Commonly used terms of MOVEMENT

  • Inversion means turning sole of the foot inward.
  • Flexion means bending of a part or decreasing the angle between body parts. 
  • Extension means straightening a part or increasing the angle between body parts. 
  • Adduction means moving toward the median plane of the body in the coronal plane. In the digits (fingers and toes), adduction refers to drawing them together. 
  • Abduction means moving away from the median plane of the body in the coronal plane. In the digits (fingers and toes), abduction means spreading them. 

  • Rotation means moving a part of the body around its long axis. 
  • Medial rotation means turning the anterior surface medially. 
  • Lateral rotation means turning the anterior surface laterally. 
  • Pronation is a medial rotation of the forearm and hand so that the palm faces posteriorly. 
  • Supination is a lateral rotation of the forearm and hand so that the palm faces anteriorly, as in the anatomical position. 

  • Eversion means turning sole of foot outward. 
  • Dorsiflexsion means decreasing the angle of the ankle joint. 
  • Plantarflexion means increasing the angle of the ankle joint. 
  • Circumduction is the circular movement of the limbs, or parts of them, combining in sequence the movement of flexion, extension, abduction and adduction. 
  • Protrusion (protraction) means to move the jaw anteriorly. 
  • Retrusion (retraction) means to move the jaw posteriorly. 


Each heart beat results in 3 "waves" or deflections on an ECG. The electrical activation (depolarization)of the upper chambers of the heart (the atria) results in the low amplitude P wave. The subsequent electrical activation (depolarization) of the lower chambers of the heart (the ventricles) results in the high amplitude QRS complex. Repolarization of the atria is a low amplitude signal that occurs during the time of the high amplitude QRS and consequently, is not seen on a standard ECG. Replolarization of the ventricles results in the T wave.

The flat lines before the P wave, between the P and QRS and after the T wave are said to be at the baseline of that ECG tracing. The line connecting the QRS to the T wave is called the ST segment and is normally quite close to the baseline.

A QRS complex can have positive (upwards) or negative (downwards) deflections. If it starts with an initial negative deflection, that deflection is called a Q wave. The first upward deflection is called a R wave. A negative deflection following an R wave is called an S wave. If there is only one negative deflection without an R wave, that is called a QS complex. A second R wave following an S wave is called an R'   ("R-primed") wave. The above tracing shows a large R wave and small S wave.

Time is represented on the horizontal, x-axis on ECGs. The distance between 2 vertical lines is 1 millimeter representing 0.04 seconds with a recorder sweep speed of 25 millimeters per second. The vertical, y-axis represents the amplitude or strength of the electrical signal in millivolts. Poorly reproduced in the above figure are horizontal lines spaced 1 millimeter apart. Each horizontal line represents 0.1 millivolts.
The heart rate is calculated by dividing 60,000 by the time (in milliseconds) between 2 consecutive R waves.
The time it takes for electricity to be conducted from the atria to the ventricles is represented by the PR interval. This is measured from the beginning of the P wave to the beginning of the QRS complex.
The time it takes for the ventricles to become electrically activated is represented by the QRS duration. This is measured from the beginning of the QRS to the end of the QRS.
The total amount of time the ventricles are electrically active (from onset of depolarization to completion of repolarization) is represented by the QT interval. This is measured from the onset of the QRS to the end of the T wave.

The voltage of the P wave and QRS complex is proportional to the total amount of muscle being depolarized. A higher than normal voltage implies overgrowth of the muscle of that chamber. Since the left ventricle has a lot more muscle than the right ventricle, the QRS complex primarily represents electrical events of the left ventricle.
An actual ECG is recorded by placing electrodes on each limb and 6 electrodes on the chest. The first chest lead is called V1 and is placed just to the right of the breastbone. Chest lead V2 is placed just to the left of the breastbone. Chest leads V3 through V6 are sequentially further to the left.

This allows the recording of 12 ECG leads:

  • Lead I treats the right arm as negative and left arm as positive.
  • Lead II treats the  left arm as negative and the left leg as positive .
  • Lead III treats the right arm as negative and the left leg as positive.
  • Lead aVR treats the right arm as positive and the other limb electrodes as negative.
  • Lead aVL treats the left arm as positive and the other limb electrodes as negative.
  • Lead aVF treats the left foot as positive and the other limb electrodes as negative

Each of the 6 chest leads is a positive lead. The patient's back is considered the negative electrode for each.
A standard ECG machine records leads I, II and III simultaneously, then aVR, aVL, and aVF simultaneously, then V1, V2, and V3 simultaneously and finally V4, V5, and V6 simultaneously:

This 12 lead ECG recorded 3 heart beats from I, II, III; 3 beats from aVR, aVL, aVF; 3 beats from V1, V2, V3 and 4 beats from V4, V5, V6. You should be able to recognize a QRS complex for each beat in each lead and, in most leads, a preceding P wave and subsequent T wave.
The electrical signal that starts in the atria and travels down to the ventricle is of course moving through three dimensions. Each lead inscribes a positive deflection for that component of the net electrical vector that is travelling towards its positive electrode and a negative deflection  for that component of the net electrical vector that is travelling towards its negative electrode. Thus, by knowing the position of each lead, you can determine the direction the electrical signal is travelling. Looking at the heart's electrical activity with 12 leads is like looking at a three dimensional object from 12 different angles.
Different lead sets "look" at different parts on the heart. Leads II, III and aVF all treat the foot electrodes as positive and thus reflect activity at the bottom or inferior wall of the heart.

Leads I, aVL, V5 and V6 have their positive electrodes on the left side of the body and thus reflect activity of the left-most (lateral) wall of the heart.
Leads V1, V2, V3 and V4 have their positive electrodes on the front of the body and thus reflect activity of the front (anterior wall) of the heart.
Here are some common things doctors look for on an ECG. There are examples of these throughout the

ECG gallery.

Depression of the ST segment below the baseline or inversion of the normal T wave deflection can indicate myocardial ischemia-a shortage of blood flow and oxygen that is not quite severe enough to permanently damage the muscle. Elevation of the ST segment above the baseline is the earliest ECG sign of a heart attack (myocardial infarction) where the blood flow and oxygen supply are so low or absent that the heart muscle is dying. Some hours later, Q waves will appear in leads that don't normally have them if the heart attack is not aborted in time.The ST segment elevation often resolves with time but the abnormal Q waves tend to persist.
The leads that show these ST segment abnormalities or Q waves will let you know which part of the heart is affected by these processes.

Abnormal heart rhythms are diagnosed by noting the rate of the P waves and QRS complexes, whether expected P waves or QRS complexes are absent and alterations in the normal 1:1 relationship between the P wave and QRS complexes. The ECG gallery also includes examples of abnormal heart rhythms

Microcirculation Structure and Function

The microcirculation is comprised of arterioles, capillaries, venules, and terminal lymphatic vessels.


Small precapillary resistance vessels (10-50 µ) composed of an endothelium surrounded by one or more layers of smooth muscle cells.
Richly innervated by sympathetic adrenergic fibers and highly responsive to sympathetic vasoconstriction via both a 1 and a 2 postjunctional receptors.
Represent a major site for regulating systemic vascular resistance.
Rhythmical contraction and relaxation of arterioles sometimes occurs (i.e., spontaneous vasomotion).
Primary function within an organ is flow regulation, thereby determining oxygen delivery and the washout of metabolic by-products.
Regulate, in part, capillary hydrostatic pressure and therefore influence capillary fluid exchange.


Small exchange vessels (6-10 µ) composed of highly attenuated (very thin) endothelial cells surrounded by basement membrane – no smooth muscle.
Three structural classifications:
Continuous (found in muscle, skin, lung, central nervous system) – basement membrane is continuous and intercellular clefts are tight (i.e., have tight junctions); these capillaries have the lowest permeability.

Fenestrated (found in exocrine glands, renal glomeruli, intestinal mucosa) – perforations (fenestrae) in endothelium result in relatively high permeability.

Discontinuous (found in liver, spleen, bone marrow) – large intercellular gaps and gaps in basement membrane result in extremely high permeability.

Large surface area and relatively high permeability (especially at intercellular clefts) to fluid and macromolecules make capillaries the primary site of exchange for fluid, electrolytes, gases, and macromolecules.
In some organs, precapillary sphincters (a circular band of smooth muscle at entrance to capillary) can regulate the number of perfused capillaries.


Small exchange vessels (10-50 µ) composed of endothelial cells surrounded by basement membrane (smallest postcapillary venules) and smooth muscle (larger venules).
Fluid and macromolecular exchange occur most prominently at venular junctions.
Sympathetic innervation of larger venules can alter venular tone which plays a role in regulating capillary hydrostatic pressure.

Terminal Lymphatics

Composed of endothelium with intercellular gaps surrounded by highly permeable basement membrane and are similar in size to venules – terminal lymphatics end as blind sacs.
Larger lymphatics also have smooth muscle cells.
Spontaneous and stretch-activated vasomotion is present which serves to "pump" lymph.
Sympathetic nerves can modulate vasomotion and cause contraction.
One-way valves direct lymph away from the tissue and eventually back into the systemic circulation via the thoracic duct and subclavian veins (2-4 liters/day returned).




