Q:1 A 43 years old male pale looking man presents with complaint of difficulty in breathing on exertion.

He has history of Inflammatory Bowel Disease followed by surgical removal of terminal portion of Ileum 3 years back. His blood picture reveals: Hemoglobin 8.7 gm/dl MCV (Mean Corpuscular Volume) 106 fl (normal range 80-100 fl) a) Why he suffered from breathing difficulty? (1) b) What is type of anemia in this case? (1) c) Which nutrient is deficient in this patient? (1) d) Describe the pathogenesis (mechanism of development of ailment) of his disease. (2) Key: 1 a) Decreased hemoglobin concentration in this patient results in tissue hypoxia. Hypoxia stimulates respiratory centre leading to increased rate of respiration. As a result, the respiratory muscles become over-worked leading to exhaustion resulting into difficulty in breathing. (1) b) Megaloblastic anemia. c) Vitamin B12 is deficient. (1) (1)

d) Maturation Failure of RBCs, caused by poor absorption of Vitamin B12, (which is required for RBC maturation) from the Gastrointestinal Tract due to surgical removal of ileum (from where B12 is normally absorbed) as a treatment of inflammatory bowel disease. 3 to 4 years of defective B12 absorption are usually required to deplete its stores & cause maturation failure anemia.

Q.2 Mention the 1st , 2nd, 3rd and 4th lines of defense against infection. Name the components of reticulo-endothelial system. (4 + 1 marks) