# Structural Biochemistry/Cell Signaling Pathways/Circulatory System
## Circulatory System

The Circulatory System is an organ system that transfers the body's essentials such as blood cells, nutrients, gases, and etc. to and from the cells in order to maintain homeostasis. Under the circulatory system, there are two systems: cardiovascular system and the lymphatic system. The cardiovascular system consists of the heart, blood, and blood vessels, while the lymphatic system is composed of the lymph, lymph nodes, and lymph vessels.
Not all organisms require a circulatory system. Its primary purpose is to distribute nutrients and essential elements like oxygen throughout the cell. Smaller organisms, or those with a high surface area relative to their volume, do not need a circulatory system because transfer can take place directly across their cellular membranes. Flatworms are an example of this; due to their size and shape, cells can obtain nutrients and remove waste without the need for an extensive circulatory system because diffusion is sufficient. Human beings, however, require a circulatory system due to their size; for example, oxygen would not be able to effectively diffuse into organ cells without a circulatory system because oxygen would have to go through our skin and into organ cells for them to receive oxygen. In such a case, an internal circulatory system, a network of blood vessels, veins, and arteries, is beneficial because nutrients and oxygen can be gathered at a central location and distributed throughout the body.
Open/Closed Circulatory system
In open circulatory system is the circulatory fluid bathes the organs directly. In these animals, the circulatory fluid, called hemolymph is the same as interstitial fluid. The heart pumps hemolymph through vessels into sinuses, fluid-filled spaces where materials are exchanged between the hemolymph and cells. Arthropods and most mollusks have an open circulatory system.
A closed circulatory system circulates blood entirely within vessels, so the blood is distinct from the interstitial fluid. One or more hearts pump blood into large vessels that branch into smaller ones and the interstitial fluid bathing the cells. For example, annelids, such as earthworms have closed circulatory system. This is often called cardiovascular system.

### Blood Vessels

Arteries, veins, and capillaries are the three main types of blood vessels. Within each type, blood flows in only one direction. (1) Arteries carry blood away from the heart to organs throughout the body. (2) Veins carry blood back to the heart. (3) Capillaries are microscopic vessels with very thin, porous walls. Capillaries also touch every organ in the body.

### Chambers

The hearts of all vertebrates contain two or more muscular chambers. The chambers that receive blood entering the heart are called atria. The chambers that pump blood out of the heart are called ventricles.

## Single Circulation

The blood passes through the heart once in each complete circuit. In single circulation, blood that leaves the heart passes through two capillary beds before returning to the heart. When blood flows through a capillary bed, blood pressure drops substantially. Fish undergo single circulation, they have a two-chambered heart and single circuit. The blood must pass through two capillary beds. The capillary bed is where exchange takes place while oxygen is loaded and carbon dioxide is being unloaded. The blood collects in the first capillary bed and continues onto the second capillary bed. Two capillary beds are problematic because blood pressure decreases as it branches off into smaller branches and this occurs twice in single circulation causing blood pressure to decrease dramatically. The contraction of muscles and movement helps the system get blood back to the heart. This is why single circulation works for fish because they are constantly moving.

## Double Circulation

The circulatory systems of amphibians, reptiles, and mammals have two distinct circuits.

### Pulmonary Circulation

Pulmonary circulation is the portion of the circulatory system which carries oxygen-depleted blood away from the heart, to the lungs, and then returns oxygenated blood back to the heart. The pathway that blood takes in the pulmonary circuit starts at the right section of the heart. Oxygen-depleted blood from the body enters the heart through the right atrium where it pumped through the right atrioventricular valve and into the right ventricle. The blood is then pumped into the two pulmonary arteries, one for each lung, and travels into the lungs. The pulmonary arteries carry the deoxygenated blood to the lungs while the pulmonary veins carry oxygenated blood to the red blood cells. There they release carbon dioxide and then pick up oxygen during respiration. Now that the blood has been oxygenated, it leaves the lungs via the pulmonary veins and it returns to the left heart, completing the pulmonary cycle. The blood enters the left atrium and is pumped through the left atrioventricular valve and into the left ventricle. From here, the blood is distributed to the body via the systemic circulation before once again returning to the pulmonary circulation to pick up more oxygen.

### Systemic Circulation

Systemic circulation, as indicated with the word "system" in the title itself, is all throughout the body. This circulation's key role is to provide nourishment to all of the tissues located throughout your body. However, it does not benefit the heart and lungs because they have their own systems. Nonetheless, systemic circulation is a vital supporting piece of the circulatory system as a whole. The blood vessels, which consist of the arteries, veins, and capillaries, are responsible for the delivery of oxygen and nutrients to the tissue. Oxygen rich blood enters the blood vessels through the heart's major artery called the aorta. There exists the application of forceful contraction of the heart's left ventricle which compels the blood to flow through the aorta and into smaller arteries to distribute throughout the body. As a matter of fact, the inside layer of an artery is very smooth, thus allowing blood to flow rather quickly. As the atrium contracts in the heart, more blood is filling the ventricles. Eventually, the atrioventricular valve closes. The ventricles undergo isovolumetric contraction, which is when the ventricles contract but the volume does not change. Once the pressure in the ventricles exceeds the pressure in the aorta will that aortic valve open. In comparison to the inside layer of the artery, the outside of the artery is relatively strong, allowing blood to flow forcefully. As the blood flows through the arteries, the velocity of flow is fast. This is because the cross-sectional area of the arteries is small, and linear velocity is inversely proportional to the cross-sectional area. Once blood reaches the capillaries, the velocity decreases because capillaries have a large cross-sectional area. The second to last step of this systemic process involves oxygen-rich blood entering the capillaries where the oxygen and nutrients are then released. The process concludes with the collection of waste products and waste-rich blood that flow into veins to be taken back to the heart. The rest of the work is left to pulmonary circulation, which is mentioned in the section above. Other key aspects of systemic circulation include the fact that blood passes through the kidneys, which is known as renal circulation. During this phase, the kidneys filter as much of the waste from blood as possible. Blood also makes its way through the small intestine, which is known as portal circulation. In this phase, the blood from the small intestine collects in the portal vein which then passes through the liver. To explain with more specificity, the liver filters sugars from blood, storing them for later.

### Coronary Circulation

While pulmonary and systemic circulation provide oxygen and nutrients for the rest of the body, it is crucial not to forget about the heart's everlasting desire for nutrients as well. This is pursued through coronary circulation which refers to the movement of blood through the tissues of the heart. Despite the fact that blood fills the chambers of the heart, the muscle tissue of heart which is referred to as myocardium, is so thick to the point that it requires blood vessels to deliver blood deep into it. These blood vessels, responsible for delivering oxygen-rich blood to the myocardium, are known as coronary arteries. The vessels responsible for the removal of deoxygenated blood from the heart muscle are known as cardiac veins. The coronary arteries, when healthy, are capable of autoregulation to maintain coronary blood flow at levels appropriate to the needs of the heart muscle. The critical nature of coronary arteries are illustrated by means of classification as the "end circulation" because they represent the only source of blood supply to the myocardium.
The coronary circulation of the heart consists of blood (a fluid that carries materials between the outside world and the cells of the body), a lot of blood vessels (carrying blood throughout the body to deliver those nutrients to the various cells), and the main component of the coronary circulation system, the heart (which forces blood into the blood vessels. The pressure that the heart produces to push blood through the blood vessels is called the blood pressure. If the blood pressure becomes inadequate to produce a large enough force for the blood to move into the vessels, certain cells become starved for Oxygen, a condition referred to as ischemia.
In coronary circulation, in order to understand how the heart and the blood vessels can respond to autonomic and endocrine input and how they change their behavior, it is essential to look carefully at each of the components in the cardiovascular system. The heart consists of two separate pumps, joined together. These two halves of the heart are connected by parallel sets of blood vessels in series with one another. The right heart receives blood from most of the body and pumps the blood into the vessels of the lungs (the pulmonary circulation); the left heart receives blood from the lungs and pumps the blood into vessels into the rest of the body (the systemic circulation). Both the right and left heart are separated in themselves into two subsections, the atria and ventricles. Veins leading to the right heart are connected to the right atrium at first. The bloods that enters the right atrium is then pumped into the right ventricle, which is separated from the right atrium by the bicuspid valve. Once in the right ventricle, the blood circulates through arteries and veins in the pulmonary circulation into the left atrium. Once in the left atrium, the blood is allowed into the left ventricle as the mitral (tricuspid) valve opens and closes due to blood pressure differences in the two compartments.
After release into the left ventricle, blood is propelled past the aortic valve to flow to the rest of the body. For the reason that the left ventricle must produce enough force to send the blood through the rest of the body, the muscles of the left ventricle are much stronger than the muscles of the right ventricle.
The output of blood in the two halves of the heart must be exactly equal to one another on a minute-to-minute basis or else blood will be backed up in either the systemic or pulmonary circulation, which leads to major problems for the entire circulatory system. Damage to the heart results in a heart pump with less efficiency. In congestive heart failure, the left heart forces more blood than the right heart, a condition that is referred to as systemic edema. This condition can be treated with drugs that increase fluid excretion and that increase the strength of the heart as a whole. In left heart failure, the right heart pumps more blood than its counterpart, a condition referred to as pulmonary edema. This condition interferes with gas exchange in the lungs and can produce suffocation. If the heart becomes extremely weak overall, a condition referred to as congestive heart failure occurs. In congestive heart failure, residual blood pressure in the heart causes the heart to become abnormally full, greatly stretching the heart muscles. Under this condition, the heart becomes unable to even contract strongly and is unable to force any blood into the great arteries. This situation must be remedied immediately or death follows.

## Body Fluids

Body fluids are primarily distributed among three major compartments in the circulatory system. These three compartments are the volume inside of the cells (the intracellular compartment), the volume inside the circulatory system itself (the plasma compartment), and the volume that lies between the circulatory system and the intracellular compartment (the interstitial compartment). Under normal conditions, the three different compartments are in osmotic equilibrium with one another, but they do contain different distributions of solutes. There is a lot of organic anion (mostly proteins) inside cells, essentially none in the interstitial fluid, and a little in the plasma. Sodium and potassium ions are distributed with the inverse concentration profiles across cell membranes. The total number of millimoles of solute is equal in each of the three compartments. Cell membranes separate the intracellular and interstitial compartments. Capillary walls separate the interstitial and plasma compartments. Materials that must be exchanged between the different compartments must cross these barriers in order to reach the other side.
In all cases, the basic techniques of measuring body fluids consists of diluting an appropriate marker molecule (Evan's blue, inulin, H2O) into the volume that you would like to measure, allowing it to mix thoroughly in the compartment, and then measuring the concentration of the marker. The basic calculation is based on the equation volume = (quantity/concentration). There are, however, several possible sources of error tin this method.These errors include an inadequate mixing of the marker within the compartment, loss of the molecule marker by metabolism or excretion, and leakage into other compartments. an ideal marker substance for these measurements has the characteristics of going only into the compartment that is measured, is broken down or excreted very slowly compared to mixing time, and is lost as a simple exponential function of time (therefore allowing the extrapolation back to its initial concentration from the data. the plasma volume is measured using Evan's blue, which binds to blood cells and plasma proteins. The interstitial volume is measured using molecules that equilibrate between the plasma and the interstitial fluid, but that won't enter cells (inulin). Total body water is measured by deuterated or tritiated H2O, and with subtraction an intracellular volume is measured.
Body fluid compartments are separated by layers composed of cells that are arranged side-by-side with one another. The layer of cells that solutes and water traverse as they move between compartments are epithelia cells or endothelia cells. Chemical species move across there cell walls driven by concentration gradients or pressure gradients. These chemical species may traverse the capillary walls by either a transcellular pathway of through a paracellular pathway, or even both. Most cells of the epithelial layer are polarized, meaning that the properties of the cell membrane facing the interstitial fluid are different from the properties of the cell membrane of the very same cells facing the lumen of the tube. Chemical species can cross the paracellular pathway if there is a driving force on them and if they aren't too big. Passage through the transcellular pathway is more complex in that a transporter molecule may be needed to facilitate diffusion across the cell membrane.

### Blood

The composition of mammalian blood is 55% plasma and 45% cellular elements.
Plasma Plasma is about 90% water, the dissolved salts are an essential component of the blood. Some of these ions buffer the blood, which in humans normally has a pH of 7.4.
Cellular elements Two classes of cells: red blood cells, which transports oxygen, and white blood cells, which function in defense. Blood also contains platelets, fragments of cells that are involved in the clotting processes.

## Mammalian Heart

One complete sequence of pumping and filling is a cardiac cycle. The contraction phase of the cycle is called systole while the relaxation phase is called diastole.

### Cardiac Cycle

For an adult human at rest with a heart rate of about 72 beats per minute, one complete cardiac cycle takes about 0.8 second. (1) During when atria and ventricle are in diastole, blood returning from the large veins flow into the atria and ventricle through the AV valves. (2) A brief period of atrial systole then forces all blood remaining in the atria into the ventricles. (3) During the remainder of the cycle, ventricular systole pumps blood into the large arteries through the semi-lunar valves.

### Maintaining heart beat

* Sinalatrial (SA) node depolarizes.
* Electrical signal is passed to the AV node.
* Depolarization spreads to atria.
* Depolarization is passed down the bundle of Hiss to the apex of the heart.
* Depolarization spreads upward from the apex, through the bundle branches. The bundle branches divide into left and right bundle branches.
* The message is passed through the Purkinje fibers, causing the ventricles to contract.
The SA node is called the pacemaker of the heart because it has the fastest rhythm, about 80beats per minute. Every time the SA produces an action potential, the message is relayed the heart as described above. If the SA node becomes damaged and the message is not passed down, the AV node will take over as the heart's pace maker. The AV node beats a lot slower, only about 40beats per minute. Although this will be enough to keep a person alive, contraction will be too slow for strenuous activity. Doctors will recommend putting in an artificial pace maker in such a case.

## Electrocardiogram

The electrical activity of the heart, as described above, is measured with an electrocardiogram, or an ECG. This measurement is taken using electrodes on the skin, which are capable of picking up electrical fields from signals conducted within the heart. Because body fluids are saline, they can conduct signals well. ECG's are recorded from limb or chest leads. A typical ECG consists of a P wave, QRS wave (complex), and a T wave. ECG's are small potentials and are only a few millivolts in amplitude. The P wave correlates to atrial depolarization, which occurs just before atrial contraction. The QRS complex correlates to ventricular depolarization, which occurs just before ventricular contraction. The final T wave is due to ventricular repolarization which occurs during ventricular relaxation. There is a temporal relationship between the cardiac action potentials and the ECG record.
ECG's are valuable because they are non-invasive methods to monitor the condition of the heart in a relatively simple way. Vector analysis is used to analyze the heart as well and can indicate the position of damage to the heart.
There are several issues that can occur in the conducting paths of the heart, which overall cause an ECG to look much different:
In a first-degree block, there is a delay in the depolarization of the ventricles, therefore making the P-R interval prolonged. In a second-degree block, the P waves are sometimes not followed by the QRS-complex or could be completely missing. In a third-degree block, the P waves and QRS complex occur completely independent of each other.
In atrial fibrillation, the waves can all be out of order, but this is not as big of an issue because the ventricles are still functioning normally and are simply having the wrong atrial impulses. This would make an irregular heartbeat occur. The In ventricular fibrillation, the waves are scattered all around and this is a fatal heart problem if not taken care of immediately.

### Pacemaker cells

Pacemaker cells help initiate the rhythmic depolarization of the heart. It is what leads the heart to beat in a rhythmic pattern. The heart does not receive transmitters from the nervous system to function it to contract. Instead, the heart has a combination of pacemaker cells and conducting fibers to maintain autonomic depolarization. The two pacemaker cells are sino-atrial node and atrio-ventricular node. Conducting fibers such as the Bundle of His and Purkinje Fibers help take the electrical current to all the ventricular muscle system. This process is important because the heart contracts synchronously and without the transmission of electrical current through the conducting fibers, the heart would not function properly. Pacemaking cells also contribute to the pacemaking potential, in which the depolarization occur differently than normal cardiac action potential.

### Control of the Heart Rhythm

The SA node in the heart is made up of a group of cells which is also called a pacemaker because it sets the timer at which all the cardiac muscles contract. The pacemaker generates a wave of signals that conduct through the atria and causes both atria to contract simultaneously. Signals travel from the SA node to the AV node, another group of cells that receives the current from the first node. There is a delay that takes place at the AV node because the atria must empty completely and all the blood must flow in before the ventricles are able to contract. After the delay, the AV node is now able to send the current through the bundle branches into the apex of the heart where it spreads throughout the ventricles of the heart through Purkinje fibers triggering a contraction.

