AV node is from the left.  They are fighting over the AV node.
    • The AV node speeds or slows down the rate of conduction; it determines how quickly it passes the electrical activity to the Bundle of His
    • The AV node is always beat to the punch by the SA node – under parasympathetic control the SA node will slow the conduction rate of the AV node and under sympathetic it will increase the conduction rate of the AV node.
    • There is Parasympathetic and sympathetic innervation of atrial cardiac muscle cells.
    • Only the sympathetic system innervates the ventricular cardiac muscle cells.
      • In ventricular muscle cells it Catecholamines will increase cAMP.
        • This activates a Protein Kinase.
        • The activated Protein Kinase phosphorylates:
          • Calcium channels in the sarcolema
            • This increases the calcium intake into the cell – in cardiac muscle cell, some calcium comes in from the outside and some comes in from the sarcoplasmic reticulum + terminal cisterns – increasing available calcium.
          • Troponin – Tn-I – inhibits Tn-C from binding calcium – shortens length of time Calcium stays on Tn-C.
          • Phospholamban – increase calcium uptake by the sarcoplasmic reticulum so terminal cisterns have more.
        • The faster the heart beat, the more calcium that is going to come out, the faster the Calcium will be on the thing so you will have a shorter contraction.  This shortens the action potential and quickens the beat. It does not change the rate.
    • Parasympathetic fibers don't innervate the ventricles, any lengthening of the beat is just the lack of sympathetic stimulation.
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Lecture 16

 
 

  • Plasma Globulins, Continued
    • Beta 1 - 1
      • 1 – Haemopexin – it binds Heme group (not hemoglobin) – should the heme unit break off, Haemopexin will bind it, and then the liver will take up the whole thing.
      • 1 – Transferrin – is an iron carrier in the blood, there is no free iron in the blood.
        • When we are absorbing iron, it will be taken by transferrin to be taken to where it is utilized – to make heme.
      • 1 - C4 – Complement Factor – we will learn more about this when we talk about the Immune System
    • Beta 2 - 2
      • 2 – Lipoprotein – (IDL (Intermediate Density Lipoprotein) and HDL (High Density Lipoprotein = this is the Bad Cholesterol)
      • 2 – C3 – Complement Factor – most prevalent complement factor
      • 2 – Angiotensinogen – is the blood protein that renin would break off parts of it to create Angiotensin I, going to the ACE enzyme, and form Angiotensin II, it is a powerful protein for raising your blood pressure
      • 2 – Plasminogen – it functions in blood clotting
    • Gamma - 
      • - Fibrinogen – it is activated by Thrombin to start making a clot
      • - Ig-A – Immunoglobin
      • - Ig-M – Immunoglobin
      • - Ig-G – Immunoglobin
        • The above three are Immunoglobins, and they carry on the immune response.  Immunoglobins are antibodies in various forms that can stimulate something to be produced.
        • Gamma globulin shots are used when we take a blood protein from someone who has antigens, and we give it to someone else who does not have these antigens so that that person can fight off an immune response
  • Blood Clotting:
    • http://en.wikipedia.org/wiki/Coagulation

