The Sliding Filament mechanism of muscle contraction.

When a muscle contracts the light I bands disappear and the dark A bands move closer together. This is due to the sliding of the actin and myosin myofilaments against one another. The Z-lines pull together and the sarcomere shortens

The thick myosin bands are not single myosin proteins but are made of multiple myosin molecules. Each myosin molecule is composed of two parts: the globular "head" and the elongated "tail". They are arranged to form the thick bands.

It is the myosin heads which form crossbridges that attach to binding sites on the actin molecules and then swivel to bring the Z-lines together

Likewise the thin bands are not single actin molecules. Actin is composed of globular proteins (G actin units) arranged to form a double coil (double alpha helix) which produces the thin filament. Each thin myofilament is wrapped by a tropomyosin protein, which in turn is connected to the troponin complex. 

The tropomyosin-troponin combination blocks the active sites on the actin molecules preventing crossbridge formation. The troponin complex consists of three components: TnT, the part which attaches to tropomyosin, TnI, an inhibitory portion which attaches to actin, and TnC which binds calcium ions. When excess calcium ions are released they bind to the TnC causing the troponin-tropomyosin complex to move, releasing the blockage on the active sites. As soon as this happens the myosin heads bind to these active sites.

COPD and Cancer

A.    Chronic Obstructive Pulmonary Disease (COPD)

1.    Common features of COPD

a.    almost all have smoking history
b.    dyspnea - chronic "gasping" for air
c.    frequent coughing and infections
d.    often leads to respiratory failure

2.    obstructive emphysema - usually results from smoking

a.    enlargement & deterioration of alveoli
b.    loss of elasticity of the lungs
c.    "barrel chest" from bronchiole opening during inhalation & constriction during exhalation

3.    chronic bronchitis - mucus/inflammation of mucosa

B.    Lung Cancer

1.    squamous cell carcinoma (20-40%) - epithelium of the bronchi and bronchioles
2.    adenocarcinoma (25-35%) - cells of bronchiole glands and cells of the alveoli
3.    small cell carcinoma (10-20%) - special lymphocyte-like cells of the bronchi
4.    90% of all lung cancers are in people who smoke or have smoked 
 

The Adrenal Glands

The adrenal glands are two small structures situated one at top each kidney. Both in anatomy and in function, they consist of two distinct regions:

• an outer layer, the adrenal cortex, which surrounds
• the adrenal medulla.

The Adrenal Cortex

cells of the adrenal cortex secrete a variety of steroid hormones.

• glucocorticoids (e.g., cortisol)
• mineralocorticoids (e.g., aldosterone)
• androgens (e.g., testosterone)

• Production of all three classes is triggered by the secretion of ACTH from the anterior lobe of the pituitary.

Glucocorticoids

They Effect by raising the level of blood sugar (glucose). One way they do this is by stimulating gluconeogenesis in the liver: the conversion of fat and protein into intermediate metabolites that are ultimately converted into glucose.

The most abundant glucocorticoid is cortisol (also called hydrocortisone).

Cortisol and the other glucocorticoids also have a potent anti-inflammatory effect on the body. They depress the immune response, especially cell-mediated immune responses. 

Mineralocorticoids

The most important of them is the steroid aldosterone. Aldosterone acts on the kidney promoting the reabsorption of sodium ions (Na⁺) into the blood. Water follows the salt and this helps maintain normal blood pressure.

Aldosterone also

• acts on sweat glands to reduce the loss of sodium in perspiration;
• acts on taste cells to increase the sensitivity of the taste buds to sources of sodium.

The secretion of aldosterone is stimulated by:

• a drop in the level of sodium ions in the blood;
• a rise in the level of potassium ions in the blood;
• angiotensin II
• ACTH (as is that of cortisol)

Androgens

The adrenal cortex secretes precursors to androgens such as testosterone.

Excessive production of adrenal androgens can cause premature puberty in young boys.

In females, the adrenal cortex is a major source of androgens. Their hypersecretion may produce a masculine pattern of body hair and cessation of menstruation.

Addison's Disease: Hyposecretion of the adrenal cortices

Addison's disease has many causes, such as

• destruction of the adrenal glands by infection;
• their destruction by an autoimmune attack;
• an inherited mutation in the ACTH receptor on adrenal cells.

Cushing's Syndrome: Excessive levels of glucocorticoids

In Cushing's syndrome, the level of adrenal hormones, especially of the glucocorticoids, is too high.It can be caused by:

• excessive production of ACTH by the anterior lobe of the pituitary;
• excessive production of adrenal hormones themselves (e.g., because of a tumor), or (quite commonly)
• as a result of glucocorticoid therapy for some other disorder such as
  • rheumatoid arthritis or
  • preventing the rejection of an organ transplant.

The Adrenal Medulla

The adrenal medulla consists of masses of neurons that are part of the sympathetic branch of the autonomic nervous system. Instead of releasing their neurotransmitters at a synapse, these neurons release them into the blood. Thus, although part of the nervous system, the adrenal medulla functions as an endocrine gland.The adrenal medulla releases:

• adrenaline (also called epinephrine) and
• noradrenaline (also called norepinephrine)

Both are derived from the amino acid tyrosine.

Release of adrenaline and noradrenaline is triggered by nervous stimulation in response to physical or mental stress. The hormones bind to adrenergic receptors  transmembrane proteins in the plasma membrane of many cell types.

Some of the effects are:

• increase in the rate and strength of the heartbeat resulting in increased blood pressure;
• blood shunted from the skin and viscera to the skeletal muscles, coronary arteries, liver, and brain;
• rise in blood sugar;
• increased metabolic rate;
• bronchi dilate;
• pupils dilate;
• hair stands on end (gooseflesh in humans);
• clotting time of the blood is reduced;
• increased ACTH secretion from the anterior lobe of the pituitary.

All of these effects prepare the body to take immediate and vigorous action.

Hypoxia

• Hypoxia is tissue oxygen deficiency
• Brain is the most sensitive tissue to hypoxia: complete lack of oxygen can cause unconsciousness in 15 sec and irreversible damage within 2 min.
• Oxygen delivery and use can be interrupted at several sites

• Causes:
  • Hypoxic: high altitude, pulmonary edema, hypoventilation, emphysema, collapsed lung
  • Anemic: iron deficiency, hemoglobin mutations, carbon monoxide poisoning
  • Ischemic: shock, heart failure, embolism
  • Histotoxic: cyanide poisoning (inhibits mitochondria)

• Carbon monoxide (CO) poisoning:
  • CO binds to the same heme Fe atoms that O₂ binds to
  • CO displaces oxygen from hemoglobin because it has a 200X greater affinity for hemoglobin.
  • Treatment for CO poisoning: move victim to fresh air. Breathing pure O₂ can give faster removal of CO

• Cyanide poisoning:
  • Cyanide inhibits the cytochrome oxidase enzyme of mitochondria
  • Two step treatment for cyanide poisoning:
    • 1) Give nitrites
      • Nitrites convert some hemoglobin to methemoglobin. Methemoglobin pulls cyanide away from mitochondria.
    • 2) Give thiosulfate.
      • Thiosulfate converts the cyanide to less poisonous thiocyanate.

Production of Hormones

The kidneys produce and interact with several hormones that are involved in the control of systems outside of the urinary system.

Calcitriol. Calcitriol is the active form of vitamin D in the human body. It is produced by the kidneys from precursor molecules produced by UV radiation striking the skin. Calcitriol works together with parathyroid hormone (PTH) to raise the level of calcium ions in the bloodstream. When the level of calcium ions in the blood drops below a threshold level, the parathyroid glands release PTH, which in turn stimulates the kidneys to release calcitriol. Calcitriol promotes the small intestine to absorb calcium from food and deposit it into the bloodstream. It also stimulates the osteoclasts of the skeletal system to break down bone matrix to release calcium ions into the blood.
 
Erythropoietin. Erythropoietin, also known as EPO, is a hormone that is produced by the kidneys to stimulate the production of red blood cells. The kidneys monitor the condition of the blood that passes through their capillaries, including the oxygen-carrying capacity of the blood. When the blood becomes hypoxic, meaning that it is carrying deficient levels of oxygen, cells lining the capillaries begin producing EPO and release it into the bloodstream. EPO travels through the blood to the red bone marrow, where it stimulates hematopoietic cells to increase their rate of red blood cell production. Red blood cells contain hemoglobin, which greatly increases the blood’s oxygen-carrying capacity and effectively ends the hypoxic conditions.
 
Renin. Renin is not a hormone itself, but an enzyme that the kidneys produce to start the renin-angiotensin system (RAS). The RAS increases blood volume and blood pressure in response to low blood pressure, blood loss, or dehydration. Renin is released into the blood where it catalyzes angiotensinogen from the liver into angiotensin I. Angiotensin I is further catalyzed by another enzyme into Angiotensin II.

Angiotensin II stimulates several processes, including stimulating the adrenal cortex to produce the hormone aldosterone. Aldosterone then changes the function of the kidneys to increase the reabsorption of water and sodium ions into the blood, increasing blood volume and raising blood pressure. Negative feedback from increased blood pressure finally turns off the RAS to maintain healthy blood pressure levels.

Heart sounds

Heart sounds are a result of beating heart and resultant blood flow . that could be detected by a stethoscope during auscultation . Auscultation is a part of physical examination that doctors have to practice them perfectly.
Before discussion the origin and nature of the heart sounds we have to distinguish between the heart sounds and hurt murmurs. Heart murmurs are pathological noises that results from abnormal blood flow in the heart or blood vessels.
Physiologically , blood flow has a laminar pattern , which means that blood flows in form of layers , where the central layer is the most rapid . Laminar blood flow could be turned into turbulent one .

Turbulent blood flow is a result of stenotic ( narrowed ) valves or blood vessels , insufficient valves , roughened vessels` wall or endocardium ,  and many diseases . The turbulent blood flow causes noisy murmurs inside or outside the heart.

Heart sounds ( especially first and second sounds ) are mainly a result of closure of the valves of the heart . While the third sound is a result of vibration of ventricular wall and the leaflets of the opened AV valves after rapid inflow of blood from the atria to ventricles . 

Third heart sound is physiologic in children but pathological in adults.

The four heart sound is a result of the atrial systole and vibration of the AV valves , due to blood rush during atrial systole . It is inaudible neither in adults nor in children . It is just detectable by the phonocardiogram .

Characteristic of heart sounds :

1. First heart sound  (S1 , lub ) : a soft and low pitch sound, caused by closure of AV valves.Usually has two components ( M1( mitral ) and T1 ( tricuspid ). Normally M1 preceads T1.

2. Second heart sound ( S2 , dub) : sharp and high pitch sound . caused by closure of semilunar valves. It also has two components A2 ( aortic) and P2 ( pulmonary) . A2 preceads P2.

3. Third heart sound (S3) : low pitched sound.

4. Fourth heart sound ( S4) very low pitched sound.

As we notice : the first three sounds are related to ventricular activity , while the fourth heart sound is related to atrial activity.
Closure of valves is not the direct cause for heart sounds , but sharp blocking of blood of backward returning of blood by the closing valve is the direct cause.