### Patterns of Blood Pressure

There are three properties including cross sectional area, blood flow velocity and blood pressure that that explain the pattern of blood flow from arterioles into the capillaries. Blood flow from arteries to arterioles to capillaries slows due to the increase in total cross sectional area. The number of capillaries is extremely high making the cross sectional area much greater in the capillary beds than in arteries or any other part of the circulatory system. Blood flow here is also slow because the exchange of material is taking place. The increase of cross sectional area correlates to the decrease in the speed of blood flow because arteries must transfer blood to many capillaries. However, it is noted that there is a slight increase when the blood enters the vein again. This is because the veins and venules have a slightly larger cross sectional area than capillaries. As a result, the change in diameter aids in speeding up the blood flow into the veins. As blood enters the capillary bed, the capillaries have narrow diameter which produces resistance to blood flow. This resistance causes much of the pressure that is generated by the heart to disperse. Arteries have the ability to keep blood pressurized at all times. The pressure in the arteries during ventricular systole is called systolic pressure and is the highest pressure in the arteries. Pressure in the arteries during diastole is called diastole pressure, which in comparison to systolic pressure is much lower.

### Capillary Function

In the capillary bed, there are two forces that are in charge of driving the diffusion of water outward or inward. These two forces are known as blood pressure and osmotic pressure, opposing forces in the capillaries. Osmotic pressure is established by the protein albumin which is always present in the blood. Albumin is too large of a protein to be transferred out of the blood, as a result the osmotic pressure is always constant because ultimately, the proteins cannot leave the capillary beds and they are the ones that maintain this pressure. The blood pressure is established by systolic and diastolic pressure in the arteries. When the blood pressure is higher than the osmotic pressure, there is an outward flow of fluid. On the other hand, when the osmotic pressure is higher than the blood pressure, there is an inward flow of fluid. There is usually more exchange leaving the capillary then coming back. Much fluid is lost that does not return to the circulatory system.

## Cardiovascular Disease

Disorders of the heart and blood vessels. Cardiovascular diseases range from a minor disturbance of vein or heart valve function to a life-threatening disruption of blood flow to the heart of brain.

### Congestive Heart Failure

One side of the heart is weaker than the other, causing unequal pumping of blood from the two halves of the heart. People can be born with the disease, but usually occurs when one side of the heart is damaged.
* Right heart failure occurs when the left ventricle pumps more blood than the right ventricle. Blood becomes backed up and collects in the body, leading to a condition called systemic edema. The accumulation of excess fluid causes the arms to be swollen constantly. Fortunately, right heart failure is not very serious or life threatening. They can easily be treated with drugs that increase cardiac contraction.
* Left heart failure occurs when the right ventricle pumps more blood than the left ventricle. This causes blood to collect in the lungs, leading to pulmonary edema. The collection of blood can lead to suffocation, and possible death. Unlike right heart failure, left heart failure is very serious and must be treated immediately.
Both the left and right ventricles must be contracting the same amount of blood at all times. Even though left ventricle contraction is stronger than the right, the same amount of blood is pumped.
The leading causes of heart failure are diseases that damage the heart such as coronary heart disease (CHD), high blood pressure, and diabetes. Many of these risk factors cannot necessarily be changed or reversed. Leading risk factors that are capable of being changed in a lifetime include, tobacco use, unhealthy blood-cholesterol levels, physical inactivity, and being overweight/obesity. Leading risk factors that cannot be changed include heredity, aging, being male and ethnicity.
Tobacco use harms the cardiovascular system in many different ways, such as by damaging the lining of the arteries and reducing the "good" cholesterol in the body. Nicotine in specific raises the heart rate and the blood pressure of the body. Depletion of the oxygen supply in the blood is caused by the inhalation of carbon monoxide. Those who smoke and those who are exposed to smoke are capable of experiencing heart-related problems.
In the United States, heart failure is acknowledged as a common condition and affects about 5.8 million Americans. Heart failure has no cure however many treatments such as pharmaceutical medications and lifestyle modifications can help people relieve some symptoms and help them live longer. Current treatment options for advanced heart failure include the implantation of left ventricular assist devices (LVAD) to help the heart mechanically continue pumping blood. Currently, LVAD implants are being used as destination therapy or bridge to transplantation of artificial hearts.
References http://www.nhlbi.nih.gov/health/health-topics/topics/hf/

