HYPOXIA

Hypoxia is defined as a deficiency of oxygen at the tissue level. There are many potential causes of hypoxia, but they can be classified into four general categories:

• Hypoxic hypoxia also termed hypoxemia, in which the arterial pO2 is reduced.
• Anemic hypoxia or carbon monoxide hypoxia, in which the arterial pO2 is normal but the total oxygen content of the blood is reduced because of inadequate numbers of erythrocytes, deficient or abnormal hemoglobin, or competition for the Hb molecule by carbon monoxide.
• Ischemic hypoxia (also called hypo perfusion hypoxia), in which blood flow to the tissues is too low.
• Histotoxic hypoxia, in which the quantity of oxygen reaching the tissues is normal but the cell is unable to utilize the oxygen because a toxic agent- cyanide for e.g., has interfered with the cell's metabolic machinery. Hypoxic hypoxia is a common cause of hypoxia.

The primary causes of hypoxic hypoxia in disease are as follows:

• Hypoventilation may be caused by : 1) A defect anywhere along the respiratory control pathway, from the medulla through the respiratory muscles.2) Severe thoracic age abnormalities. 3) Major obstruction of the upper airway.
• Diffusion impairment results from thickening of the alveolar membranes or a decrease in their surface area. Some of the diseases that produce hypoxia also produce carbon dioxide retention and an increased arterial pCO2 (hypercapnia).
• A shunt is an anatomical abnormality of the cardiovascular system that causes mixed venous blood to bypass ventilated alveoli. Arterial pCO2, generally does not increase because the effect of the shunt on arterial pCO2 is counter-balanced by the increased ventilation reflexively stimulated, by the hypoxemia.
• Ventilation-perfusion inequality  is by far the most common cause of hypoxemia. It occurs in chronic obstructive lung diseases. Arterial pCO2 may be normal or increased, depending upon how much ventilation is reflexively stimulated.

The administration of pure oxygen may cause such patients to stop breathing; consequently, such individuals are typically treated with a mixture of air and oxygen rather than 100% O2.

How does function of vasa recta related to urine volume ?

The blood vessels in the medulla (vasa recta) form hairpin loops that run parallel to the loop of Henle and medullary collecting ducts. The blood enters the top of the vessel loop at an osmolarity of 300 mOsmol/L, as the blood flows down the loop deeper and deeper into the medulla, sodium and chloride do indeed diffuse into, and water out of the vessel. However, after the bend in the loop is reached, the blood then flows up the ascending vessel loop, where the process almost completely reversed. Thus, the hairpin loop structure of the vasa recta minimizes excessive loss of solute from interstitium by diffusion. At the same time, both the salt and water being reabsorbed from the loop of Henle and collecting ducts are carried away in equivalent amounts of bulk flow, as determined by the usual capillary Starling forces. This maintains the steady-state counter current gradient set up by the loops of Henle. Because of NaCl and water reabsorbed from the loop of Henle and collecting ducts, the amount of blood flow leaving the vasa recta is at least twofold higher than the blood flow entering the vasa recta.finally the total blood flow going through all of the vasa recta is a small % of the total of the renal blood flow. This helps to maintain or minimize the washout of the hypertonic interstitium of medulla.
As urea passes through the remainder of the nephron, is reabsorbed, secreted into the tubule and then reabsorbed again. This traps urea, an osmotically active molecule, in the medullary interstitium, thus increasing its osmolarity, in fact, urea contributes to the total osmolarity of the small medulla.
Urea is freely filtered in the glomerulus. Approx. 50% of the filtered urea is reabsorbed in the proximal tubule, and the remaining 50% enters the loop of Henle. So the thin descending and ascending limbs of the loop of Henle, urea that was accumulated in the medullary interstitium is secreted back into the tubular lumen of facilitated diffusion, virtually all of the urea that was originally filtered in the glomerulus is present in the fluid that enters the distal tubule. Some of the original urea is reabsorbed from the distal tubule and cortical collecting duct. Thereafter, about half of the urea is reabsorbed from the medullary collecting duct, whereas only 5% diffuses into the vasa recta.
One remaining amount is secreted back into the loop of Henle. 15% of the urea originally filtered remains in the collecting duct and is excreted in the urine. This recycling of urea through the medullary interstitium and minimal uptake by the vasa recta traps urea there and contributes to the high osmolarity.
 

HOW IS ACTION POTENTIAL IN HEART MUSCLE GENERATED

As in skeletal muscle and neuron, similarly in heart the depolarizing phase of action potential is mainly due to the opening of voltage-gated sodium channels. Sodium entry depolarizes the cell and sustain the opening of more sodium channel in positive feedback fusion. Unlike in other excitable tissue, in cardiac muscle the reduction  in sodium permeability is not accompanied by membrane repolarization. The membrane remain depolarized at plateau of 0 mV.
The reason for continued polarization is potassium permeability stays below the resting value and a marked increase occurs in the membrane permeability to calcium. The original membrane depolarization causes voltage-gated calcium channels in the plasma membrane to open, which results in flow of calcium ions down their electrochemical gradient into the cell.
The channels open slower than sodium channel. They are L-type calcium channels because they remain open for prolonged period. Ultimately repolarization does occur when calcium channel slowly inactivate, and another subtype of potassium channel open.
SA node cell does not have steady resting potential, but instead undergo slow depolarization. This gradual depolarization is known as pacemaker potential. Three ion channel mechanism contribute to pacemaker potential. First is progressive reduction in potassium permeability. Potassium channel, which opened during the repolarization phase of previous action potential, gradually closes due to the membrane's return to negative potential. Second, pacemaker cells have unique set of channel that open when the membrane potential is at negative value. These non specific cation channel conduct mainly an inward, depolarizing sodium current by F-type sodium channel. The third pacemaker channel is a kind of calcium channel that opens only briefly but contributing an inward calcium current and an important final depolarizing boost to pacemaker potential by T-type calcium channels.

  

What are the body's responses to maintain water electrolyte?

SODIUM REGULATION:

In healthy individuals, urinary sodium excretion increases when there is an excess of sodium in the body and decreases when there is a sodium deficit. The responses that regulate urinary sodium excretion are initiated mainly by various cardiovascular baroreceptors, such as the kidney that monitor the filtered load of sodium.

The regulation of cardiovascular pressures by baroreceptors also simultaneously achieve regulation of total body sodium. Plasma (sodium) volume is an important determinant of the blood pressures in the veins, cardiac chambers and arteries. Thus, the chain linking total body sodium to cardiovascular pressures is completed., low total-body sodium leads to low plasma volume, hence to low cardiovascular pressure. These low pressures via baroreceptors, initiate reflexes that influences renal arterioles and tubules so as to lower GFR and increase sodium reabsorption. These events decrease sodium excretion, thereby retaining sodium in the body and prevents decrease in plasma volume.

Conversely, an increase in GFR is usually elicited by neuroendocrine inputs when an increased total body sodium level increases plasma volume. This increased GFR contributes to the increased renal sodium loss that returns extracellular volume to normal.

IN CASE OF SODIUM DEPLETION:

The renal sympathetic nerves directly innervate the juxtaglomerular cells, and an increase in the activity of these nerves stimulates renin secretion. Other two inputs for controlling renin release- Intrarenal baroreceptors and the macula densa (contained within the kidneys). Renin  , enzyme secreted by juxtaglomerular cells, splits a small polypeptide, angiotensin 1 from a larger plasma protein angiotensinogen (produced by liver). Angiotensin 1 is a biologically inactive peptide that undergoes further cleavage to form the active agent i.e., angiotensin 2, carried by enzyme angiotensin-converting enzyme (ACE) (found in high conc. on luminal surface of capillary endothelial cells). Angiotensin 2 stimulates secretion of aldosterone. 

Aldosterone, a steroid hormone produced by adrenal cortex stimulates sodium reabsorption by the distal convoluted tubule and the cortical collecting ducts. In the absence of aldosterone, sodium is not reabsorbed but is excreted. 

IN CASE OF EXCESS OF SODIUM

Another controller is Atrial Natriuretic Peptide (ANP), also known as Atrial Natriuretic Factor (ANF)or Hormone (ANH). Cells in the cardiac atria synthesize and secrete ANP. ANP acts on several tubular segments to inhibit sodium reabsorption, it also increases GFR contributing to increased sodium excretion.

ANP also directly inhibits aldosterone secretion, which loads to an increase in sodium excretion. ANP secretion increases because of the expansion of plasma volume that accompanies an increase in  body sodium. The specific stimulus is increased atrial distension. 

WATER REGULATION:

A decreased extracellular fluid volume, due to for example, diarrhea, elicits an increase in aldosterone release via activation of renin-angiotensin system, but this decreased extracellular volume also triggers an increase in vasopressin secretion. The increased vasopressin increases the water permeability of the collecting ducts. More water is passively reabsorbed and less is excreted, so water is retained to help stabilize the extracellular volume. Vasopressin is secreted by posterior pituitary, in response to reflex initiated by several baroreceptors in the cardiovascular system. The baroreceptors decrease their rate of firing when cardiovascular pressure decrease, therefore baroreceptors transmit fewer impulses via afferent neurons and ascending pathway to hypothalamus and the result is increased vasopressin secretion.

Vasopressin increases water permeability by bringing aquaporins to the cell surface. Conversely, increased cardiovascular pressure cause more firing by the baroreceptors, resulting in a decrease in vasopressin secretion.

In some cases, changes in total body water with no corresponding change in total body sodium are compensated for by altering water excretion without altering sodium excretion. Under conditions due predominantly to water gain or loss, the receptors that initiate the reflexes controlling vasopressin secretion are osmoreceptors in the hypothalamus. These receptors are responsive to changes in osmolarity. Deficits of salt and water must eventually be compensated for by ingestion of these substances, because the kidneys cannot create new sodium ions or water. The subjective feeling of thirst is stimulated by an increase in plasma osmolarity and by a decrease in extracellular fluid volume. The brain centers that mediate thirst are located in hypothalamus. 

POTASSIUM REGULATION:

Potassium is freely filterable in the renal corpuscle. Normally, the tubules reabsorb most of this filtered potassium so that very little of  the filtered potassium appears in the urine. However, the cortical collecting ducts can secrete potassium, and changes in potassium excretion are due mainly to changes in potassium secretion by this tubular segment.

During potassium depletion, when the homeostatic response is to minimize potassium loss, there is no potassium secretion by the cortical collecting ducts. Only a small amount of filtered potassium that escapes tubular reabsorption is excreted. In the tubular segment (cortical duct), the K+ pumped into the cell across the basolateral membrane by Na+/K+ ATPases diffuses into the tubular lumen through K+ channels in the luminal membrane. Thus the secretion of K+ by cortical collecting duct is associated with the reabsorption of sodium by this segment.

When a high potassium is ingested, plasma potassium concentration increases, though very slightly , and this drives enhanced basolateral uptake via the Na+/K+ ATPase pumps. Thus, there is an enhanced K+ secretion. And in a low potassium diet or a negative potassium balance, reduces K+ secretion and excretion, thereby helping to reestablish potassium balance.

A second factor linking potassium secretion to potassium balance is the hormone aldosterone, aldosterone enhances the tubular potassium secretion by this tubular potassium secretion by this tubular segment. Aldosterone secreting cells of the adrenal cortex are sensitive to the potassium concentration of the extracellular fluid. So increase K+ levels, directly stimulate the adrenal cortex to produce aldosterone, hence facilitating its enhanced secretion.  

BICARBONATE REGULATION:

Bicarbonate is completely filterable at the renal corpuscles and undergoes significant tubular reabsorption in the proximal tubule, ascending loop of Henle, and in cortical collecting ducts. The kidneys eliminate or replenish hydrogen ions from the body by altering plasma bicarbonate concentration.

CO2 combines with H2O to form H2CO3, a reaction catalyzed by the enzyme carbonic anhydrase. The H2CO3 immediately dissociates to yield H+ and bicarbonate HCO3-. The HCO3- diffuses down its conc. gradient across the basolateral membrane into the interstitial fluid and then into the blood. Simultaneously H+ is secreted into the lumen. Depending on the tubular segment, this secretion is achieved by some combination of primary H+ ATPase pumps, primary H+/K+ ATPase pumps, and Na+/H+ counter transporters. The secreted H+, however is not excreted. Instead it combines in the lumen with a filtered HCO3- and generates CO2 and H2O, both of which can diffuse into the cell and be available for another cycle of hydrogen ion generation. In this manner, no net charge change in plasma bicarbonate concentration has occurred. 

However bicarbonate can be added by renal metabolism of glutamine and excretion of ammonium and by combining H+ with phosphate (HPO42-) rather than by HCO3- (filtered) and getting excreted as H2PO4-.

    

Mechanism of urine concentration after glomerulus filteration

The kidneys produce a small volume of urine when the plasma concentration of vasopressin is high. Under these conditions, the urine is concentrated (hyperosmotic) relative to plasma. The ability of the kidneys to produce hyperosmotic urine is a major determinant of the ability to survive with limited water intake. Urinary concentration takes place as tubular fluid flows through the medullary collecting ducts. The interstitial fluid surrounding these ducts is very hyperosmotic. In the presence of vasopressin, water diffuses out of the ducts into the interstitial fluid of the medulla and then enters the blood vessels of the medulla to be carried away.
The proximal tubule always reabsorbs Na+ and water in the same proportions. Along the entire length of the ascending limb, sodium and chloride are reabsorbed from the lumen into the medullary interstitial fluid. In the upper (thick) portion of the ascending limb, this reabsorption is achieved by transporters. However  , in lower (thin) limb, this is a passive process.
The ascending limb is relatively impermeable to water. The net result is that the interstitial fluid of the medulla becomes hyperosmotic compared to the fluid in the ascending limb because solute is reabsorbed without water.
The descending limb does not reabsorb NaCl and is highly permeable to water. Therefore, a net diffusion of water occurs out of the descending limb into the more concentrated interstitial fluid until the osmolarities are equal again.
The loop countercurrent multiplier causes the interstitial fluid of the medulla to become concentrated. It is this hyperosmolarity that will draw water out of the collecting ducts and concentrate the urine. The countercurrent multiplier system concentrates the descending- loop fluid, but then lowers the osmolarity in the ascending loop so that the fluid entering the distal convoluted tubule is actually more dilute (hypoosmotic) - 100 mOsmol/L than the plasma. The fluid becomes even more dilute during its passage through the distal convoluted tubule. This hypoosmotic fluid then enters the cortical collecting duct. In the presence of vasopressin, water reabsorption occurs by diffusion from the hypoosmotic fluid in the cortical collecting duct until the fluid in this segment becomes isosmotic to the interstitial fluid and peritubular plasma of the cortex i.e., until it is once again at 300 mOsmol/L. The isosmotic tubular fluid then enters and flow through the medullary collecting ducts. In the presence of high plasma concentration of vasopressin, water diffuses out of the ducts into the medullary interstitial fluid as a result of the high osmolarity that the loop countercurrent multiplier system and urea trapping establish there. This water then enters the medullary capillaries and is carried out of the kidneys by the venous blood. Water reabsorption occurs all along the lengths of the medullary collecting ducts so that, in the presence of vasopressin, the fluid at the end of  these ducts has essentially the same osmolarity as the interstitial fluid surrounding the bend in the loops - that is, at the bottom of the medulla. By this means, the final urine is hyperosmotic.

Sequence of events in ovarian follicular cycle and spermatogenesis.

OVARIAN FOLLICULAR CYCLE :

Throughout their life in ovaries, the egg exist in structure knows as follicle. Follicle begin as primordial follicles, which consist of one primary oocyte surrounded by single layer of cell called granulosa cell. Further development from the primordial follicle stage is characterized by an increase in the size of oocyte, a proliferation of the granulosa cell into multiple layers, and the separation of the oocyte from inner granulosa cell by a thick layer of material the zona pellucida. Despite the presence of zona pellucida, the inner layer of granulosa cell remain closely associated with the oocyte by mean of cytoplasmic protein that transverse the zona pellucida and form gap junction with oocyte. As follicle grows by mitosis of granulosa cells, connective tissue cell surrounding the granulosa cell differentiates and form layer known as theca. Shortly after this, the primary oocyte reaches full size and a fluid filled space, the antrum, begin to form in the midst of the granulosa cell as a result of fluid they secrete. The progression of some primordial follicle to the preantral and early antral stages occur throughout infancy and childhood, and then during the entire menstrual cycle. Although most of the follicle in the ovaries are still primordial, relatively constant number of preantral and early antral follicles are also always present. At the beginning of each menstrual cycle, 10 to 25 of these preantral and early antral follicle begin to develop into larger antral follicles. About one week into the cycle, a further selection process occurs, only one of the larger antral follicle, the dominant follicle, continue to develop. The non-dominant follicle that had begun to enlarge undergo a degenerative process called atresia which is an example of programmed cell death or apoptosis. The dominant follicle enlarges mainly as a result of an increase in fluid, causing the antrum to expand.

SPERMATOGENESIS:

The undifferentiated germ cell, which are termed spermatogonia begin to divide mitotically at puberty. The daughter cell of this first division then divide again and again for a specified number of division cycles. So that a clone of spermatogonia is produced from each stem cell spermatogonium. Some differentiation, occur in addition to cell division. The cells that result from the final mitotic division and differentiation in the series called primary spermatocytes. Each primary spermatocyte increase markedly in size and undergoes the first meiotic division to form two secondary spermatocytes, each of which contains 23 two-chromatid chromosomes. Each secondary spermatocyte undergoes the second meiotic division to form spermatids. Thus, each primary spermatocyte, containing 46 two-chromatid chromosomes, produce four spermatid, each containing 23 one-chromatid chromosomes. The final phase of spermatogenesis is the differentiation of the spermatid into spermatozoa (sperm).

 

  

HOMEOSTATIC CONTROL OF IRON BY RBC

Iron is the element to which oxygen binds on a hemoglobin molecule within an erythrocyte. Small amounts of iron are lost from the body via urine, feces, sweat and cells sloughed from the skin. Women lose additional amount via menstrual blood. In order to remain in iron balance, the amount of iron lost  from the body must be replaced by ingestion of iron containing foods.
Disruption of iron balance can result in either iron deficiency leading to inadequate Hemoglobin production or excess of iron in the body (hemochromatosis) leading to abnormal iron deposits and damage to various organs like liver, heart etc.
 The hemostatic control of iron balance resides primarily in the intestinal epithelium, which actively absorbs iron from ingested food. Normally, only a small fraction of ingested iron is absorbed. However, this fraction is increased or decreased in a negative feedback manner, depending upon the state of body's iron balance- the more iron in the body, the less ingested iron is absorbed.
The body has a considerable store of iron, mainly in liver, bound up in a protein called ferritin. Ferritin serves as a buffer against iron deficiency. About 50% of total body iron is in hemoglobin, 25% in the other heme-containing proteins in the cells of the body and 25% is in liver ferritin.
The recycling of iron is very efficient. As old erythrocytes are destroyed in the spleen their iron is released into the plasma and bound to an iron transport plasma protein called transferrin. Transferrin delivers almost all of this iron to the bone marrow to be incorporated into new erythrocytes.
Recirculation of erythrocyte iron is very important because it involves 20 times more iron per day than the body absorbs and excretes.

HOW DOES ENTEROHEPATIC CIRCULATION HELP IN LIPID DIGESTION ?

Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transported back to the liver.
Bile salts and lecithin are synthesized in the liver and help solubilize fat in the small intestine. During the digestion of a fatty meal, most of the bile salts entering the intestinal tract via the bile are absorbed by specific Na+ coupled transporters in the ileum. The non-polar portions of phospholipids and bile salts associate with the non-polar interior of lipid droplets, leaving the polar portions exposed at the water surface. They repel other lipid droplets that are similarly coated with these emulsifying agents, thereby preventing their reaggregation into larger fat droplets. The coating of lipid droplets with emulsifying agents speeds up the digestion of lipids by the action of lipase mediated by colipase (binds lipase and holds it on lipid surface).
The absorbed bile salts are then returned via the portal vein to the liver, where they are once again secreted into bile. Uptake of bile salts from portal blood into hepatocytes is driven by secondary active transport coupled to Na+. During the digestion of a meal, the entire bile salt content of the body may be recycled several times by enterohepatic circulation.

JUSTIFICATIONS

1. PLATELET PLUG DOES NOT DISLODGE FROM THE DAMAGED                 ENDOTHELIAL SITE.

When vessel is injured, it disrupt the endothelium and expose the underlying connective tissue collagen fibers. Platelet adhere to collagen, largely via an intermediatry called von Willebrand factor (VWF), a protein secreted by endothelial cell and platelet. Binding of platelet to collagen triggers the platelet to release the content of their secretory vesicles. Some of agent changes cause new platelet to adhere to the old one, a positive feedback phenomena which rapidly create 'platelet plug'. The platelet plug can completely seal small break in blood vessel wall. Its effectiveness is further enhanced by another property of platelet contraction. Platelet contains a very high concentration of actin and myosin, which are stimulated to contract in aggregated platelets. This causes compression and strengthening of platelet plug makes it unable to dislodge from the damaged endothelial site.

2. DEFICIENCY OF VITAMIN K CAN LEAD TO CLOTTING DISORDER.

The fat soluble vitamin K is essential for the functioning of several protein involved in blood clotting. Vitamin K is a cofactor for synthesis of blood coagulation factor 2, 7,9 and 10 and inhibitors such as protein C and S and bone matrix protein. Vitamin K act as cofactor for an enzyme that enable specific protein to bind calcium ion. The ability to bind calcium ion is required for the activation of the seven vitamin-K dependent blood clotting  factors. The liver requires this vitamin to produce prothrombin and several other clotting factor. 

3. THE FLOW RATE IN THE CAROTID SINUS REGULATE THE MEAN            ARTERIAL PRESSURE.

Arterial pressure originates primarily with arterial receptors that respond to change in pressure. Two major vessel that supplying the head, the common carotid arteries divided into two smaller arteries. At these divisions, the wall of artery is thinner than usual and contain a large number of branching vine like nerve ending. this portion is called carotid sinus. Its nerve endings are highly sensitive to stretch or distortion. The degree of wall stretching is directly related to the pressure within the artery. Thus, the carotid sinuses serve as pressure receptor or baroreceptor. The primary integrating center for the baroreceptor reflexes is a diffuse network of highly interconnected neuron called the medullary cardiovascular center located in the medulla oblongata. The neuron in this center receives input from various baroreceptors. This input determines the action potential frequency from cardiovascular center along neural pathway that terminates upon the cell bodies and dendrites of the vegus neuron to heart and sympathetic neuron to heart, arterioles and veins. When the arterial baroreceptors increase their rate of discharge, the result in decrease in sympathetic outflow to the heart, arteries and veins and an increase in parasympathetic outflow to the heart. A decrease in baroreceptor firing rate result in opposite pattern. If arterial pressure decreases, the discharge rate of arterial baroreceptor also decreases. Fewer impulses travel up the afferent nerve to the medullary cardiovascular center and induces: (1) increased heart rate because of increased sympathetic activity to the heart and decreased parasympathetic activity. (2) increased ventricular contractility because of increased sympathetic activity to the ventricular myocardium. (3) arteriolar constriction (4) increased venous constriction. The net result is an increased cardiac output, increased total peripheral resistance and return of blood pressure toward normal. Conversely, an increase in arterial blood pressure for any reason causes increased firing of the arterial baroreceptor, which reflexly induce a compensatory decrease in cardiac output and total peripheral resistance.

