The Stomach :

The wall of the stomach is lined with millions of gastric glands, which together secrete 400–800 ml of gastric juice at each meal. Three kinds of cells are found in the gastric glands

• parietal cells
• chief cells
• mucus-secreting cells

Parietal cells : secrete

Hydrochloric acid : Parietal cells contain a H⁺ ATPase. This transmembrane protein secretes H⁺ ions (protons) by active transport, using the energy of ATP.

Intrinsic factor: Intrinsic factor is a protein that binds ingested vitamin B₁₂ and enables it to be absorbed by the intestine. A deficiency of intrinsic factor  as a result of an autoimmune attack against parietal cells  causes pernicious anemia.

Chief Cells : The chief cells synthesize and secrete pepsinogen, the precursor to the proteolytic enzyme pepsin.

Secretion by the gastric glands is stimulated by the hormone gastrin. Gastrin is released by endocrine cells in the stomach in response to the arrival of food.

The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal. However, scattered through the pancreas are several hundred thousand clusters of cells called islets of Langerhans. The islets are endocrine tissue containing four types of cells. In order of abundance, they are the:

• beta cells, which secrete insulin and amylin;
• alpha cells, which secrete glucagon;
• delta cells, which secrete somatostatin, and
• gamma cells, which secrete a polypeptide of unknown function.

Beta Cells

Beta cells secrete insulin in response to a rising level of blood sugar

Insulin affects many organs. It

• stimulates skeletal muscle fibers to
  • take up glucose and convert it into glycogen;
  • take up amino acids from the blood and convert them into protein.
• acts on liver cells
  • stimulating them to take up glucose from the blood and convert it into glycogen while
  • inhibiting production of the enzymes involved in breaking glycogen back down (glycogenolysis) and
  • inhibiting gluconeogenesis; that is, the conversion of fats and proteins into glucose.
• acts on fat (adipose) cells to stimulate the uptake of glucose and the synthesis of fat.
• acts on cells in the hypothalamus to reduce appetite.

Diabetes Mellitus

Diabetes mellitus is an endocrine disorder characterized by many signs and symptoms. Primary among these are:

• a failure of the kidney to retain glucose .
• a resulting increase in the volume of urine because of the osmotic effect of this glucose (it reduces the return of water to the blood).

There are three categories of diabetes mellitus:

• Insulin-Dependent Diabetes Mellitus (IDDM) (Type 1) and
• Non Insulin-Dependent Diabetes Mellitus (NIDDM)(Type 2)
• Inherited Forms of Diabetes Mellitus

Insulin-Dependent Diabetes Mellitus (IDDM)

IDDM ( Type 1 diabetes)

• is characterized by little or no circulating insulin;
• most commonly appears in childhood.
• It results from destruction of the beta cells of the islets.
• The destruction results from a cell-mediated autoimmune attack against the beta cells.
• What triggers this attack is still a mystery, although a prior viral infection may be the culprit.

Non Insulin-Dependent Diabetes Mellitus (NIDDM)

Many people develop diabetes mellitus without an accompanying drop in insulin levels In many cases, the problem appears to be a failure to express a sufficient number of glucose transporters in the plasma membrane (and T-system) of their skeletal muscles. Normally when insulin binds to its receptor on the cell surface, it initiates a chain of events that leads to the insertion in the plasma membrane of increased numbers of a transmembrane glucose transporter. This transporter forms a channel that permits the facilitated diffusion of glucose into the cell. Skeletal muscle is the major "sink" for removing excess glucose from the blood (and converting it into glycogen). In NIDDM, the patient's ability to remove glucose from the blood and convert it into glycogen is reduced. This is called insulin resistance. NIDDM (also called Type 2 diabetes mellitus) usually occurs in adults and, particularly often, in overweight people.

Alpha Cells

The alpha cells of the islets secrete glucagon, a polypeptide of 29 amino acids. Glucagon acts principally on the liver where it stimulates the conversion of glycogen into glucose (glycogenolysis) which is deposited in the blood.

Glucagon secretion is

• stimulated by low levels of glucose in the blood;
• inhibited by high levels, and
• inhibited by amylin.

The physiological significance of this is that glucagon functions to maintain a steady level of blood sugar level between meals.