• Baroreceptors are especially abundant in the:
  a) carotid sinuses [located in wall of ICA just above carotid bifurcation]
  b) walls of the aortic arch
• Impulses are transmitted from:
  a) carotid sinus via the glossopharangeal nerve (CN-IX) to the medulla
  b) aortic arch via the vagal nerve (CN-X) to the medulla

response of baroreceptors to pressure

 < 60 mmHg see no stimulation of baroreceptors

  • 60 - 160 mmHg see maximum stimulation
  • see maximum   at normal pressures [I = impulses]
  • the baroreceptors respond much more to a rapidly changing pressure than to a stationary pressure
  • they adapt in 1 — 2 days to whatever pressure they are exposed to; have no long term effect in BP regulation

baroreceptor reflex
• stimulated baroreceptors inhibit vasoconstrictor centre of medulla —>
 i) vasodilation of peripheral vasculature
 ii) decreased HR & contractility
 —> reduced BP
 [low BP has an opposite effect]
• baroreceptors play a major role in maintaining BP during postural changes


 Chemoreceptors are located in the:
  a) carotid bodies [located in the carotid bifurcation]
  b) aortic bodies in walls of the aortic arch
Impulses are transmitted via the vagus [along with nerve fibres from baroreceptors] into the vasomotor centre
Each body has its own blood supply —> each body is in close contact with arterial blood

chemoreceptor reflex
1° reduced arterial BP —> reduced O2; increased CO2 & H+ —> stimulate chemoreceptors —> excite vasomotor centre —> increase BP
 [& increased resp stim]
1°reduced O2; increased CO2 & H+ —> stimulate chemoreceptors —> excite vasomotor centre —> increase BP
Only works strongly with BP < 80 mm Hg


• Both the atria & pulmonary arteries have stretch receptors in their walls—low pressure receptors
• pulmonary artery receptors are similar to baroreceptors in operation, atrial receptors operate as follows:

atrial reflexes
stretched atria —>
 1) slight reflex vasodilation of peripheral arterioles —>
  i) reduced peripheral resistance —> reduced BP back down to normal
  ii) increased blood flow into capillaries —> increased capillary pressure —>    third space shifting —> reduced blood volume
 2) reflex dilatation of afferent arterioles of kidney —> increased urine production
 3) stimulate hypothalamus —> decreased ADH —> reduced resorption of H2O in    kidney —> increased urine secretion
 4) increased HR [Bainbridge reflex] —> offload fluid from heart


• reduced blood flow to vasomotor centre in brain stem —> ischaemia of medulla —> increased local[CO2] —> excite vasomotor centre —> increased BP
• has a tremendous magnitude in increasing BP: is one of the most powerful activators of the sympathetic vasoconstrictor system
• Only becomes active at arterial BP < 50 mmHg — ‘last ditch stand’
• Cushing reaction: increased Intracranial pressure —> compression of arteries in brain —> CNS ischaemic response —> increased BP

note that in all the above reflexes, the increased sympathetic output not only stimulates the arteries & arterioles but also constricts the veins —> increased mean systemic pressure —> increased cardiac output —> increased BP



• Sympathetic stimulation —> stimulate adrenal medulla —> release of Ad & NAd —> excite heart; vasoconstrict most blood vessels
• May act on metarterioles which are not innervated


  • Reduced BP —> hypothalamus secretes vasopressin via post pituitary —> direct vasoconstriction —> increased peripheral resistance/MSFP —> increased BP
  • Very potent; plays an important role in correcting BP when is acutely dangerously low —> important short term role
  • Important long term role as ADH (same substance)


  • at least 20 minutes are required before this system can become fully active
  • it has a relatively long duration of action


The maintenance of ionic concentration gradients across the membrane. The maintenance of these concentration gradients requires the expenditure of energy (ATP hydrolysis) coupled with ionic pumps. Consider for a moment the concentration gradients for Na+ and K+. Whenever an action potential is generated, Na+ enters the cell and K+ leaves the cell. While the number of ions moving across the sarcolemmal membrane in a single action potential is very small relative to the total number of ions, after many action potentials are generated, there would occur a significant change in the extracellular and intracellular concentration of these ions. To prevent this from occurring (i.e., to maintain the concentration gradients for Na+ and K+), there is located on the sarcolemma an energy dependent (ATP-dependent) pump system (Na+/K+-ATPase) that pumps Na+ out of the cell and K+ into the cell. Normal operation of this pump is essential for the maintenance of Na+ and K+ concentrations across the membrane. If this pump stops working (as occurs under anoxic conditions when ATP is lost), or if the activity of the pump is inhibited (as occurs with cardiac glycosides such as digitalis), Na+ accumulates within the cell and intracellular K+ falls. This causes depolarization of the resting membrane potential.  Furthermore, it is important to note that this pump is electrogenic in nature because it extrudes 3 Na+ for every 2 K+ entering the cell.  By pumping more positive changes out of the cell than into the cell, the pump activity creates a negative potential within the cell.  This potential may be up to -10 mV.  Inhibition of this pump, therefore, causes depolarization resulting not only from changes in Na+ and K+ concentration gradients, but also from the loss of an electrogenic component of the membrane potential.  
Because Ca++ enters the cell during action potentials, it is necessary to maintain its concentrations gradients.  This is accomplished by Ca++ pumps and exchangers on the membrane.

Neurohumoral mechanism maintaining normal cardiac output and blood pressure

Acute haemorrhage :

 1) Rapidly acting pressure control mechanisms; to return blood pressure to  physiological levels. All are nervous mechanisms:
  i) Baroreceptor
  ii) Chemoreceptor
  iii) CNS ischaemic response

 2) Long term mechanisms for arterial pressure regulation; to return blood  volume to normal levels. Essentially involves kidney control via several  hormonal mechanisms:
  i) Renin — Angiotensin
  ii) Aldosterone

Atropine (Muscarinic Receptor Antagonist)

The vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their primary neurotransmitter. ACh binds to muscarinic receptors (M2) that are found principally on cells comprising the sinoatrial (SA) and atrioventricular (AV) nodes. Muscarinic receptors are coupled to the Gi-protein; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation of KACh channels that increase potassium efflux and hyperpolarizes the cells.

Increases in vagal activity to the SA node decreases the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential (phase 4 of the action potential); this decreases heart rate (negative chronotropy). The change in phase 4 slope results from alterations in potassium and calcium currents, as well as the slow-inward sodium current that is thought to be responsible for the pacemaker current (If). By hyperpolarizing the cells, vagal activation increases the cell's threshold for firing, which contributes to the reduction the firing rate. Similar electrophysiological effects also occur at the AV node; however, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node (negative dromotropy). In the resting state, there is a large degree of vagal tone on the heart, which is responsible for low resting heart rates.

There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular muscle. Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy) and even smaller decreases in ventricular contractility.
Muscarinic receptor antagonists bind to muscarinic receptors thereby preventing ACh from binding to and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very effectively block the effects of vagal nerve activity on the heart. By doing so, they increase heart rate and conduction velocity.

Specific Drugs and Therapeutic Indications 

Atropine is a muscarinic receptor antagonist that is used to inhibit the effects of excessive vagal activation on the heart, which is manifested as sinus bradycardia and AV nodal block. Therefore, atropine can temporarily revert sinus bradycardia to normal sinus rhythm and reverse AV nodal blocks by removing vagal influences.

Side Effects and Contraindications

The anticholinergic effects of atropine can produce tachycardia, pupil dilation, dry mouth, urinary retention, inhibition of sweating (anhidrosis), blurred vision and constipation. However, most of these side effects are only manifested with excessive dosing or with repeated dosing. Atropine is contraindicated in patients with glaucoma.

Adrenergic and Cholinergic Receptors

Sympathetic adrenergic nerves are found in the heart where they innervate the SA and AV nodes, conduction pathways, and myocytes.Sympathetic adrenergic fibers are also found innervating arteries and veins in the peripheral vasculature.These adrenergic nerves release the neurotransmitter, norepinephrine (NE), which binds to specific receptors in the target tissue. The heart is also innervated by parasympathetic cholinergic nerves derived from the vagus nerves.Acetylcholine (ACh) released by these fibers binds to muscarinic receptors in the target tissue.The vasculature in some organs of the body is innervated by either parasympathetic cholinergic fibers or by sympathetic cholinergic fibers. These nerves release ACh, which binds to muscarinic receptors on the smooth muscle and/or endothelium.

In the heart, NE released by sympathetic nerves preferentially binds to 1 adrenoceptors causing positive inotropy, chronotropy, and dromotropy.Postjunctional 2 adrenoceptor stimulation has similar cardiac effects and becomes increasingly important in heart failure because 1 adrenoceptors become down regulated. NE can also bind to 1 adrenoceptors on myocytes causing small increases in inotropy.Circulating catecholamines (NE and epinephrine) (not shown in diagram) released by the adrenal medulla also binds to these same alpha and beta adrenoceptors on the heart.
In blood vessels, NE preferentially binds 1 adrenoceptors to cause smooth muscle contraction and vasoconstriction. Similar responses occur when NE binds to postjunctional 2 receptors located on some blood vessels. NE can also bind to postjunctional 2 adrenoceptors which causes vasodilation (this can be observed during alpha adrenoceptor blockade), although this vasodilator effect of NE is relatively minor and overwhelmed by alpha adrenoceptor-mediated vasoconstriction. Circulating epinephrine (not shown in diagram) binds to the 2 adrenoceptors to cause vasodilation in some organs.
NE regulates its own release by acting upon prejunctional 2 (inhibits release) and 2 (facilitates release) adrenoceptors.
In the heart, ACh released by cholinergic nerves bind to a subclass of cholinergic receptors called M2 muscarinic receptors. This produces negative inotropy, chronotropy, and dromotropy in the heart. Prejunctional M2 receptor activation inhibits NE release and is one mechanism by which vagal stimulation overrides sympathetic stimulation in the heart.
In blood vessels, M2 receptors on the vascular endothelium are coupled to the formation of nitric oxide (NO) which causes vasodilation; however, ACh causes smooth muscle contraction through a smooth muscle M3 receptor when formation of NO is blocked. This latter finding has been used to assess coronary vascular dysfunction in humans in which NO production is diminished in diseased coronary arteries.
Some arterial blood vessels, for example in skeletal muscle, are innervated by sympathetic cholinergic nerves that release ACh and cause vasodilation. This may contribute to active hyperemia in skeletal muscle, particularly at the onset of exercise.
Neurotransmitter binding to the adrenergic and cholinergic receptors activates signal transduction pathways that that cause the observed changes in cardiac and vascular function.
Drugs are available for blocking adrenergic and cholinergic receptors. For example, beta-blockers are used in the treatment of angina, hypertension, arrhythmias, and heart failure. Alpha-blockers are used in treating hypertension. Muscarinic receptor blockers such as atropine are used to treat electrical disturbances (e.g., bradycardia and conduction blocks) associated with excessive vagal stimulation of the heart. Many of these adrenergic and cholinergic blockers are relatively selective for a specific receptor subtype.

Regulation of Pacemaker Activity

The SA node displays intrinsic automaticity (spontaneous pacemaker activity) at a rate of 100-110 action potentials ("beats") per minute. This intrinsic rhythm is primarily influenced by autonomic nerves, with vagal influences being dominant over sympathetic influences at rest.This "vagal tone" brings the resting heart rate down to 60-80 beats/min.The SA node is predominantly innervated by efferent branches of the right vagus nerves, although some innervation from the left vagus is often observed.Experimental denervation of the right vagus to the heart leads to an abrupt increase in SA nodal firing rate if the resting heart rate is below 100 beats/min. A similar response is noted when a drug such as atropine is administered. This drug blocks vagal transmission at the SA node by antagonizing the muscarinic receptors that bind to acetylcholine, which is the neurotransmitter released by the vagus nerve.
Parasympathetic (vagal) activation, which releases acetylcholine (ACh) onto the SA node, decreases pacemaker rate by increasing gK+ and decreasing slow inward gCa++ and gNa+; the pacemaker current (If) is suppressed.These ionic conductance changes decrease the slope of phase 4 of the action potential, thereby increasing the time required to reach threshold. Vagal activity also hyperpolarizes the pacemaker cell during Phase 4, which results in a longer time to reach threshold voltage.
To increase heart rate, the autonomic nervous system increases sympathetic outflow to the SA node, with concurrent inhibition of vagal tone.Inhibition of vagal tone is necessary for the sympathetic nerves to increase heart rate because vagal influences inhibit the action of sympathetic nerve activity.Sympathetic activation, which releases norepinephrine (NE),increases pacemaker rate by decreasing gK+ and increasing slow inward gCa++ and gNa+; the pacemaker current (If) is enhanced.These changes increase the slope of phase 4.

Pacemaker activity is also altered by hormones.For example, hyperthyroidism induces tachycardia and hypothyroidism induces bradycardia. Circulating epinephrine causes tachycardia by a mechanism similar to norepinephrine released by sympathetic nerves.
Changes in the serum concentration of ions, particularly potassium, can cause changes in SA nodal firing rate.Hyperkalemia induces bradycardia or can even stop SA nodal firing.Hypokalemia increases the rate of phase 4 depolarization and causes tachycardia.It apparently does this by decreasing gK during phase 4.
Cellular hypoxia (usually due to ischemia) depolarizes the membrane potential causing bradycardia; severe hypoxia completely stops pacemaker activity.
Various drugs used as antiarrhythmics also affect SA nodal rhythm. Calcium-channel blockers, for example, cause bradycardia by inhibiting the slow inward Ca++ currents during phase 4 and phase 0.Drugs affecting autonomic control or autonomic receptors (e.g., beta-blockers, muscarinic antagonists) directly or indirectly alter pacemaker activity. Digitalis causes bradycardia by increasing parasympathetic (vagal) activity on the SA node; however, at toxic concentrations, digitalis increases automaticity and therefore can cause tachyarrhythmias.This toxic effect is related to the inhibitory effects of digitalis on the membrane Na+/K+-ATPase, which leads to cellular depolarization, increased intracellular calcium, and changes in ion conductances.

Autonomic Innervation of the Heart and Vasculature

The medulla, located in the brainstem above the spinal cord, receives sensory input from different systemic and central receptors (e.g., baroreceptors and chemoreceptors) as well as signals from other brain regions (e.g., hypothalamus). Autonomic outflow from the brainstem is divided principally into sympathetic and parasympathetic (vagal) branches. Efferent fibers of these autonomic nerves travel to the heart and blood vessels where they modulate the activity of these target organs.
The heart is innervated by vagal and sympathetic fibers. The right vagus nerve primarily innervates the SA node, whereas the left vagus innervates the AV node; however, there can be significant overlap in the anatomical distribution. Atrial muscle is also innervated by vagal efferents, whereas the ventricular myocardium is only sparsely innervated by vagal efferents. Sympathetic efferent nerves are present throughout the atria (especially in the SA node) and ventricles, including the conduction system of the heart.
Cardiac function is altered by neural activation. Sympathetic stimulation increases heart rate (positive chronotropy), inotropy and conduction velocity (positive dromotropy), whereas parasympathetic stimulation of the heart has opposite effects.Sympathetic and parasympathetic effects on heart function are mediated by beta-adrenoceptors and muscarinic receptors, respectively.

Sympathetic adrenergic nerves travel along arteries and nerves and are found in the adventitia (outer wall of a blood vessel). Varicosities, which are small enlargements along the nerve fibers, are the site of neurotransmitter release. Capillaries receive no innervation. Activation of vascular sympathetic nerves causes vasoconstriction of arteries and veins mediated by alpha-adrenoceptors.

Parasympathetic fibers are found associated with blood vessels in certain organs such as salivary glands, gastrointestinal glands, and in genital erectile tissue. The release of acetylcholine (ACh) from these parasympathetic nerves has a direct vasodilatory action (coupled to nitric oxide formation and guanylyl cyclase activation). ACh release can stimulate the release of kallikrein from glandular tissue that acts upon kininogen to form kinins (e.g., bradykinin). Kinins cause increased capillary permeability and venous constriction, along with arterial vasodilation in specific organs.

Sinoatrial Node Action Potentials why its called primary pacemaker

Sinoatrial Node Action Potentials

Cells within the sinoatrial (SA) node are the primary pacemaker site within the heart. These cells are characterized as having no true resting potential, but instead generate regular, spontaneous action potentials. Unlike most other cells that elicit action potentials (e.g., nerve cells, muscle cells), the depolarizing current is carried primarily by relatively slow, inward Ca++ currents instead of by fast Na+ currents. There are, in fact, no fast Na+ currents operating in SA nodal cells.
SA nodal action potentials are divided into three phases.
Phase 0 depolarization is primarily due to increased gCa++ (Ca++ conductance). Because the movement (or conductance) of Ca++ through their channels is not rapid (hence, the term "slow inward Ca++ channels"), the rate of depolarization (slope of Phase 0) is much slower than found in other cardiac cells (e.g., Purkinje cells).

  • Repolarization occurs (Phase 3) as gK+ increases and gCa++ decreases. 
  • Spontaneous depolarization (Phase 4) is due to a fall in gK+ as potassium channels close and to a small increase in gCa++. A slow inward Na+ current also contributes to Phase 4, and is thought to be responsible for what is termed the pacemaker or "funny" current (If). Once this spontaneous depolarization reaches threshold (about -40 mV), a new action potential is triggered. 

During depolarization, the membrane potential (Em) moves toward the equilibrium potential for Ca++, which is about +134 mV. During repolarization, gCa++ (relative Ca++ conductance) decreases and gK+ (relative K+ conductance) increases, which brings Em closer toward the equilibrium potential for K+. Therefore, the action potential in SA nodal cells is primarily dependent upon changes in Ca++ and K+ conductances as summarized below and in the above figure:

Em = g'K+ (-96 mV) + g'Ca++ (+134 mV)

Although pacemaker activity is spontaneously generated by SA nodal cells, the rate of this activity can be modified significantly by external factors such as by autonomic nerves, hormones, drugs, ions, and ischemia/hypoxia.
Regulation of Pacemaker Activity
The SA node displays intrinsic automaticity (spontaneous pacemaker activity) at a rate of 100-110 action potentials ("beats") per minute. This intrinsic rhythm is primarily influenced by autonomic nerves, with vagal influences being dominant over sympathetic influences at rest. This "vagal tone" brings the resting heart rate down to 60-80 beats/min.

The SA node is predominantly innervated by efferent branches of the right vagus nerves, although some innervation from the left vagus is often observed. Experimental denervation of the right vagus to the heart leads to an abrupt increase in SA nodal firing rate if the resting heart rate is below 100 beats/min. A similar response is noted when a drug such as atropine is administered. This drug blocks vagal transmission at the SA node by antagonizing the muscarinic receptors that bind to acetylcholine, which is the neurotransmitter released by the vagus nerve.
Parasympathetic (vagal) activation, which releases acetylcholine (ACh) onto the SA node, decreases pacemaker rate by increasing gK+ and decreasing slow inward gCa++ and gNa+; the pacemaker current (If) is suppressed.

These ionic conductance changes decrease the slope of phase 4 of the action potential, thereby increasing the time required to reach threshold. Vagal activity also hyperpolarizes the pacemaker cell during Phase 4, which results in a longer time to reach threshold voltage.
To increase heart rate, the autonomic nervous system increases sympathetic outflow to the SA node, with concurrent inhibition of vagal tone. Inhibition of vagal tone is necessary for the sympathetic nerves to increase heart rate because vagal influences inhibit the action of sympathetic nerve activity. Sympathetic activation, which releases norepinephrine (NE), increases pacemaker rate by decreasing gK+ and increasing slow inward gCa++ and gNa+; the pacemaker current (If) is enhanced. These changes increase the slope of phase 4.
Pacemaker activity is also altered by hormones. For example, hyperthyroidism induces tachycardia and hypothyroidism induces bradycardia. Circulating epinephrine causes tachycardia by a mechanism similar to norepinephrine released by sympathetic nerves.

Changes in the serum concentration of ions, particularly potassium, can cause changes in SA nodal firing rate.Hyperkalemia induces bradycardia or can even stop SA nodal firing. Hypokalemia increases the rate of phase 4 depolarization and causes tachycardia. It apparently does this by decreasing gK during phase 4.

Cellular hypoxia (usually due to ischemia) depolarizes the membrane potential causing bradycardia; severe hypoxia completely stops pacemaker activity.
Various drugs used as antiarrhythmics also affect SA nodal rhythm. Calcium-channel blockers, for example, cause bradycardia by inhibiting the slow inward Ca++ currents during phase 4 and phase 0. Drugs affecting autonomic control or autonomic receptors (e.g., beta-blockers, muscarinic antagonists) directly or indirectly alter pacemaker activity. Digitalis causes bradycardia by increasing parasympathetic (vagal) activity on the SA node; however, at toxic concentrations, digitalis increases automaticity and therefore can cause tachyarrhythmias.This toxic effect is related to the inhibitory effects of digitalis on the membrane Na+/K+-ATPase, which leads to cellular depolarization, increased intracellular calcium, and changes in ion conductances.

Is Hypovolemic shock is a particular form of shock?

Hypovolemic shock

Hypovolemic shock is a particular form of shock in which the heart is unable to supply enough blood to the body. It is caused by blood loss or inadequate blood volume.

Causes, incidence, and risk factors:

Loss of approximately one-fifth or more of the normal blood volume produces hypovolemic shock. The loss can be from any cause, including external bleeding (from cuts or injury), gastrointestinal tract bleeding, other internal bleeding, or from diminished blood volume resulting from excessive loss of other body fluids (such as can occur with diarrhea, vomiting, burns, and so on). In general, larger and more rapid blood volume losses result in more severe shock symptoms.
In another form of shock called cardiogenic shock, there is adequate blood volume, but the heart is unable to pump the blood effectively.

A brief description of cardiac anatomy

Cardiac Anatomy

The detailed anatomy of the heart can be found in anatomy textbooks.  The following presents only a brief description of cardiac anatomy so that the physiology of the cardiac cycle can be understood.
The heart consists of four chambers: the right atrium, right ventricle, left atrium, and left ventricle. The right atrium receives blood from the superior and inferior vena cavae, which returns venous blood to the heart from the body.  The right atrium is a highly distensible chamber so that it can accommodate the venous return and maintain a low pressure (0-3 mmHg).  The actual pressure within the right atrium depends upon the volume of blood within the atrium and the compliance of the atrium.  Blood flows from the right atrium, across the tricuspid valve, and into the right ventricle.  The free wall of the right ventricle is not as thick as the left ventricle, and anatomically, it wraps itself around part of the larger, and thicker, left ventricle.  The outflow tract of the right ventricle is the pulmonary artery which is separated from the ventricle by the semilunar pulmonic valve.  Blood returns to the heart from the lungs via four pulmonary veins that enter the left atrium.  The left atrium, like the right, is highly compliant, although quantitatively less compliant than the right.  Therefore, the left atrial pressure is higher than the right atrial pressure (6-10 mmHg compared to 0-3 mmHg).  Blood flows from the left atrium, across the mitral valve, and into the left ventricle.  The left ventricle has a very thick muscular wall so that it can generate high pressures during contraction.  Blood from the left ventricle is ejected across the aortic valve and into the aorta.
The tricuspid and mitral valves (also called atrioventricular, or AV valves) have fibrous strands (chordae tendineae) on their leaflets that attach to papillary muscles located on the respective ventricular walls.  The papillary muscles contract during ventricular contraction and generate tension on the valve leaflets via the chordae tendineae to prevent the AV valves from bulging back into the atria and becoming incompetent.  The semilunar valves (pulmonic and aortic) do not have analogous attachments.

Difference between Open angle Glaucoma and Closed angle Glaucoma

Glaucoma refers to certain eye diseases that affect the optic nerve and cause vision loss. Most, but not all, of these diseases typically produce elevated pressure inside the eye, called intraocular pressure (IOP). Normal IOP is measured in millimeters of mercury and can range from 10-21 mm Hg. An elevated IOP is the most important risk factor for the development of glaucoma.
Elevated IOP is sometimes called ocular hypertension

Many factors are associated with an increased risk of developing glaucoma, some of which are elevated IOP, a family history, ethnic background, and older age.
The two main types of glaucoma are angle closure and open angle.
In angle-closure glaucoma, the normal drainage canals within the eye are physically blocked. Angle-closure glaucoma can be acute (sudden) or chronic (long-lasting). In acute angle-closure glaucoma, a sudden increase in IOP occurs because of the buildup of fluid known as aqueous humor. Acute angle-closure glaucoma is considered an emergency because optic nerve damage and vision loss can occur within hours of the onset of the problem. Chronic angle-closure glaucoma may cause vision damage without symptoms.

In open-angle glaucoma, the drainage system remains open. Open-angle glaucoma also may cause vision damage without symptoms.

Normal (or low) tension glaucoma is an unusual and poorly understood form of the disease. In this type of glaucoma, the optic nerve is damaged even though the IOP is consistently within a range usually considered normal.

Childhood glaucoma is rare and starts in infancy, childhood, or adolescence. It is similar to open-angle glaucoma, and few, if any, symptoms are present in the early stage. Blindness can result if it is left untreated. Like most types of glaucoma, this childhood form is thought to be inherited.

Congenital glaucoma is a type of childhood glaucoma that usually appears soon after birth, although it may be delayed until later in the first year of life. Unlike childhood glaucoma, though, congenital glaucoma often has noticeable signs that may include tearing, light sensitivity, and cloudiness of the cornea. This type of glaucoma is more common in boys and can affect one or both eyes.

Secondary glaucoma refers to an increased IOP that is a result of a structural problem within the eye. This secondary type may be the result of injury to the eye or other medical conditions. This form of glaucoma is different because treatment is aimed at treating the underlying cause as well as lowering the increased pressure within the eye.

Interaction of Hormones at Target Cells

  • Permissiveness – one hormone cannot exert its

effects without another hormone being present.
Estrogen and thyroid hormone

  • Synergism – more than one hormone produces

the same effects on a target cell
Glucagon and epinephrine

  • Antagonism – one or more hormones opposes the action of another hormone.Glucagon and insulin

What measures can be taken to avoid decompression sickness?

Over the past 20 years diving has become extremely popular, both at home and abroad. But diving is not without its dangers. It is vital to attend a recognised diving school for training, and subsequently make sure that you keep your skills up to date.

Diving must be planned and carried out in a responsible manner, making sure that first aid equipment and relevant telephone numbers are at hand should an accident take place. Finally, it is important to know the signs of decompression sickness and to be able to give first aid to an affected diver.

What is decompression sickness?

Decompression sickness, also called the bends, is caused by nitrogen bubbles forming in the bloodstream and tissues of the body. The bubbles occur if you move from deep water towards the surface (where the surrounding pressure is lower) in too short a space of time.

Symptoms occur soon after the dive has finished and, in the most serious cases, it can lead to unconsciousness or death.

If you suspect decompression sickness, stop the dive, initiate first aid, and summon assistance from a specialist in divers' medicine. Treatment is 100 per cent oxygen on site and during transportation, followed by treatment in a decompression chamber.

What are the symptoms?

The symptoms of decompression sickness vary because the nitrogen bubbles can form in different parts of the body.

The diver may complain of headache or vertigo, unusual tiredness or fatigue. He or she may have a rash, pain in one or more joints, tingling in the arms or legs, muscular weakness or paralysis. Less often, breathing difficulties, shock, unconsciousness or death may be seen.

The symptoms generally appear in a relatively short period after completing the dive. Almost 50 per cent of divers develop symptoms within the first hour after the dive, 90 per cent within six hours and 98 per cent within the first 24 hours.

In practice this means symptoms that appear more than 24 hours after the dive are probably not decompression sickness.

An exception is if the diver has travelled in an aircraft or has been travelling in the mountains. Under these circumstances, low pressure can still trigger decompression sickness more than 24 hours after the last dive. As a result, it is wise not to fly within 24 hours of a deep dive.
Why does it happen?

Nitrogen makes up 70 per cent of the air we breathe (in the air around us and in our diving bottles). During a dive, large amounts of nitrogen are taken into the body's tissues. This is because the diver is breathing air at a higher pressure than if they were at the surface.

The quantities of dissolved nitrogen depend on the depth and duration of the dive. The deeper and longer the dive, the more nitrogen is taken up by the body. This does not present a problem as long as the diver remains under pressure.

As the diver begins to ascend to the surface, the surrounding pressure falls, and nitrogen is released from the body via the lungs when the diver breathes out. If the rate of ascent exceeds that at which nitrogen can be released, it forms bubbles in the blood and tissues (similar to opening a bottle of fizzy drink too quickly).

To minimise the risk of bubbles forming and divers developing decompression sickness, various tables have been drawn up that show the relationship between a given depth of water and the time a diver can stay down.

In addition, divers are advised to make a safety stop every 5m, and not to ascend at a pace of more than 10m a minute. If the dive has been deep or of long duration, it may be necessary to stop one or more times on the way up, making so-called decompression stops.

However, following the advice of the tables is no guarantee of avoiding decompression sickness. This is because the risk of developing decompression sickness is not only determined by the depth and length of the dive, but also by any safety/decompression stops. Factors such as cold, current, exertion and lack of fluid also play a part.

Personal characteristics such as age, sex, percentage of body fat and physical condition must also be considered. Women are more at risk of decompression sickness than men. Similarly, the risk becomes greater the older the diver and also depends on the level of physical fitness.

How is it diagnosed?

In most cases, the diving history (ie information on the number of dives, diving depth, dive time, rate of ascent and decompressions) as well as information on contributory factors such as cold, current, work and the diver's physical condition will give some indication as to whether it could be decompression sickness.

After a thorough examination, which includes investigating balance, coordination, sense of touch, reflexes and muscular strength, the doctor can build up a complete picture to evaluate whether decompression sickness is likely.

The doctor will also decide if the diver requires treatment in a decompression chamber (also called a hyperbaric or recompression chamber).

What measures can be taken to avoid decompression sickness?

  • Dive within the limits set out in the diving tables.
  • Keep your rate of ascent to a maximum 10m/min.
  • Don't plan any dives that need a decompression stop in the water.
  • Make a three-minute safety stop at a depth of 5m.
  • Don't dive more than three times in one day.
  • If you plan more than one dive in one day, start by making the deepest dive first.
  • If you are diving for several days in a row, have a dive-free day after two to three days.
  • Don't do any hard work before or after diving.
  • Drink lots of liquid before diving. Lack of fluid due to heat or excess alcohol is dangerous.
  • Make sure you are in good physical condition and well rested. Have regular medical checkups.
  • Make sure there is an interval of at least 24 hours between diving and travel by air or climbing up mountains. If you have had decompression treatment, the recommended interval before the next dive is at least 48 hours. 

Recovery after decompression sickness

Mild forms of decompression sickness can resolve themselves without treatment or by breathing 100 per cent oxygen at the site of the accident.

However, if there is any suspicion of decompression sickness, the diver must be examined by a doctor. This is because although it might not seem serious at the time, the condition may deteriorate.

If the diver receives treatment at an early stage, the chances of avoiding permanent injury are good. The longer that treatment is delayed, the greater the risk of serious consequences.

You should take a rest from diving after treatment for decompression sickness. The length of this rest depends on the severity of the decompression sickness and the effects of treatment, and should be discussed with a specialist in divers' medicine.

How is decompression sickness treated?

There is no medicine that is used as a matter of routine in treating decompression sickness.
At the diving station and during transport
100 per cent oxygen by mask, at a rate of 10-15litres/min.
Give the diver plenty of fluid to drink.
Give first aid if the diver is unconscious.
Prevent the diver from exerting himself or getting cold.

In hospital and specialised centres
A decompression chamber is a steel tank that can be pressurised. There are decompression chambers in various places in the UK - some of these are situated at naval centres. The pressure in a decompression chamber can be increased by closing the doors and pumping air in.
During treatment for decompression sickness, pressure is increased to correspond to the pressure found 18m under water. In some cases, the pressure in the chamber is set at 50m.
The diver breathes pure oxygen through a mask, which improves exhalation of nitrogen. At depths in excess of 18m, and also after adequate intervals, the mask can be removed in the chamber. Pressure in the chamber is reduced gradually until the diver reaches surface pressure again.
Treatment typically lasts between five and six hours.
Throughout treatment a specially trained helper stays with the diver in the chamber. The diver's condition is closely monitored by further examination of coordination and balance, sense of touch, etc.
If necessary, the diver's medical specialist can join the diver in the chamber, but otherwise takes charge of the treatment outside the chamber in co-operation with the specially trained helper.
After treatment, the diver will be kept for 24 hours for observation in case his condition deteriorates.
In most instances one course of treatment is adequate, but occasionally several treatments may be needed.
After treatment for decompression sickness, a diver should take a rest from diving. The length of this rest should be discussed with a specialist in divers' medicine.

Neutral polar amino acids versus Charged amino acids

Neutral polar amino acids: Ser, Thr, Cys, Asn, and Gln

  • The sidechains of these amino acids are polar and consequently they are more easily accommodated
  • on the surface of proteins than the nonpolar amino acids. The hydroxyl (–OH) groups in Ser and
  • Thr, as well as the carboxyl (C=O) and amine (NH2) groups of Asn and Gln, are often involved in
  • hydrogen bonds. By forming hydrogen bonds with other amino acid residues these amino acids
  • can be accommodated in the protein interior.
Charged amino acids: Asp, Glu, Arg, Lys, His

The sidechains of these amino acids carry a charge at neutral pH. Asp and Glu have negatively
charged carboxylate groups, while His has a positively charged imidazole ring. These amino acids
are often used to chelate certain metal ions. For example, the carboxylate group of Asp is often
used to chelate Ca2+ while the imidazole nitrogen atoms of His are often involved in Zn2+ coordination
(as exemplified by the zinc finger proteins). We will see later that the imidazole ring of His has
special properties that make it one of the most common amino acid residues at enzyme active
sites. Lys has a positively charged amine group, and Arg has a positively charged guanidinium
moiety. The charged amino acids are usually found on the surface of proteins where they can
interact with water molecules (but remember that ionic interactions involving these residues will
be much stronger when they are buried in the protein interior).

Hypoxia and its types

Hypoxia is a state of oxygen deficiency in the body which is sufficient to cause an impairment of function. Hypoxia is caused by the reduction in partial pressure of oxygen, inadequate oxygen transport, or the inability of the tissues to use oxygen.
In brief, is kind of the same as being exposed to high altitude. In both cases, oxygen to your brain and muscles is reduced.

Hypoxic Hypoxia is a reduction in the amount of oxygen passing into the blood. It is caused by a reduction in oxygen pressure in the lungs, by a reduced gas exchange area, exposure to high altitude, or by lung disease. [This is the hypoxia that is a hazard to aviators.]

Hypemic Hypoxia is defined as a reduction in the oxygen carrying capacity of the blood. It is caused by a reduction in the amount of hemoglobin in the blood or a reduced number of red blood cells. A reduction in the oxygen transport capacity of the blood occurs through blood donation, hemorrhage, or anemia. A reduction in the oxygen carrying capacity of the blood occurs through drugs, chemicals, or carbon monoxide. [This hypoxia usually experienced by smokers.]

Stagnant Hypoxia is an oxygen deficiency due to poor circulation of the blood or poor blood flow. Examples of this condition are high "G" forces, prolonged sitting in one position or hanging in a harness, cold temperatures, and positive pressure breathing. [This hypoxia usually experienced when sitting for hours in a boring class.]

Histotoxic Hypoxia is defined as the inability of the tissues to use oxygen. Examples are carbon monoxide and cyanide poisoning. Certain narcotics, chewing tobacco, and alcohol will prevent oxygen use by the tissues. [This hypoxia usually experienced after drinking too much.]

Mechanisms of action of (HBOT) Hyperbaric oxygen therapy

Hyper" means increased and "baric" relates to pressure. Hyperbaric oxygen therapy (HBOT) refers to intermittent treatment of the entire body with 100-percent oxygen at greater than normal atmospheric pressures. The earth's atmosphere normally exerts 14.7 pounds per square inch of pressure at sea level. That pressure is defined as one atmosphere absolute (abbreviated as 1 ATA). In the ambient atmosphere we normally breathe approximately 20 percent oxygen and 80 percent nitrogen. While undergoing HBOT, pressure is increased up to two times (2 ATA) in 100% oxygen. In the Sechrist monoplace chambers utilized at our facilities, the entire body is totally immersed in 100-percent oxygen. There is no need to wear a mask or hood. This increased pressure, combined with an increase in oxygen to 100 percent, dissolves oxygen in to the blood and in all body tissues and fluids at up to 20 times normal concentration—high enough to sustain life with no blood at all.