    • Platelets are very important for blood clotting.  They have small packets of granules, and they contain 3 types of granules:
      • Alpha - Granule: contain:
        • Albumin
        • Growth Factor called Platelet Derived Growth Factor
        • Clotting Factors
      • Delta - Granule: contain:
        • Serotonin – extremely powerful vasoconstrictor (if one is bleeding, we want to vasocontrict to stop the bleeding)
        • ADP (Non-metabolic) – it is acting as a signaler (it is not taking part in metabolism)
        • Catecholamines
      • Lambda - Granule: contain:
        • Lysosomal enzymes – (they are lysozymes) can attack bacteria and digest parts of their walls.
    • When there are no damaged vessels, the platelets circulate through the blood without sticking to anything.
    • In a damaged vessel there is exposed collagen, and when the platelets come into contact with Collagen, ADP, or Thrombin it is going to be activated.
    • Clotting is a Positive Feedback System, so there have to be mechanisms to shut it off so it does not get carried away with itself.   Clotting is a series of Positive and Negative Feedback systems.
      • Platelets are activated by collagen, ADP, and thrombin – tends to be a Positive Feedback System.
      • The activated platelet cell has a thickened outer layer that grows spikes (called Pseudopodia) – the layer is so thick that you cannot travel through it so the granules discharge and travel through the Canaliculi – the holes of the Canaliculi are where the Pseudopodia form.
      • The activated platelets will start to stick to other activated platelets and they will also start to stick to the area of the injury.
        • They will keep sticking together until they get a fairly large glob of platelets this is called a Platelet Plug.
          • The formation of this Platelet Plug is the first step in blood clotting.
          • These Platelet Plugs alone can stop blood loss in small vessels and capillaries (ex. Flicking someone can break capillaries and vessels)
      • Platelets release a Prostaglandin called Thrombaxane A2 – it acts for 30 seconds, which causes aggregation of platelets and vasoconstriction. This is a Positive Feedback System.
      • At the same time, endothelial cells release a Prostaglandin called Protacyclin – it acts for 2 minutes and prevents platelet aggregation/prevents clotting. This whole idea is that it limits the size of the Platelet Plug to the injury site, allowing other vessels to stay open and function.
      • This is how Aspirin works, it interferes with Prostaglandins. When you take the aspirin you are interfering with both, but since Protacyclin is produced by a cell, the cell recovers more quickly so more of it is produced. Thrombaxin A2 takes longer because it has to be replenished from the Megakaryoblast, and new platelets must be made. Aspirin acts as an Anti-coagulant and thins the blood.
    • Damaged blood vessels constrict:
      • Damaged blood vessels vasoconstrict in response to Serotonin.
        • People who slit their wrists very rarely die because the vessels will close right off.
      • Constriction is due to:
        • Pain
        • Smooth muscle injury
        • Damaged Endothelial release factors that cause vaso-constriction.
        • Platelets release a lot of factors too.
    • Clot Formation – you don't need to memorize the stair step, but know what is said about the stair-step.
      • There are lots of roman numerals.
      • The numbers are meaningless – they did not name them in the order that they worked into the stair step, they named them in the order they were discovered, you get jumping around.
      • Stair-Step Reaction will occur when you need a large clot.  Clotting happens with larger injuries.  The fundamental reaction is:
        • Fibrinogen (soluble in plasma, water soluble)  changes to Fibrin (insoluble protein, makes loose strands).
          • After the strand form we get Covalent Crosslink between the Fibrin strands, which are referred to as Stabilization.
          • The plasma will become gel-like when it comes in contact with the Fibrin fibers – it will entrap blood cells and be like a gelatinous mass (it looks reddish b/c there is cells inside).

            There are 2 factors:

      • Extrinsic factor – is an enzyme called Thromboplastin – it is released by damaged tissue – it activates Factor VII (part of the stair-step).  It is called a factor b/c it comes from outside of the blood and is released by damaged tissue.
        • Factor VII activates Factor X or IX of the stair step.
      • Intrinsic factor – is Factor XII – it gets activated – which activates the stair-step mechanism, but also activates proteins that activate Factor XII – this is a Positive Feedback Mechanism.
        • If you pull blood out of a vein and put it in a glass tube it will clot.  But it is not making Thromboplastin.  The cause of this is that the blood touches glass or collagen and it activates itself.
      • Both Extrinsic and Intrinsic pathways will lead to a blood clot.
      • Both pathways of blood clotting starts with Prothrombin changing to Thrombin.
        • Thrombin causes Fibrinogen to change to Fibrin
        • It also activates Factor XIII
        • The activated Factor XIII causes Stabilization of the Covalent Crosslinks to form.
      • There is a circulating blood protein protease inhibitor called Anti-thrombin III – it prevents blood clotting formation (by blocking Thrombin) in non-injured vessels.
      • Dissolving Blood Clot: getting rid of the clot – Clot Lysis
        • All endothelial cells, except for those in the brain (in the cerebral microcirculation), produce Thrombomodulin (it is stuck at the surface of the endothelial cell – it is not released).  When Thrombin binds to Thrombomodulin, it activates Protein-C (a blood Protein).  Protein-C will inactivate Factor VIII and Factor V, stopping the stair-step reaction from going through.
        • How do we dissolve this: so we have Plasminogen tries to change to Plasmin. Plasmin is going to destroy/break down Fibrin, and it will essentially lyse the clot. 
        • Plasminogen cannot change to Plasmin b/c there is an inhibitor enzyme that prevents this.  However, Protein-C says to that inhibitor to shut up.  We are inhibiting the inhibitor.
        • As soon as Protein-C says shut up, the clot will start to dissolve and Plasminogen will change to Plasmin.
          • There is an enzyme that is present all the time that converts Plasminogen to Plasmin.
        • Protein C inactivates the enzyme that inhibits Plasmin production – so more Plasmin will be produced and the clot breaks down.

           
           

  • The Heart

     
     

    • Cardiac Muscle:
      • There is no neural stimulus for muscle contraction (neurons just regulate the muscles), instead the stimulus for contraction originates in the Pace Making Tissue
      • The SA node is Pace Making Tissue of the heart and it is known as the Pace Maker of the heart
      • Pace Making Tissue is Self-Depolarizing
      • There is a centralized pace maker and the excitation can then spread over the heart.
      • Resting = -60milivolts, Threshold = -40milivolts, Peak = about +10milivolts.
        • This represents an action potential in the SA node.
        • First we have the Depolarization action potential of Pace Making Tissue (Depolarization is due to Ca2+ NOT Na+)
        • We have Repolarization, which is due to the opening of the Potassium channels at the top, and it will go down to -60 mv, but there is NO Hyperpolarization (no going below the resting membrane potential) – but the K+ channels keep closing
        • Then the Potassium channels close, and the closing of the Potassium channels actually raises the action potential.
        • Starting at -60mv, at halfway up this action potential it will be up at about -50mv (since the threshold will be at -40mv), and at this point (the lower part of the rising action potential) we will have the opening of Calcium T-channels, which will raise the action potential up to -40mv, which in turn will fire another action potential due to the opening of the Calcium L-channels (this is the higher part of the action potential).
          • –50mv Calcium T channels opening (transient, not open very long)
          • –40mv Calcium L channels open (L=long)
        • Pre-Potential is the initial increase of the action potential, which is started by the over-closing of the Potassium channels, which in turn drives the Calcium T-channels to start opening. This causes a change in mv, and causes the Calcium L-channels to open allowing the action potential to peak.
        • The Calcium L channel closes and the whole process repeats, thereby causing beats.
        • Self-Stimulation is due to the SA node and the AV node. However, the AV node fires slower than the SA node, so the SA node is always considered the Pace Maker of the heart, and the AV node never gets a chance to complete this. The AV node fires due to the SA node firing.
          • If something happens to the SA node, the AV node can take over and function as a pacemaker for the heart.
        • Heart tissue contains Gap Junctions between cells so it can pass electrical activity from cell to cell – this is called Syncytial (excitation sweeps over the cell)
        • Only in the Ventricles, there is a conducting system called the Perkinje Fiber System, which is specialized tissue – it carries excitation to many parts of the Ventricles and tries to keep the synchronous contraction in the Ventricles. Makes for quick fast contractions throughout almost all of the Ventricles.
          • Recall: the Left ventricle is the big cup here, so the L and R have to be synchronous in order to function properly, and it can't be slowly sweeping over the surface
        • The Atria – it is slow contraction, which feeds into the ventricles, and has a sweeping action.
        • The ventricles have to pump all over the body so they must contract quickly (they can't sweet).

           
           

      • A typical Action Potential of a Ventricular Cell
        • Start at -90mv for resting membrane potential, and then the Sodium channels open (with other channels opening, but much slower than the Na channels)
        • Goes up and peaks at +20mv
        • Then the Sodium channels closes quickly at the top and the action potential starts to come back down and levels off at 0mv. This leveling off is due to the Calcium channels opening
        • Both T and L Calcium channel are open at this plateau stage, but L has the main effect because they stay open longer.
          • These channels let some sodium in, but they are more responsible for letting a lot more calcium in
          • The Calcium channels close and the Potassium channels take over the repolarization return the ventricular cell back down to the resting membrane potential of -90mv.
          • This process continues, but the process can be shortened depending on how fast your heart is beating.
          • The average heart rate is approximately 75 beats per min – the action potential lasts for 0.250 seconds

          • The action potential shortens to 0.150 seconds if your heart rate increases to 200 beats per minutes (this is the maximum pulse).
            • The faster your heart beats the short the action potential becomes
            • A long action potential means there is a long Absolute Refractory Period
        • Although the Sarcoplasmic reticulum is less extensive in cardiac muscle than it is in skeletal muscle, the cardiac muscle cannot pick up the calcium as quickly. But it is 3 times slower than skeletal muscle. Even though it is 3 times slower it can't be fired again and all the Ca will be going in before it gets a chance to fire again b/c the Absolute Refractory Period is too long.
        • The T-Tubule itself is 5 times the diameter of a T-Tubule in skeletal muscle (much larger in size)
        • The action potential comes across the surface of the cell and goes down to the T-Tubule where it is hitting a Calcium L channel there (just like in skeletal muscle). The Calcium L channel is going to allow the influx of Calcium thus hitting the Ryanodine receptors. The Calcium L channel is going to be sitting around Ryanodine receptors.
          • In the T-tubule the action potential runs into the Calcium L-channel. The Calcium-L Channel were called Dihydropyridine receptors in skeletal muscle b/c they 95% of them didn't allow any Calcium in at all and it was the physical motion that caused the opening of the Ryanodine receptors. But it is called a Calcium-L channel in cardiac muscle because there are no physical connections to the Ryanodine receptors and it does NOT have any Tetrads.
          • It is functioning solely as a Calcium L channel in cardiac muscle. There is only 1 Calcium channel for every 5 to 10 Ryanodine receptors and they are spread all over.
          • The Ryanodine receptors are all opened by Calcium influx, not by physical motion (like in skeletal muscle). There is NOT a physical connection to them like in skeletal muscle.
        • The calcium will stay out in the cytoplasm longer because the sarcoplasmic reticulum is less extensive – it stays out 45 miliseconds.
        • Once the heart beats it has to relax (it is impossible not to relax in between).
        • The excitation will sweep over the surface of the cell first, and then it will hit a T-Tubule and the T-Tubules are going to be similar
        • The Triads are the 2 Terminal Cisterns and a T-Tubule
        • WE have a similar set up in cardiac muscle, but the Triads are over the A-I junctions, so there are 2 Triads per sarcomere
        • In cardiac muscle the Triad sits over the Z-disk, so there is only 1 Triad per sarcomere
      • There is no way to have a sustained contraction in cardiac muscle, the calcium comes back in, the refractory period for the action potential is far longer than the amount of time that the calcium stays out there. This means that the muscle must contract.
      • The Contractile response of the heart begins at the peak of the action potential and lasts 1.2 times as long as the action potential.
      • Non-damaged Myocardium does not beat on it is own, it needs a Pacemaking tissue (like the SA node).
        • Damaged (cut into pieces) myocardium still beats when it is cut off from its nerve supply
      • Ringer's Lactated Solution – essentially IV fluid.
        • Sidney Ringer – cut frog hearts out. The beat of the heart was intrinsic and he wanted to know what was causing it to beat. The heart would sit on the table and still beat. It wasn't innervations that were causing it to beat and he found that if he passed distilled water through it he could actually make the heart beat longer.
        • He wrote a paper, but he had to take it out of the journal that it got published in when he found out that his lab tech was putting tap water into the hearts (he originally thought it was distilled water). So he went back and adjusted the ion concentration of the water, and he actually found out the he could keep a frog heart beating for up to a week all by just changing the fluid going through it.
        • If a patient comes in with unbalanced electrolytes or burns or something else, they are treated with this solution.