4. IF THE SALIVARY GLANDS ARE UNABLE TO SECRETE AMYLASE,           STARCH DIGESTION IS NOT MUCH AFFECTED.

The digestion of starch begins in the mouth by the action of enzyme, salivary amylase secreted by salivary gland. Digestion briefly continues in the upper part of the stomach before gastric acid destroy the amylase. If salivary gland does not secrete amylase, starch get digested in the small intestine by pancreatic amylases. The exocrine portion of pancreas secrete bicarbonate ions and a number of digestive enzymes into duct that converge into pancreatic duct which joins common bile duct coming from the liver. The enzymes secreted by pancreas digest fat, polysaccharides, proteins, and nucleic acid. Starch digestion occur by non-proteolytic enzyme amylase into disaccharides. Theses are further broken down into monosaccharides which are transported across the intestinal epithelium into the blood. 

5. SA NODE FUNCTION AS A PACEMAKER FOR THE ENTIRE HEART.

The heart is a dual pump in which the left and right  side of the heart pump blood separately, but simultaneously into systemic and pulmonary vessels. Contraction of cardiac muscles, like that of skeletal muscle and smooth muscle, is triggered by depolarization of the plasma membrane  gap junction interconnected myocardial cell and allow action potential to spread from one cell to another. Thus, the initial excitation of one cardiac cell eventually result in the excitation of all cardiac cell. This initial depolarization normally arises in a small gap of conducting system cell called the sinoatrial (SA) node, located in right atrium near the entrance of the superior vena cava. The action potential then spread from SA node throughout the atria and then into and throughout the ventricles. The SA node is the normal pacemaker for the entire heart. Its depolarization normally generates the action potential the action potential that leads to the depolarization of all other cardiac muscle cells. The action potential initiated in the SA node spreads throughout the myocardium, passing from cell to cell by way of gap junctions. Depolarization first spreads through the muscle cell of the atria, with conduction rapid enough that the right and left atria contracts essentially at the same time. The link between atrial depolarization and ventricular depolarization is a portion of conducting system called atrioventricular (AV)node, at the base of the right atrium.  

factors that contribute to muscle fatigue

MUSCLE FATIGUE :- 

It refers to the decline in muscle force generated over sustained periods of activity or due to pathological issues. Different factors that contribute are:-

• Lactic acid accumulation: It is a byproduct of anaerobic respiration which strongly contributes to muscle fatigue. In aerobic respiration, pyruvate produced by glycolysis is converted into ATP in mitochondria via Krebs cycle. With insufficient oxygen, pyruvate accumulates in the muscle fiber in the form of lactic acid. This reduces the pH, making it more acidic and producing the stinging feeling. this inhibits anaerobic respiration, inducing fatigue.
• Ion Imbalance:  Contraction of a muscle requires Ca2+ ions to interact with troponin, exposing the actin binding site to the myosin head. With extensive exercise, the osmotically active molecules outside of the muscles are lost through sweating. This loss changes the osmotic gradient, making it more difficult for the required Ca2+ ions to be delivered to the muscle fibers. this sometimes leads to muscle cramps. 
• Metabolic Fatigue:-  Depletion of required substrates such as ATP or glycogen. Accumulation of Mg2+ ions or reactive oxygen species can also induce fatigue. 

MEMORY

Memory is a relatively permanent storage form of learned information. Memory encoding defines the neural processes that change an experience into memory of that experience. Memory can be viewed in two broad categories called declarative and procedural memory.

• Declarative Memory (Explicit memory) :- It is the retention and recall of conscious experiences that can be put into words. The hippocampus, amygdala and other parts of limbic system are required for the formation of declarative memories. e.g., general knowledge of the world, like names and facts.
• Procedural Memory (Implicit or reflexive memory) :- It is the memory of how to do things. This is the memory for skilled behavior independent of conscious understandings. e.g., riding a bicycle. individuals can suffer severe deficits in declarative memory but have intact procedural memory. Primary areas of brain involved in procedural memory are regions of sensorimotor cortex, basal nuclei and cerebellum.

Memory can also be classified in terms of duration also:-

• Working memory (short term memory):- Registers and retains incoming information for a short time- a matter of seconds to minutes - after its input. e.g., child recalling steps of a recipe while cooking his favorite meal.
• Long term memory:- Short term memories may be converted into long term memories which may be shorted for days to years and recalled at a later time. The process by which short time memories become long term memories is called consolidation.

Working memory is interrupted when a person becomes unconscious from a blow on head, and memories are abolished for all that happened for a variable period of time before the below, a condition called retrograde amnesia.

Anterograde amnesia results from damage to limbic system and associated structures. Patients with this condition lose their ability to consolidate short term declarative memories into long term memories. 

Working memory is susceptible to external interference such as an attempt to learn conflicting information. While, long term memory can survive deep anesthesia, trauma, all of which disrupt normal patterns of neural conduction in brain. Thus, working memory requires electrical activity in neurons.

One model for storage of memory is Long term potentiation.(LTP), in which certain synapses undergo a long lasting increase in their effectiveness when they are heavily used. An analogous process, Long term Depression (LTD), decreases the effectiveness of synaptic contacts between neurons. 

WHAT IS SLEEP?

Sleep is a fundamental necessity of a complex nervous system. It is a homeostatic requirement, similar to need for food and water. The EEG pattern changes profoundly in sleep. There are two phases of sleep dependent on whether or not the eyes move behind the closed eyelids:

• NREM (Non Rapid Eye Movement)
• REM (Rapid Eye Movement)

The initial phases of sleep - NREM sleep - is subdivided into 3 stages:-

• In stage N1 sleep, theta waves begin to be interspersed among alpha pattern in EEG. There is light sleep, aroused by moderate stimuli etc. 
• In stage N2, high frequency bursts called sleep spindles and large amplitude K complexes occasionally interrupt theta rhythm. delta waves first appear along with theta rhythm .
• In stage N3 sleep, as it  continues, the pattern becomes delta rhythm N3, referred to as slow-wave sleep.

NREM sleep normally takes 30 to 45 mins and then process reverses itself; EEG ultimately resumes a small amplitude, high frequency similar to alert, awake state. 

REM sleep is also called paradoxical sleep because even though a person is asleep and difficult to arouse, his or her EEG pattern shows intense activity that is similar to that observed in awake state. In fact, brain oxygen consumption is higher during REM sleep than NREM or awake state.

If uninterrupted, these stages occur in cyclical fashion, tending to move from NREM stages, then back up to N2, and then to an episode of REM sleep. The average total nights sleep comprises 4-5 such cycles, each lasting 90-100 mins. Significantly, more time is spent in NREM during first few cycles, but time spent in REM sleep increases towards the end of undisturbed night.

Skeletal muscle tension, already decreased during NREM sleep, is markedly inhibited during REM sleep. Exceptions include eye muscles which undergo rapid bursts of contractions that give this sleep stage its name. Respiratory muscles are also active during REM sleep, rate of breathing is frequently increased compared to awake, relaxed state.

During NREM sleep, there is pulsatile releases of hormones from anterior pituitary such as GH and GnRH, so adequate sleep is essential for normal growth in children and regulation of reproductive function in adults. Decrease in BP, heart rate and respiratory rate also occur during NREM sleep. REM sleep is associated with increase and irregularity in BP, heart rate and respiratory rate.

Electroencephalogram (EEG)

EEG:

EEG stands for electroencephalogram. EEG portrays the electrical potential difference between different points on the surface of the scalp. EEG is a useful tool in identifying the different states of consciousness.

Electrodes are attached to head by a salty paste that conducts electricity, pick up electrical signals generated in brain and transmit them to a machine that records them as EEG. Action potentials in individual neurons are also far too small to be picked up on EEG. Rather, EEG patterns are largely due to synchronous graded potentials i.e., summed post synaptic potentials in brain neurons that underlie the recording electrodes. The majority of electrical signal recorded in EEG originate in pyramidal cells of cortex. The processes of these cells lie close to and perpendicular to the surface of brain, and the EEG records post synaptic potentials- in their dendrites.
 
EEG patterns are complex waveforms with large variations in both amplitude and frequency. A large amplitude indicates that many neurons are being activated simultaneously and vice versa. Amplitude may range from 0.5 to 100 mV (about 100 times smaller than an action potential). The frequency of wave indicates how often it cycles from maximal to minimal amplitudes and back. It may vary from 0.5 to 40 Hz or higher. Low EEG frequencies indicate less responsive states, such as sleep whereas high frequency indicate increased alertness.

Wave patterns may vary not only as a function of state of consciousness but also according to where on scalp they are recorded. Clusters of thalamus neurons provide a fluctuating action potential frequency output through neurons leading from thalamus to cortex. The cortical synaptic activity comprises most of recorded EEG signal. This synchronicity reflects degree of synchronous firing of thalamic neuronal clusters that are generating EEG.

EEG is used in diagnosis of and treatment of epilepsy and in diagnosis of coma and brain death, It was also used in detection of brain areas damaged by tumor, blood clots or hemorrhage.

SPERM CAPACITATION AND ACROSOMAL REACTION

SPERM CAPACITATION:

Sperm can enter the uterus within minutes of ejaculation. Furthermore, the sperm can usually survive for up to a day or two within the cervical mucus, but the sperm are not able to fertilize the egg until they have resided in the female tract for several hours and been acted upon by secretions of the tract. This process, is called sperm capacitation.

Capacitation causes:

• The previously wavelike regular beats of the sperm's tail to be replaced by a more whip like action that propels the sperm forward in strong surges.
• The sperm's plasma membrane to become altered so that it will be capable of fusing with the surface membrane of the egg,

ACROSOME REACTION:

Many sperm, after moving between the granulosa cells of the corona radiata still surrounding the egg, bind to the zona pellucida. The zona pellucida glycoprotein functions as receptors for sperm surface proteins. The sperm head has many of these proteins and so becomes bound simultaneously to many sperm receptors on the zona pellucida. This binding triggers what is termed as acrosome reaction in the bound sperm.

The plasma membrane of the sperm head is altered so that the underlying membrane-bound acrosomal enzymes are now exposed to the outside- that is, to the zona pellucida. the enzymes digest a path through the zona pellucida as the sperm, using its tail, advances through this coating.

Differences between cortical reaction and acrosomal reaction.

CORTICAL REACTION:

• This reaction takes place within the egg.
• In this reaction the secretory vesicles are cortical granules.
• It prevents polyspermy by establishing a permanent barrier to additional sperm entry.

ACROSOMAL REACTION:

• This reaction takes place within the sperms.
• In this reaction, the secretory vesicles is an acrosome.
• This reaction allows the sperm by exocytotic release of acrosomal enzymes to penetrate the zona pellucida of the egg.

difference between glial cells and neuronal cells

GLIAL CELLS:

• They are the secondary supporting cells which are involved in the regulation of homeostasis of the nervous system and protection.
• These cells have only one processes i.e., axons and Nissl granules are absent , but have dendrites.
• They have the ability to undergo cell division with age.
• Glial cells cannot generate action potential but have a resting potential.
• glial cells do not have chemical synapses.

NEURONAL CELLS:

•  Neurons are the basic structural units which are involved in the transmission of impulses throughout the body during coordination of voluntary and involuntary actions.
• These cells have two processes. one axon and one dendrite. And Nissl granules are also present.
• They lack the ability of regeneration and are non-renewable and keep to their original form till death.
• Neurons can generate an action potential.
• Neurons have synapses that uses neurotransmitters.

difference between systole and diastole.

SYSTOLE:

• It is the contraction phase of the cardiac cycle of the heart.
• In the systole stage, when the heart contracts, it pumps the blood from the heart chambers into the aorta and a pulmonary artery.
• The blood pressure of the systole stage is high for a normal person, it is 120.
• The systolic pressure undergoes considerable fluctuations at different conditions like the extent of work done by heart.

DIASTOLE:

• It is the relaxation phase of the cardiac cycle of the heart.
• In a diastole stage, when the heart relaxes, it allows the heart chambers to be filled with blood from vena cava and pulmonary veins.
• The blood pressure of the diastole stage is low. for a normal person it is 80.
• The diastolic pressure undergoes much less fluctuations in health and remains within a limited range.

Difference between sympathetic nervous system and parasympathetic nervous system.

SYMPATHETIC NERVOUS SYSTEM:

• Its major function is to mobilize the body's fight or flight responses to prepare the body for intense physical activity.
• It has very short neurons and hence a faster system.
• Body speeds up and becomes more alert.
• Increases heart rate.
• Contracts the muscle.
• Adrenal gland releases adrenaline.
• Glycogen to glucose conversion increases for muscle energy.

PARASYMPATHETIC NERVOUS SYSTEM:

• Its general function is to control the homeostasis and the body's rest-and-digest response.
• It has longer pathways (neurons) and hence slower system.
• It restores the body to a calm state.
• Decreases heart rate.
• Muscles relax.
• No involvement of adrenal gland.
• No such increase of glucose.

Difference between central nervous system and peripheral nervous system.

CNS:

• CNS consists of the brain and spinal cord.
• Its major functions is to organize and analyze the information obtained from sensory organs.
• CNS controls all the voluntary functions of the body
• It carries significantly short nerve impulses.
• A damage to CNS causes a global effect on the body.
• Most nerves are incapable of regenerating its nerve fibers.

PNS:

•  PNS consists of sensory receptors, sensory neurons and motor neurons.
• Its major function is to transmit sensory information to the CNS and pass motor impulses to the effector organs.
• PNS controls and influences all the involuntary functions of the body.
• It is composed of long nerve fibers.
• A damage to PNS causes a local effect on the body.
• Most nerves can be regenerated.

An accident trauma victim with acute haemorrhage in absence of blood is advised a saline drip with reconstituted albuminas.

This is because it restores blood volume and attenuates hormonal responses preventing further blood loss. Saline fluid resuscitation produces physiologic benefits to the haemorrhagic patients by improving mean arterial pressure hence preventing uncontrolled bleeding.

Renal failure can lead to anemia. Why?

Anemia is a condition in which body has fewer red blood cells than normal. Anemia normally occurs in people with chronic kidney disease (CKD)- the permanent, partial loss of kidney function. This is because healthy kidneys produce a hormone called erythropoietin(EPO) , which controls erythrocyte production in bone marrow, which then carry oxygen throughout the body. Other causes of anemia in people with kidney diseases can be blood loss from hemodialysis.