While some of the mechanisms of action of HBOT, as they apply to healing and reversal of symptoms, are yet to be discovered, it is known that HBOT:

1.greatly increases oxygen concentration in all body tissues, even with reduced or blocked blood flow;
2stimulates the growth of new blood vessels to locations with reduced circulation, improving blood flow to areas with arterial blockage;
3.causes a rebound arterial dilation after HBOT, resulting in an increased blood vessel diameter greater than when therapy began, improving blood flow to compromised organs;
4.stimulates an adaptive increase in superoxide dismutase (SOD), one of the body's principal, internally produced antioxidants and free radical scavengers; and  greatly aids the treatment of infection by enhancing white blood cell action and potentiating germ-killing antibiotics.While not new, HBOT has only lately begun to gain recognition for treatment of chronic degenerative health problems related to atherosclerosis, stroke, peripheral vascular disease, diabetic ulcers, wound healing, cerebral palsy, brain injury, multiple sclerosis, macular degeneration, and many other disorders (see conditions treated). Wherever blood flow and oxygen delivery to vital organs is reduced, function and healing can potentially be aided with HBOT.
5. increase by eight-fold the number of circulating stem cells throughout the body. Healthy recovery of injured and diseased tissues is the ultimate goal and stem cells play an essential role.

One of the world's most experienced authorities on hyperbaric medicine was Dr. Edgar End, clinical professor of environmental medicine at the Medical College of Wisconsin, who voiced his opinion on HBOT's value for the treatment of stroke in this way: "I've seen partially paralyzed people half carried into the (HBOT) chamber, and they walk out after the first treatment. If we got to these people quickly, we could prevent a great deal of damage."

Using a Sechrist monoplace chamber, HBOT is administered in a transparent, cylindrical, acrylic chamber, approximately 8 feet long and 3 feet in diameter. The patient is first made comfortable on a cot-like stretcher and rolled into the chamber. While in the chamber, the patient has full 360-degree vision through the transparent enclosure. The chamber is equipped with microphones and speakers. The patient can watch TV, listen to music, read, nap, or talk with the chamber operator, family, or whoever is outside. During treatment, usually lasting between an hour to one and on-half hours, the patient is surrounded by and inhales pure oxygen while pressure within the chamber is increased from 1-1/2 to 2 times the outside pressure. That increase in pressure is equivalent to what a scuba diver would experience at from 22 to 30 feet below the surface of the water. At the end of treatment, the patient is gradually decompressed to normal pressure and leaves the chamber.

HBOT can also used in conjunction with EDTA chelation therapy when atherosclerosis, or blocked flow of blood is a problem, as is often the case in stroke, slow healing wounds, and macular degeneration. Results can be dramatic. Patients with cerebral vascular disease recover from complications of stroke more readily following HBOT. At the same time, EDTA chelation therapy can restore a more normal flow of blood and prevent future strokes. The same holds true for potentially gangrenous legs and feet caused by blocked circulation, and for slow-healing diabetic ulcers. HBOT relieves pain, helps fight infection, and keeps threatened tissues alive while chelation therapy gradually blood flow on a more lasting basis.

Posttranslational modification of proteins

  • Some proteins contain amino acids other than the standard 20. These modified amino acids
  • include hydroxyproline, methylhistidine, and phosphoserine. However, each of these amino acids
  • is clearly derived from one of the standard 20 amino acids. These amino acids are made by
  • posttranslational modification of the protein after it has been released from the ribosome; you
  • will learn more about posttranslational modification of proteins

How are amino acids linked to form proteins?

Proteins consist of amino acids linked together via peptide bonds. In this way, polymers ranging in size from just a few amino acids to thousands of amino acids can be created. A peptide bond is formed by condensing the carboxyl group of one amino acid with theamine group of another amino acid to form a special type of amide bond known as a peptide bond. This condensation reaction eliminates water and requires an input of energy.Once an amino acid has been covalently linked to form a polypeptide it is referred to as an
amino acid residue (usually abbreviated to residue). Thus, it is incorrect to use the
terminology “50 amino acid protein”; the correct usage is “50-residue protein”.

Do the amino acids form chemical series?
Unfortunately (especially from a pedagogical viewpoint!), the sidechains of the amino acids do
not form a natural series. At a very early stage of evolution, certain sidechains were selected for a
variety of reasons, some of them possibly random. The sidechains are not easy to remember, but
they can be conveniently subdivided into several classes based on their chemical properties.

Aliphatic nonpolar amino acids: Gly, Ala, Met, Val, Val, Leu, and Ile
These amino acids become progressively more nonpolar (hydrophobic) as one moves from Gly to
Leu/Ile. They also differ substantially in shape and relative bulkiness. These amino acids prefer to
be buried within the interior of protein molecules to minimize their exposure to water. Proline has
a cyclic sidechain in which the end is covalently linked to the amine group of the amino acid.
Thus, strictly speaking, Pro is an imino acid. The Gly aC is achiral.

Aromatic nonpolar amino acids: Phe, Tyr, and Trp
Phe is the most hydrophobic amino acid. Tyr and Trp, on the other hand, are amphipathic; they
have both polar and nonpolar portions. The polar groups (–OH in Tyr and >NH in Trp) can
engage in hydrogen bonding. The aromatic amino acids, like most conjugated compounds, absorb
light strongly in the near ultraviolet region of the spectrum. The approximate absorption maxima
in this region for each of these amino acids is 257 nm (Phe), 275 nm (Tyr), and 280 nm (Trp).

Amino acids are the building blocks of proteins

Amino acids are the building blocks of proteins
Amino acids are the building blocks of proteins. A protein is hydrolyzed into its constituent
amino acids when incubated in 6 M HCl at 120˚ C for 24 h. Proteins are in fact linear (i.e.,
unbranched) polymers of amino acids. Similarly, DNA is a linear polymer of nucleic acids, and
complex carbohydrates are either linear or branched polymers of simple sugars (monosaccharides).
The protein ‘alphabet’ consists of 20 amino acids, each of which is coded for by a specific triplet of
bases in DNA (although there is some degeneracy in this code). The protein alphabet is over two
million years old is the same for viruses, bacteria, plants, and animals. Glycine was the first amino
acid to be discovered in 1820, while the last was threonine in 1935.
Basic structure of an amino acid
An amino acid is a carboxylic acid with an amino group. All of the naturally occurring amino
acids are a-amino acids. They all contain a single hydrogen atom (H), a carboxyl (COOH) group
and an amine (NH2) group attached to a central a-carbon atom. The fourth position on the tetrahedral
a-carbon is filled by a sidechain (denoted “R”) which varies and is in fact what distinguishes one
amino acid from another. At physiological pH, the carboxyl and a-amino groups are both ionized.

The a-carbon atom of each amino acid (except glycine) is chiral because it has four different
substituents. Hence, there are two different stereoisomers which are mirror images of one another.

If you look down the aC–H bond of an amino acid with the H atom closest to you, the L-stereoisomer spells “CORN” when the substituents are read in a clockwise direction, while the mirror-image
D-stereoisomer spells “CORN” when read in an anticlockwise direction. All of the twenty naturally
occurring amino acids are of the L-configuration (except glycine, which is achiral).

The discovery of proteins

Amino acids I

The discovery of proteins

In the 1830s, the Dutch chemist Gerardus Johannes Mulder (1802–1880) recognized that, after
extraction of soluble sugars, organic acids, salts, and fats from organic matter, there was always
an insoluble residue. He showed that this residue contained—in order of decreasing
amount—carbon, oxygen, nitrogen, and hydrogen (with small amounts of sulfur and phosphorus).

In 1838 the Swedish chemist Jöns Jacob Berzelius (1779–1848) suggested to Mulder that these
substances be called proteins, from the Greek word proteios (prwteios), meaning “of primary
importance”. This name was prophetic, as we now know that proteins are absolutely vital for the
function of all living cells. While some cells can function quite well in the absence of DNA (e.g.,
human erythrocytes), no cell can survive without its armament of proteins.
Functions of proteins
Each living cell contains many thousands of proteins. In fact, a typical cell synthesizes ~15,000
proteins of which ~2000 are abundant (50,000 copies each), with the rest present in only low
numbers. Proteins perform a diverse range of functions, including the following:

1. Enzymes: These protein molecules act as biological catalysts. They can enhance reaction rates
by factors of 100,000 (105) to 1 billion (109). Enzymes catalyze the vast majority of reactions that
occur in living organisms.

2. Storage proteins: Various ions and small molecules are stored by being complexed with specific
proteins. For example, iron is stored by ferritin in the liver, and can be transported between
tissues by complexation with transferrin. Hemoglobin in human red blood cells is used to transport
O2 and CO2 around the body.

3. Transport proteins: Some proteins are able to transport ions and small molecules from one side
of a cell membrane to the other side (the membrane could be the plasma membrane or the
membrane surrounding an organelle such as the mitochondrion). A good example is the glucose
transporter which is used to facilitate the entry of glucose into cells.

4. Mechanical work: Specialized assemblies of proteins can do mechanical work, such as the
contraction of muscle and the separation of chromosomes at mitosis.

5. Antibodies: Our immune system consist of a vast repertoire of these proteins, which bind to
and signal the elimination of specific foreign particles such as viruses and bacteria.

6. Structural proteins: These proteins provide mechanical support and shape to cells and hence to
tissues and organisms. The “skeleton” of a cell is comprised of a complicated network of interacting
proteins which are attached to the plasma membrane and physically support it. An excellent
example is the cytoskeleton of the human erythrocyte, which allows the cell to be elastically
deformed in a reversible manner as it passes through capillaries of smaller diameter than the cell
itself. Another good example is collagen, which comprises a quarter (by mass) of mammalian

7. Regulatory proteins: These include hormones, such as insulin and glucagon, which regulate
biochemical activities only in cells which contain specific receptors for the hormone molecule.
Various nuclear proteins also act as regulators by determining which part of the genetic information
(chromosomal DNA) is read at a particular point in time.

Importance of Cancer (Neoplasm)

Importance of Cancer:
  • 1,400,000 new cases of serious cancer each yr in U.S.
  • 900,000 new cases of skin cancer each yr
  • 560,000 deaths from cancer this yr
  • 1 in 3 Americans will develop cancer

Neoplasia means new growth

Neoplasm = new growth
Tumor and neoplasm mean the same thing
Oncology = study of neoplasms
Abnormal mass of tissue, the growth of which exceeds and is uncoordinated w/ that of the normal tissues and persists in the same excessive manner after cessation of the stimuli that evoked the change
Mass is purposeless, preys on host, and is virtually autonomous
Growth of neoplasm competes w/ normal cells and tissues for energy and nutritional substrate
Autonomy is not complete; all depend on vascular supply, some depend on endocrine support

Tumors are
Progressive---autonomous: independent of normal growth control, and continue to grow regardless of requirements, and in the absence of any external stimuli.
Purposeless---No benefit: abnormal mass serves no useful purpose.
Parasitic---Draws benefit, but does harm: endogenous in origin but draw nourishment from the body while contributing nothing to its function.


2.Malignant = cancer
The term neoplasm does not mean cancer

All tumors have two basic components:

1. Proliferating neoplastic cells that make up their parenchyma
  • The parenchymal cells represent the functional components of an organ.
  • The parenchymal cells of a tumor determine its behavior and are the component for which a tumor is named.

2. Supportive stroma made up of connective tissue, blood vessels and lymph structure.
The supporting tissue carries the blood vessels and provides support for tumor survival and growth.

what are the classification of neoplasms ?

Classification of neoplasms.

Neoplasms are divided into benign and malignant. This is an important distinction, because it affects treatment and prognosis.
Benign neoplasms usually form a well circumscribed mass, while malignant neoplasms have poorly defined margins, with component cells infiltrating the surrounding tissues.
Benign neoplasms do not metastasis, while malignant ones do (they shed cells which grow at distant sites).
The cells of malignant neoplasms look more abnormal.
The differences are listed in more detail in the table below.

Feature Benign neoplasm Malignant neoplasm
Macroscopic appearance Discrete,  smooth-surfaced Irregular or ill-defined outline
Microscopic margin Blunt, pushing Infiltrative, invasive
Nucleus:cytoplasm ratio Usually normal  (1:4 or 1:6) Often high (1:1)
Nuclear pleomorphism Uncommon Common
Necrosis Very uncommon Often present
Mitotic rate Very low, normal mitoses Usually high, abnormal mitoses frequent
Clonality Oligo- or multiclonal Usually monoclonal
Metastases Never Often
Angiogenesis No Often

Differentiation Well differentiated Range from well differentiated to undifferentiated
Rate of Growth Slow growth over a period of yrs Rapid growth, sometimes erratic
Type of Growth Expansile (pushing margins) Progressive infiltration, invasion, and destruction of surrounding tissue
Separated from surrounding tissue? Yes
Has fibrous capsule composed of stroma of native tissue Poorly separated
Stromal invasion No Yes
Vascular invasion No Yes
Effect on host Often insignificant Significant
Cell shape Monomorphic Pleomorphic
Tumor giant cells
Nuclear chromatin Normal Increased, hyperchromatic
Peripheral clumping
Nucleoli Not prominent Prominent, w/ irregular shape
Neoplasms are also classified by the tissue of origin. There are six main groups:
1. Epithelial neoplasms, derived from epithelia, and from epithelial glandular structures.
2. Mesenchymal neoplasms, derived from tissues descended from mesenchyme: muscle, fibroblasts, bone, cartilage, fat, etc
3. Blood cell neoplasms, derived from cells descended from the pluripotent bone marrow stem cell.
4. Nervous system neoplasms, derived from cells of the central and peripheral nervous system.
5. Primative stem cell neoplasms.
6. Germ cell neoplasms

There are benign and malignant neoplasms in most of these groups. The nomenclature gives some information about the nature of the neoplasm:

The nomenclature
Neoplasms in general
All neoplasms have names ending in -oma. (Some other swellings do too, eg hamartoma, haematoma, granuloma).

Epithelial neoplasms
All benign epithelial neoplasms are adenomas (glandular morphology) or papillomas.
All malignant epithelial neoplasms end in -carcinoma. There are adenocarcinomas (glandular morphology), squamous cell carcinomas, transitional cell carcinomas (from epithelium of the urinary tract) and basal cell carcinomas.

Benign – end in –oma
An adenoma is a benign tumour of glandular or secretory epithelium
Tumors derived from glands, but not necessarily reproducing glandular patterns
A papilloma is a benign tumour of non-glandular or non-secretory epithelium
Produce microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces

Malignant – ends in –carcinoma
Carcinoma is any malignant neoplasm of epithelial cell origin
Polypoid cancers = malignant polyps
Adenocarcinoma has a glandular growth pattern
Squamous cell carcinoma = malignant tumor of recognizable squamous cells in any epithelium of the body

Cell type/normal tissue Benign neoplasm Malignant neoplasm
Stratified squamous epithelium Squamous cell papilloma Squamous cell carcinoma
Transitional cell epithelium eg. urogenital tract Transitional cell papilloma Transitional cell carcinoma
Glandular epithelium eg. gastrointestinal tract Adenoma Adenocarcinoma

Mesenchymal (connective tissue and muscle) neoplasms
All benign mesenchymal neoplasms start with an indication of the cell of origin, and end in -oma. All malignant mesenchymal neoplasms start with an indication of the cell of origin, and end in -sarcoma.

Benign tumors – end in –oma
Fibroma = benign tumor arising from fibroblastic cells
Meningioma = benign tumor of brain coverings
Leiomyoma = benign tumor of smooth muscle

Malignant tumors – end in –sarcoma
Have little connective tissue stroma and are fleshy
Sarcoma = any malignant neoplasm of mesenchymal origin

Normal Tissue Benign Neoplasm Malignant Neoplasm
Fibrous tissue (fibroblast) Fibroma Fibrosarcoma
Fat Lipoma Liposarcoma
Striated muscle Rhabdomyoma Rhabdomyosarcoma
Smooth muscle Leiomyoma Leiomyosarcoma
Cartilage Chondroma Chondrosarcoma
Bone Osteoma Osteosarcoma
Endothelium Haemangioma Angiosarcoma

Blood cell neoplasms
The distinction between benign and malignant is more difficult with neoplasms of blood cells as they usually do not form solid tissues. Some are more malignant than others, but it is difficult to say that any of them is benign. The nomenclature is confusing. There are four main groups of blood cell neoplasms: Leukaemias, Myeloproliferative disorders (essential thrombocythaemia, polycythaemia rubra vera, myelofibrosis, & CML), Lymphomas, & Myeloma. The -oma suffix of lymphoma and myeloma makes them seem benign, which they are not.

Nervous system neoplasms
Gliomas, neuromas. Meningiomas, ependymomas, and schwannomas, neurofibromas may be lumped in. Gliomas are malignant neoplasms derived from glial cells. The others are usually benign, but sometimes malignant. The nomenclature does not make any distinction.

Primitive stem cell neoplasms
All benign stem cell neoplasms start with an indication of the cell of origin, and end in -oma.
All malignant stem cell neoplasms start with an indication of the cell of origin, and end in -blastoma.

Normal tissue Benign neoplasm Malignant neoplasm
Kidney Cystic nephroma Nephroblastoma
Neural tissue Ganglioneuroma Neuroblastoma
Retina         - Retinoblastoma

Germ cell neoplasms
Neoplasms derived from germ cells are called teratomas. They have the capacity to differentiate along more than one cell line and often contain both mesenchymal and epithelial elements. They may be benign or malignant depending on the degree of differentiation, and the nomenclature does not make any distinction.