       
       

     
     
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Lecture 15

  • Blood Cells, Cont.
    • Hematopoietic Stem cells, cont...
    • An HSC cell can become 1.) another HSC cell, 2.) a Colony-Forming Unit (CFU-L) of Lymphocytes (dedicated to become a lymphocyte), or 3.) a CFU-GEMM cell (from this cell we get all the other cells possible)
    • From the CFU-GEMM cell we can get:
      • BFU-E  Burst Forming Unit (BFU-E) (E = erythroblast), it makes a red blood cell.
      • CFU-GM becomes a Monocyte or a Neutrophil.
      • CFU-Eo becomes an Eiosinophil.
      • CFU-Ma  becomes a Basophil (Mast cell = Ma  these are the majority of basophils and they circulate and crawl into the tissues, but a true basophil stays in circulation)
      • CFU-Meg  forms Platelets (Meg = Megakaryoblast – a huge cell that a platelet is made from – platelets are a piece of a cell)
    • At any one time in your life, the majority of the blood cells in your body came for a single HSC cell.
      • When the body decides it needs to produce blood, it only stimulates one HSC cell.  This is called Colonal Succession
      • Colonal Succession – the majority of your blood at any one time can be traced back to a single cell.

     
     

    Chemical Regulators of Hematopoiesis (there are many regulators that are causing this to happen)

    • You can tell if something is a stimulating factors b/c the abbreviation is on the other side.
    • EPO – (Erythropoietin) – causing the production of RBC's or Erythrocytes.
    • G-CSF – (Colony Stimulating Factor) – it makes Neutrophils (G = neutrophil)
    • M-CSF – makes Monocytes (M = monocyte)
    • Interleukin-2 (IL-2) – stimulates the production of Lymphocytes.
    • Interleukin-5 (IL-5) – stimulates the production of Eiosinophils
    • TPO – (Thrombopoietin) – it is a hormone and it makes Platelets
      • These are all cytokines and produced by cells and released.
    • Some of these factors are not very good a making blood, and they need the help of a synergist.
    • Synergist – it enhances the ability of these compounds to create blood cells.

     
     

    We are going to follow Erythropoiesis (The production of RBC's).