Delta Cells

The delta cells secrete somatostatin. Somatostatin has a variety of functions. Taken together, they work to reduce the rate at which food is absorbed from the contents of the intestine. Somatostatin is also secreted by the hypothalamus and by the intestine.

Gamma Cells

The gamma cells of the islets secrete pancreatic polypeptide. No function has yet been found for this peptide of 36 amino acids.

Bleeding Disorders

A deficiency of a clotting factor can lead to uncontrolled bleeding.

The deficiency may arise because

• not enough of the factor is produced or
• a mutant version of the factor fails to perform properly.

Examples:

• von Willebrand disease (the most common)
• hemophilia A for factor 8 deficiency
• hemophilia B for factor 9 deficiency.
• hemophilia C for factor 11 deficiency

In some cases of von Willebrand disease, either a deficient level or a mutant version of the factor eliminates its protective effect on factor 8. The resulting low level of factor 8 mimics hemophilia A.

A rise in blood pressure stretches the atria of the heart. This triggers the release of atrial natriuretic peptide (ANP). ANP is a peptide of 28 amino acids. ANP lowers blood pressure by:

• relaxing arterioles
• inhibiting the secretion of renin and aldosterone
• inhibiting the reabsorption of sodium ions in the collecting ducts of the kidneys.

The effects on the kidney reduce the reabsorption of water by them thus increasing the flow of urine and the amount of sodium excreted in it (These actions give ANP its name: natrium = sodium; uresis = urinate). The net effect of these actions is to reduce blood pressure by reducing the volume of blood volume in the system.

The Heartbeat

During rest, the heart beats about 70 times a minute in the adult male, while pumping about 5 liters of blood.

The stimulus that maintains this rhythm is self-contained. Embedded in the wall of the right atrium is a mass of specialized heart tissue called the sino-atrial (S-A) node. The S-A node is also called the pacemaker because it establishes the basic frequency at which the heart beats.

The interior of the fibers of heart muscle, like all cells, is negatively charged with respect to the exterior. In the cells of the pacemaker, this charge breaks down spontaneously about 70 times each minute. This, in turn, initiates a similar discharge of the nearby muscle fibers of the atrium. A tiny wave of current sweeps over the atria, causing them to contract.

When this current reaches the region of insulating connective tissue between the atria and the ventricles, it is picked up by the A-V node (atrio-ventricular node). This leads to a system of branching fibers that carries the current to all parts of the ventricles.

The contraction of the heart in response to this electrical activity creates systole.

A period of recovery follows called diastole.

• The heart muscle and S-A node become recharged.
• The heart muscle relaxes.
• The atria refill. 

The Electrocardiogram

The electrical activity of the heart can be detected by electrodes placed at the surface of the body. Analysis of an electrocardiogram (ECG or EKG) aids in determining, for example, the extent of damage following a heart attack. This is because death of a portion of the heart muscle blocks electrical transmission through that area and alters the appearance of the ECG

Control of the Heart

Although the A-V node sets the basic rhythm of the heart, the rate and strength of its beating can be modified by two auxiliary control centers located in the medulla oblongata of the brain.

• One sends nerve impulses down accelerator nerves.
• The other sends nerve impulses down a pair of vagus nerves

Accelerator Nerves

The accelerator nerves are part of the sympathetic branch of the autonomic nervous system, and  like all post-ganglionic sympathetic neurons  release noradrenaline at their endings on the heart.

They increase the rate and strength of the heartbeat and thus increase the flow of blood. Their activation usually arises from some stress such as fear or violent exertion. The heartbeat may increase to 180 beats per minute. The strength of contraction increases as well so the amount of blood pumped may increase to as much as 25-30 liters/minute.

Vigorous exercise accelerates heartbeat in two ways;

• As cellular respiration increases, so does the carbon dioxide level in the blood. This stimulates receptors in the carotid arteries and aorta, and these transmit impulses to the medulla for relay  by the accelerator nerves  to the heart.
• As muscular activity increases, the muscle pump drives more blood back to the right atrium. The atrium becomes distended with blood, thus stimulating stretch receptors in its wall. These, too, send impulses to the medulla for relay to the heart.

Distention of the wall of the right atrium also triggers the release of atrial natriuretic peptide (ANP) which initiates a set of responses leading to a lowering of blood pressure

The Vagus Nerves

The vagus nerves are part of the parasympathetic branch of the autonomic nervous system. They, too, run from the medulla oblongata to the heart. Their activity slows the heartbeat.

Pressure receptors in the aorta and carotid arteries send impulses to the medulla which relays these  by way of the vagus nerves  to the heart. Heartbeat and blood pressure diminish.

Heart is a hollow muscular organ , that is located in the middle mediastinum  between the two bony structures of the sternum and the vertebral column ( a very important location for applying Cardiopulmonary Resuscitation - CPR- ) .
It has a shape of clenched fist , which weighs about 300 grams ( with mild variation between male and female ).
  Heart has an apex that is anteriorly , inferiorly , and leftward oriented , and a base , that is posteriorly , superiorly and rightward oriented   .
 In addition to its apex and base the heart has anterior , posterior and left surfaces.
 
 The wall of the heart is composed of three layers :
 
1. Endocardium : The innermost layer , which lines the heart chambers and is in direct contact with the blood . It is composed of endothelial cells that are similar to those , that line the blood vessels , and of connective tissue too. 
 Endocardium has a smooth surface that prevents blood clotting, as it ensures laminar blood flow .

 Clinical Physiology 
 Endocarditis is the inflammation of the endocardium , which is resistant to antibiotic treatment and difficult to cure.Endocarditis usually involves heart valves and chordae tendineae too.

 2. Myocardium  : The middle layer of the cardiac wall . It is the thickest among the three layers , and is composed of two types of cardiac muscles :
a. contractile muscle cells (form about 98-99% of the cardiac muscle ) .
 b- non-contractile muscle cells ( form about 1-2 % of the cardiac muscles and are the cells that form excitatory-conductive system of the heart).
 The cardiac muscle cells are similar to the skeletal muscles in that they are striated , but similar to the smooth muscles in being involuntary and connected to each others via gap junctions , that facilitate conduction of electrical potential from one cell to the others. Desmosomes adhere cardiac muscle cells to each others .

 3- Epicardium :  is the outermost and protective layer of the heart . It is composed of connective tissue , and form the inner layer of the pericardium ( visceral pericardium - see bellow).

 Pericardium: 
The heart is surrounded by a fluid-fill sac , which is known as pericardium . Pericardium is composed of two layers ( doubled layer membrane ) , between which a fluid-fill pericardial cavity exist .

 The outer layer is called fibrous pericardium , while the inner layer is called serous pericardium , which is subdivided into parietal pericardium and visceral pericardium . The visceral pericardium is the previously mentioned outermost layer of heart ( epicardium) .
Pericardial sac plays an important role in protection of heart from external hazards and infections , as it fixes the heart and limits its motion. It also prevents excessive dilation of the heart.

Clinical physiology: 

When there is excessive fluid in the pericardial cavity as a result of pericardial effusion , a cardiac tamponade will develop . cardiac tamponade means compression of the heart within the pericardial sac , which will prevent the relaxation of the heart ( heart will not be able to fully expand ) , and thus the circulating blood volume will be decreased (obstructive shock) . This is a life threatening situation which has to be urgently cured by  pericardiocentesis . 

Chambers of the heart : 

Heart has four chambers : two atria and two ventricles . The two right and left atria are separated from the two ventricles by the fibrous skeleton , which involves the right ( tricuspid ) and left ( bicuspid ) valves. Right and left atria are separated from each other by the interatrial  septum .
The two ventricles are separated by the interventricular septum.Interventricular septum is muscular in its lower thick part and fibrous in its upper thin part.
The two atria holds the blood returning from the veins and empty it only in a given right moment into the ventricles. Ventricles pump the blood into the arteries . 

Heart valves : 

There are four valves in the heart : Two atrioventricular valves and two semi-lunar valves:
1. Atrioventricular ( AV ) valves: These valves are found between the atria and ventricles , depending on the number of  the leaflets , the right atrioventricular valve is also called tricuspid valve (has three leaflets ) , while the left one is called bicuspid valve (has two leaflets ) . The shape of the bicuspid valve is similar to the mitre of bishop , so it is also called the mitral valve.
The leaflets of the valves are attached to fibrous threads (composed of collagen fibers ) , known as chordae tendineae , which from their side are attached to papillary muscles in the ventricles. These valves prevent backward flow of blood from ventricles during the systole. 