Tetratoma – made up of a variety of parenchymal cell types representative of more than one germ layer, usually all three
Arise from totipotential cells that differentiate along various germ lines; can develop into any tissue of the body
Principally encountered in the gonads
Cystic tetratoma (dermoid cyst)
Differentiates along ectodermal lines to create a cystic tumor lined by skin replete w/ hair, sebaceous glands, and teeth str’s

Exceptions to Nomenclature:
• Following are malignant:
Melanoma Carcinomas of melanocytes
Seminoma Carcinomas of testicular origin

Principal characteristics of carcinomas and sarcomas
Feature Carcinoma Sarcoma
Origin Epithelium Connective tissues
Behaviour Malignant Malignant
Frequency Common Relatively rare
Preferred route of metastasis Lymph Blood
In-situ phase Yes No
Age group Usually over 50 years Usually below 50 years

Choristoma – ectopic rest of normal tissue; example – rest of adrenal cells under the kidney capsule

Aberrant differentiation produces a mass of disorganized, mature, specialized cells or tissue indigenous to the particular site
Example – Hamartoma in lung may contain islands of cartilage, blood vessels, bronchi, and lymphoid tissue
Totally benign

Cellular Pathology and its Morphology

Cellular Pathology

§  Pathology includes study of etiology (what initiates a process), pathogenesis (mechanism), morphology (how it’s recognized) and functional consequences (how it produces disease).
§  The three fundamental processes of cellular pathology are cell injury, cell death and cellular adaptation.  In response to stressors, cells may adapt or die/be injured. 
§  The etiology of cell injury may be extrinsic or intrinsic, including hypoxia, physical/chemical agents, drugs, infection, immunologic reactions, genetic, or nutritional problems.
§  Hypoxia is the reduction or absence of normal oxygen supply.  It may be a result of ischemia, which is the reduction or absence of blood supply.  They most often go together, but ischemia alone can be damaging from a lack of trophic substances or accumulation of toxins, and hypoxia alone can still be damaging (ex: anemia, pulmonary disease, cyanide poisoning).
§  Infarction is the process in which a portion of a tissue dies as a result of ischemia. An infarct is the end result of this process.  They may be white or red (still some blood supply to the dead tissue), but both result from the same underlying mechanism.
§  The mechanisms by which ischemia causes cell death are inter-dependent and synergistic.  Toxins often influence one of these mechanisms.  They include: 
o   Decreases in ATP – oxidative phosphorylation shuts down first in ischemia.  Pumps stop running and cells/organelles swell and have blebs, glycolysis lowers pH and chromatin clumps, protein synthesis decreases and lipids accumulate since proteins aren’t available to export lipids as lipoproteins.  These early changes are reversible. 
o   Increased intracellular Ca, which is critical to homeostasis.  Many enzymes only function within a very narrow range of [Ca].  Ischemia inactivates calcium pumps, resulting in calcium activation of enzymes and increased membrane breakdown along with decreased membrane synthesis. 
o   Membrane damage (considered the point of no return)
o   Reactive oxygen species – endogenous or exogenous free radicals.  Reperfusion of an ischemic area can add to ischemic damage, likely by sudden calcium influx or exposure to free radicals from an influx of inflammatory cells.  We have some level of antioxidant defense from vitamins C and E, glutathione peroxidase, catalase and superoxide dismutase.  But oxidative stress can result from imbalance between ROS and antioxidants.  Oxidative stress is associated with aging, diabetes, atherosclerosis, Alzheimer, etc.
§  Cell injury becomes irreversible most quickly in neurons, followed by myocardium and hepatocytes, and most slowly in skeletal muscle. 
§  Reversible cell injury is characterized by cell swelling, vacuolar degeneration, and lipid deposition (especially in the myocardium and liver).
§  Irreversible injury:  necrosis – the morphological changes in the nucleus and cytoplasm occurring after death in a living tissue, regardless of the cause of injury.  By the time necrosis is observed, the cell is dead.  This need not occur at the tissue level.
o   Features of necrosis include:  eosinophilia due to loss of RNA/ribosomes and denatured protein, nuclear changes (small-pyknosis, broken apart-karyorrhexis, or dissolved-karyolysis), INFLAMMATION.  The inflammation is the big distinguishing feature, and it usually occurs about 8 hours after cell death.  Thus, it won’t occur if the cell dies and organism also dies at the same time. 
§  Types of Necrosis:
o   Coagulative:  Results from ischemic cell death, and is seen in most tissues except for the brain.  In this type of necrosis, the tissue architecture is retained.  You typically see ‘tombstones’ of hyper-eosinophilic cells.  It typically resolves by scar formation.
o   Liquefactive:  Characterized by complete hydrolysis of dead cells, resulting in a loss of tissue architecture and usually resulting in a cyst or cavity.  This is the usual response to infarction in the brain. 
o   Abscess:  Liquefactive necrosis resulting from localized bacterial/fungal/parasitic infections.  It usually has lots of neutrophils within the abscess (pus=dead neutrophils and debris) which are the source of hydrolytic enzymes.  It often requires surgical drainage, since vasculature is commonly damaged and antibiotics won’t be delivered effectively.
o   Caseous (cheese-like): Characteristic of TB and fungal infections.  It has a center of cheese-like necrosis surrounded by a rim of inflammatory cells (all together called a granuloma).
o   Fat:  Common in the pancreas (from release of pancreatic enzymes) and breast (from minor trauma).  Membrane lipids are digested into FFAs, and combine with calcium (saponification) to form chalky white deposits.  May mimic a carcinoma clinically.
§  Cellular adaptations include hyperplasis, hypertrophy, atrophy, and metaplasia. 
§  Hyperplasia is an increase in the number of cells in a tissue/organ.  In hyperplasia, you see dividing, mitotic cells.  Hyperplasia may be physiologic, such as in lactating breasts.  But is can also be pathologic, as in endometrial hyperplasia with unopposed estrogen stimulation that results in prolonged cycles with menorrhagia (heavy bleeding).  Another example of hyperplasia is in BPH. 
§  Hypertrophy is an increase in individual cell mass, and is usually reversible.  In benign prostatic hyperplasia, bladder muscle hypertrophies as a results of needing to push the urine out with more force.  Other examples of pathologic hypertrophy may be hypertrophy of the heart in someone with aortic valve stenosis or chronic hypertension.  Hypertrophy may results from greater workload, as above, but also from increased levels of hormones (anabolic or in pregnancy, etc).  Genetic mutation in the myostatin gene has been shown to cause muscle hypertrophy in animals. 
§  Atrophy is cellular shrinkage due to a loss of substance, and may result from disuse, denervation (polio), ischemia, starvation (protein-calorie malnutrition, or marasmus), or absence of endocrine stimulation.  Ex:  menopause can result in atrophy of cells making up endometrial glands.  Ex:  cachexia, a wasting associated with cancer, AIDS and other chronic inflammatory diseases.
o   Cellular atrophy may culminate or be accompanied by progressive cell loss, and if enough occurs an organ or tissue may shrink.  In these cases, atrophy describes both cell shrinkage and cell loss. 
§  Metaplasia is the reversible replacement of one differentiated cell type by another differentiated cell type.  It can be considered an adaptive substitution by cells that can better withstand an adverse environment.  In smokers, you see squamous metaplasia where respiratory epithelium is replaced by stratified squamous cells.  Stem cells at the basement layer differentiate into squamous cells.  Metaplastic epithelium may undergo neoplastic progression to dysplasia (not yet cancer, but cells lose normal architecture on the way there), and ultimately to neoplasia (cancer w/ clonal cells having a genetic mutation).  Not all metplasias become cancers, but if the stimulus persists, they may. 
§  Cells may accumulate endogenous or exogenous substances (lipids, protein, glycogen, carbs, minerals, pigments, etc). 
o   Pigment accumulations:  anthracosis (accumulation of dark carbon pigment in city dwellers) or lipofuscin (wear and tear pigment where you have lots of cell turnover) are examples of benign pigment accumulations.
o   Intracellular lipid accumulation:  Fatty change (steatosis) is potentially reversible.  It most commonly occurs in the liver, and is caused most commonly by obesity or alcoholic liver disease.  The liver is typically enlarged and rather than red, it appears yellow/white. 
§  Cell death is not always pathologic; apoptosis is normal in embryogenesis, immune cell differentiation, menstruation, etc.  Apoptosis may be pathologic too, resulting from DNA damage (w/ p53 as a principal mediator), viral infection or CD8 T cell mediated injury. 
o   Apoptosis is mediated by caspases, cysteine protesases that require activation.  Bcl-2 is an anti-apoptotic protein, and its family contains both pro and anti apoptotic factors.  P53 stops cell division in response to DNA damage in order to facilitate recovery, and if recover fails it initiates apoptosis. 
o   Morphologically, apoptosis is characterized by nuclei breaking into apoptotic bodies.  This occurs in single cells with apoptosis, whereas necrosis tends to occur in large regions of an organ.  In apoptosis, DNA is systematically fragmented and shows as a ladder on a gel, whereas necrotic cell death breaks it down at random, resulting in a smear. 
o   Basically, apoptosis is usually physiologic, occurs in single cells, fragments DNA between nucleosomes, and produces apoptotic bodies WITHOUT inflammation.  Necrosis is usually pathologic, occurs in groups of cells, randomly fragments DNA and shows swelling, degeneration, and inflammation. 
o   Inhibition of apoptosis facilitates tumorigenesis.  HPV blocks p53 and apoptosis, and can result in squamous cell carcinoma of the cervix.  Constitutive activation of Bcl-2 blocks apoptosis and facilitates follicular lymphomas.