    • CFU–GEMM cell  becomes BFU–E (Burst Forming Unit Erythoid (E)) – the BFU-E is committed to becoming a CFU–E (Colony Forming Unit Erythroid) (this is less prolific and is a storage form), which will become a RBC.
      • The BFU is extremely prolific (need lots of RBC's), and there is lots of multiplying/reproducing going on. The RBC has to go through this stage b/c we have to make so many of them, but it is committed to becoming a RBC.  So they undergo a period where they go through a lot of mitotic cell division in the burst form. Then the cell division starts to calm down and it goes to the CFU-E (less prolific, but still multiplying). This is a storage form, waiting to get to the maturation process of becoming a RBC.
    • CFU-E cannot continue any farther without stimulation by Erythropoietin (EPO). 
    • If CFU-E does not get stimulated by EPO it will die a natural cell death and its DNA will denature.
    • If CFU-E gets stimulated by EPO then it becomes a Proerythroblast.
      • A Proerythroblast is going to go through a committed maturation process to make it a RBC and it cant be stopped.
        • Proerythroblasts have Pherotin (which is a storage form of iron) but no hemoglobin
      • The Proerythroblast will change to a Basophilic Erythroblast.
        • The nuclei in the nucleolus will disappear and chromatin material will condense and Hemoglobin production begins.  These cells are still multiplying, and they will become a Polychromatophyllic Erythroblast
      • Polychromatophyllic Erythroblasts – are the last cells capable of cell divisions at all.
        • Hemoglobin production starts to occur at full blast, and pink areas will appear.
        • It is pink because we are dealing with much larger areas than a normal red blood cell.  But when the cell shrinks, it becomes more red.
        • The Polychromatic Erythroblast becomes an Orthochromic Erythroblast.
          • Hemoglobin production slows greatly.
          • This cell has lost most of its cell organelles but it still has a nucleus.
          • At the very end of this stage, it expels the nucleus, and the nucleus will be consumed by a Macrophage.
          • The second that the nucleus is gone, it is called a Reticulocyte.
          • 3 to 5 days have elapsed since it transitioned from a Proerythroblast to this Reticulocyte stage.  This is a range, not an average.
          • The day range depends on the amount of EPO stimulating the CFU-E cells
            • The more EPO stimulating, the faster it will mature (3 days)
            • The less EPO stimulating, the slower it will mature (5 days).
          • The Reticulocyte has Ribosomes, Mitochondria (b/c Krebs cycle is occurring), and Small amounts of Hemoglobin are being produced.
          • It is the Reticulocyte that will enter into the circulation and it matures to a RBC in 2 days (from the time of Proerythroblast to where it becomes a Reticulocyte).
          • There are 250 billion Reticulocytes produced every day
          • The Reticulocyte has to mature to become a RBC/erythrocyte
          • It then becomes little more than just a sac of Hemoglobin in 2 days – an Erythrocyte.
          • The average lifespan of an erythrocyte is 100-200 days.
          • The maturation mostly took place in the Spleen, but some goes to Bone marrow, and some goes to the Circulation and matures there.
            • The cells die in the spleen after 100 days b/c they become Fragile
          • Instead of Erythroblast it can be called a Normoblast – this is okay (ex. Polychromatic Normoblast).
          • Normoblast is a physiological normal erythroblast.
            • There is no pathological condition.

     
     

    WBC's – Leukocyte Ontongeny – life according the Leukocyte

    • Neutrophils – mature in bone marrow, as immature cells they are bands, they stay there for 5 days as part of a large reserve pool (that is with the understanding that you are not having a major immune response at the time – the pool will start to empty out when you have an immune response). After the 5 days, the Neutrophils enter the circulation, they will only live for about 12 hours, and then they will die a programmed cell death. This is the most prevalent type of WBC.
      • 100 billion Neutrophils are made each day.
      • Neutrophils do not go through a Burst Forming Unit stage (where we are creating lots of these cells), and b/c of this we have to have a lot of area creating these neutrophils. 
      • 60% of the Red Marrow (the zones) in surface area is creating Neutrophils.
      • 250 billion RBC's are made each day.
      • 25% of Red Marrow is making RBC's.
    • Monocytes – will mature in Red Bone Marrow – circulate for about 1 day, and get stored in tissue for about 2 to 4 months and become a variety of cells.
    • Eosinophils – will mature in Red Bone Marrow in about 2 to 6 days, and they will circulate in the blood with a half-life of about 6-12 hours. However, if they crawl into the connective tissue, they can live there for few days (live longer).
    • Basophils and Mast Cells – Basophils are distinct from Mast Cells
      • Mast Cells – will circulate as a Basophilic fraction of the blood but it is not the same.  Mast cells travel through the circulation for a few days and then enter the tissues and live weeks or months (they have a long life), it releases a different set of chemical compounds when it is called upon in the immune response.
      • Basophils – remain in circulation living just a few days (short life).