### Atherosclerosis

The hardening of the arteries by accumulation of fatty deposits. Healthy arteries have a smooth inner lining that reduces resistance to blood flow. Damage or infection can roughen the lining and lead to an inflammation. Leukocytes are attracted to the damaged lining and begin to take up lipids, including cholesterol.
The hardening process often accompanies the natural progression of aging. High blood cholesterol due to unhealthy lifestyle as caused by a diet high in fat content, alcohol use, and limited exercise can accelerate the hardening of arteries. Other risk factors for atherosclerosis include diabetes, high blood pressure, smoking, and family history of atherosclerosis.
Diagnosis include a series of medical tests such as magnetic resonance arteriography (MRA), angiography (the use of x-rays to view the inside of arteries), and ultrasound doppler tests.

### Heart Attack

Also called a myocardial infarction, is the damage or death of cardiac muscle tissue resulting from blockage of one or more coronary arteries. Since the coronary arteries are small in diameter, they are especially vulnerable to obstruction. Such blockage can destroy cardiac muscle quickly because the constantly beating heart muscle cannot survive long with oxygen.
A heart attack may be caused by blood platelets sticking to tears in the plaque and from a blood clot that blocks blood flow to the heart. Heart attack symptoms include chest pain, anxiety, cough, fainting, light-headedness, shortness of breath, and sweating.

### Stroke

A stroke is the death of nervous tissue in the brain due to a lack of oxygen. Strokes usually result from rupture of blockage of arteries in the head. The effects of a stroke and the individual's chance of survival depend on the extent and location of the damaged brain tissue.
Strokes are also medically known as cerebrovascular disease, cerebral infarction, or cerebral hemorrhage. There are two main types of stroke called ischemic stroke and hemorrhagic stroke.
* ischemic stroke: This type of stroke occurs when a blood vessel that supplies blood to the brain is blocked by a blood clot. The clot maybe in an already narrow artery and is called a thrombotic stroke. Another pathway by which a clot can form is through a dislodged clot from another blood vessel or another part of the body and travels up to the brain. This type of stroke is known as embolic stroke. These clots consist of fat, cholesterol that create plaque.
In ischemic stroke, there are two types of stroke that can occur; embolic and thrombotic. In embolic stroke, blood clots travel from somewhere in the body to the brain. In thrombotic stroke, caused by thrombi, blood clots form where an artery has been narrowed by atherosclerosis.
* hemorrhagic stoke: This type of stroke occurs when a blood vessel in the brain is weakened and as a result, burst open. Blood starts to leak into the brain. People who already have defects in blood vessels of the brain are more likely to experience hemorrhagic stroke.
In hemorrhagic stroke, there are two different types of stroke that can occur; subarachnoid hemorrhage stroke and intra-cerebral hemorrhage stroke. In subarachnoid, there is a bleed in between the brain and the skull which usually develops from an aneurysm. In intra-cerebral hemorrhage, there is a bleed in the brain from a blood vessel which is caused from high blood pressure and its damaging effects on arteries.
The risk factors for stroke include family history, high cholesterol, age, race, unhealthy lifestyle and diet, and diabetes. Women over 35, smoke, and take birth control pills are at a very high risk of stroke.

## Angina

Overtime, arteries that are narrowed by disease can still open enough to deliver blood to the heart. However, during exertion, the heart requires more oxygen to function properly, than the narrowed arteries can process successfully. The result is called angina pectoris, which is severe chest pain. The pain can occur in the chest, shoulder, neck, arm, hand or back and usually is expressed as a tightness in one of those areas or heavy pressure. Angina can be controlled via drugs or surgical treatment but overtime can become a blocked artery or even lead to cardiac failure.

## Coronary Bypass Surgery

When an artery becomes blocked, it may become non-functional or could affect the overall blood supply to the heart. In this case, a vein would be grafted into an artery at the point above and the point below the obstructed segment.

## References

D. Silverthorn. (2009). Human Physiology 5th Edition. San Francisco, California: Benjamin Cummings
PubMed Health: Hardening of the arteries. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001224/
National Heart Lung and Blood Institute: What is Heart Failure? http://www.nhlbi.nih.gov/health/health-topics/topics/hf/
Pubmed Health: Stroke http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001740/
Insel, P.M., & Roth, W.T. (2012). Core Concepts in Health. San Diego, California: McGraw-Hill.