2. Semi-lunar valves : 

These valves are located on the base of the arteries ( aorta and pulmonary artery ) . They prevent the backward flow of blood from the arteries into ventricles.
The structure of the semilunar valves is quite different from that of the AV valves , as they have crescent-shaped cusps that do not have chorda tendinea , instead these cusps are like pockets which are filled of blood when it returns to the ventricles from the lumen of arteries during the diastole  , so they get closed and prevent the backward flow of blood.

Remember the following principles before proceeding :
- Reabsorption occurs for most of substances that have been previously filterd .
- The direction of reabsorption is from the tubules to the peritubular capillaries
- All of transport mechanism are used here.
- Different morphology of the cells of different parts of the tubules contribute to reabsorption of different substances .
- There are two routes of reabsorption: Paracellular and transcellular : Paracellular reabsorption depends on the tightness of the tight junction which varies from regeon to region in the nephrons .Transcellular depends on presence of transporters ( carriers and channels for example).

1. Reabsorption of glucose , amino acids , and proteins :

Transport of glucose occurs in the proximal tubule . Cells of proximal tubules are similar to those of the intestinal mucosa as the apical membrane has brush border form to increase the surface area for reabsorption , the cells have plenty of mitochondria which inform us that high amount of energy is required for active transport , and the basolateral membrane of the cells contain sodium -potassium pumps , while the apical membrane contains a lot of carrier and channels .

The tight junction between the tubular cells of the proximal tubules are not that (tight) which allow paracellular transport.
Reabsorption of glucose starts by active transport of  Na by the pumps on the basolateral membrane . This will create Na gradient which will cause Na to pass the apical membrane down its concentration gradient . Glucose also passes the membrane up its concentration gradient using sodium -glucose symporter as a secondary active transport.

The concentration of glucose will be increased in the cell and this will enable the glucose to pass down concentration gradient to the interstitium by glucose uniporter . Glucose will then pass to the peritubular capillaries by simple bulk flow.

Remember: Glucose reabsorption occurs via transcellular route .
          Glucose transport has transport maximum . In normal situation there is no glucose in the urine , but in uncontrolled diabetes mellitus patients glucose level exceeds its transport maximum (390 mg/dl) and thus will appear in urine .
                   
                   
                   
2. Reabsorption of Amino acids : Use secondary active transport mechanism like glucose.

3. Reabsorption of proteins : 

Plasma proteins are not filtered in Bowman capsule but some proteins and peptides in blood may pass the filtration membrane and then reabsorbed . Some peptides are reabsorbed paracellulary , while the others bind to the apical membrane and then enter the cells by endocytosis , where they will degraded by peptidase enzymes to amino acids .

4. Reabsorption of sodium , water , and chloride:

65 % of sodium is reabsorbed in the proximal tubules , while 25% are reabsorbed in the thick ascending limb of loob of Henle , 9% in the distal and collecting tubules and collecting ducts .
90% of sodium reabsorption occurs independently from its plasma level (unregulated) , This is true for sodium reabsorbed in proximal tubule and loop of Henle , while the 9% that is reabsorbed in distal ,collecting tubules and collecting ducts is regulated by Aldosterone. 

In proximal tubules : 65% of sodium is reabsorbed . The initial step occurs by creating sodium gradient  by sodium-potassium pump on the basolateral membrane . then the sodium will pass from the lumen into the cells down concentration gradient by sodium -glucose symporter , sodium -phosphate symporter and by sodium- hydrogen antiporter and others                    
                   
After reabsorption of sodium , an electrical gradient will be created , then chloride is reabsorbed following the sodium  . Thus the major cation and anion leave the lumen to the the interstitium and thus the water follows by osmosis . 65% of water is reabsorbed in the proximal tubule.

Discending limb of loop of Henle is impermeable to electrolytes but avidly permeable to water . 10 % of water is reabsorbed in the discending thin limb of loob of Henle .

The thick ascending limb of loop of Henly is permeable to electrolytes , due to the presence of Na2ClK syporter . 25% of sodium is reabsorbed here .

In the distal and collecting tubules and the collecting ducts 9% of sodium is reabsorbed .this occurs under aldosterone control depending on sodium plasma level. 1% of sodium is excreted .

Water is not reabsorbed from distal tubule but 5-25% of water is reabsorbed in collecting tubules .