     
     

     
     

     
     

    We have different types of Lymphocytes:

    • B-lymphocytes (they were created in the bone marrow) – they mature in the red bone marrow and they become immunocompetent, meaning that they are going to be able to destroy an antigen, and in the mean time self-killers are suppressed (those that say kill self, are killed). They have an antigen that they will be up and do nasty things to.
      • Once we have immunity a Memory cell is created, which does not have to go back to lymphoid tissue.
      • Naïve B-lymphocyte – are B-lymphocyte that have not found its antigen, and they travel to the lymphoid tissue through circulation.  These will die a few days after release.
        • The body is constantly making B-cells.
      • NK – Lymphocyte (Natural Killer) – are made in Red Bone Marrow, are not programmed for any specific antigen (unlike B and T cells), are released to circulation, and after it gets to the circulation it concentrates on areas of intake such as the Lungs, GI tract, and Liver (where we take in air, food and water, etc).
        • They are the first line of defense against antigens.
      • T-lymphocytes – originate in Red Bone Marrow during fetal life, and for the first few years of your life, they travel to the Thymus gland and begin to proliferate there.  The Thymus gland is the main source of the Bone marrow for T-lymphocytes.  They also become immunocompetent. 
        • The Thymus gland start to fill with fat (sometime after puberty).
        • Naïve T-lymphocytes migrate to the lymphoid tissue, and they can live an extremely long time. They can live as long as you can live. But they have to come in contact with an MHC Class I Protein in order to live for a long time.  But if they don't bump into an MHC class 1 protein they will die a programmed cell death in a few days – This is called Tickling.
        • Diestche's father was 93 years old when he died, and he had a cell that was a T-lymphocoyte that had been living in him for 91 years. 

     
     

    Platelets (are only thrombocytes in submamallian species, but in humans they are NOT thrombocytes) – they are pieces of a much larger cell.

    • Thrombopoiesis: starts with a CFU-GEMM cell  becomes a CFU-Meg (termed a Megakaryoblast)  becomes a Promegakaryocyte  becomes a Megakaryocyte.
      • The Promegakaryocyte enters into many mitotic cell divisions but it doesn't end in cytokinesis (cell splitting). The nuclei from the mitotic divisions all clump together, and we get thousands of small compartments of cytoplasm. When it is all ready to go it is called a Megakaryocyte.
    • This was occurring in the 1.) Bone marrow, but not it has to enter into the circulation. 
    • As it enters into the circulation, the blood going by quickly, and the bone marrow will be breaking off platelets from the Megakaryocytes because it is very fragile.
    • Platelet formation starts at the bone marrow, but once it gets into the blood cell, it starts to move at the same speed as the blood and it is not going to create any more platelets (i.e. break up anymore) until it gets to the first set of capillaries
    • The first set of capillaries that it gets to is in the 2.) Lungs.  This is the second place for platelet formation.
      • We start with Megakaryoctyes and then we get lots of platelets breaking off. This is the second place for platelet formation.
    • All that is left is the clump of nuclei because the cytoplasm broke up, and the clump is what a Macrophage likes to eat.
    • Circulation platelets exist for 10 days in circulation; their job is blood clotting.
    • The 2 areas of platelet formation are the Bone marrow and the Lungs

     
     

    • The way that the cells enter the circulation is through 2 impermeable membranes.
      • The blood cells get to the endothelial cell, they push on the edge of the endothelial cell, as soon as the inner membrane touches the other membrane a 4um hole will open, and everything has to crawl through it with a big squeeze.
        • A RBC is 8.6um in diameter (squeezing through this hole)
      • When one of the membranes recognizes something that needs to go through, the two impermeable membranes will merge together and a hole will form between them to allow the thing to pass through.
      • The Reticulocytes have problems, they have lost a lot of weight and they have problems getting out. 
        • In the zones where Reticulocyte formation (producing RBC's) is occurring, there will be surges in pressure so they can get the RBC's into the circulation.
    • Cells entering the tissues from the circulation (they pretty much have to go through the Pericytic Venules).
      • They are pretty much preset for where they are going to go, they are only going to enter the lymphoid tissue through Pericytic Venules (they are also called Post-Capillary Venules).
        • They have been programmed with a sensor knowing which tissue they are going for, and the sensor will bounce against the wall of the tissue that it should be going to and then it will stick out Adhesion Molecules.
        • It will bounce and keep sticking out more Adhesion Molecules; it keeps bouncing until it gets stuck.
        • Margination – occurs when the cell tumbling stops and it adheres to the endothelium.
        • Then it will find a space to crawl between the endothelial cells to get into the tissues– this is called Diapedesis.
        • It enters the tissues from the circulation using Margination and Diapedesis.
        • If it wants to get back into the circulation and go somewhere else, it will follow the lymphatic system and re-enter the circulation.

           
           

    • There are approximately 3500ml of plasma in a 70kg man.
    • Plasma is 90% water
      • 2% everything else (consists of nutrients, electrolytes, respiratory gases, and the waste products of metabolism (such as lactic acid, urea, ammonia salts etc.) – you don't have to know these
      • 8% protein
        • 60% of the plasma proteins is Albumin (the major protein that we find in blood)
          • It is created by the liver and it functions as a buffer
          • It maintains the osmotic gradient of the plasma (most of the time we think that Sodium is in this case Sodium can get in and out of the blood), but what maintains the gradient is the Albumin.
          • Albumin is a Blood Volume Expander – only used in emergencies when short of blood
            • People can be allergic to it. It used to be commonly carried in the battlefield in WWI and WWII.
          • Albumin doesn't leave the blood unless there is an immunological response where we have inflammation, and then albumin will go out through open venules

     
     

    • The Globulins:
      • We name the Globulins by their Electrophoresis bands.
        • Electrophoresis is where you take some medium and you put a drop of some group of proteins on one end, and then you run an electrical current through it, and each of the proteins will move at a different speed, thus separating the proteins out.  Today we use gels and vary the amount of electricity that we are putting through the medium.
        • We put a drop of a group of different types of proteins on paper or a gel.  Then we apply an electrical charge to it, so the proteins can separate.
        • Variations in how fast these proteins will travel are based on the type of gel or paper and the amount and length the electricity is applied for. These are all variables for the electrophoresis bands that these proteins will end up in.
      • There are 5 different Globulins: Alpha 1, Alpha 2, Beta 1, Beta 2, and Gamma (use Greek letters)
        • Alpha 1- 1
          • 1 – Lipoprotein – has to do with HDL (High Density Lipoprotein  this is the Good Cholesterol), we will explain this more during digestion and absorption of fats
          • 1 - Anti-trypsin Factor – this is a protease inhibitor
          • 1 – Anti-chymotrypsin Factor – another powerful digestive enzyme that is secreted by the pancreas.
            • Trypsin and Chymotrypsin are two powerful protein digesters that are being kicked out by the pancrease into the GI tract for digestion. Should chymotrypsin or Trypsin get to the blood stream, there are things (the Anti- from above) that will get rid of it, b/c we do not want it digesting things in the bloodstream digesting blood proteins.
          • Inter- -trypsin factor inhibitor (is between bands 1 and 2) – is a protease inhibitor.
        • Alpha 2- 2
          • 2 – Prothrombin – is an integral protein for blood clotting
          • 2 – HS – Glycoprotein – it is a carrier (HS – is a person's initials – Dietsche Syndrome, it does not carry HS).
          • 2 – Macroglobin – is a protease inhibitor
          • 2 – Haptoglobin – binds free hemoglobin – when Hb is outside of a RBC it can be extremely toxic – as soon as it binds to Hb it is picked up by the liver.
          • Pre-Beta Lipoprotein – (is between 2 and 1) is a (VLDL) Very Low Density Lipoprotein.

     
     

     
     

     
     

     
     

     
     

     
     

     
     

     
     
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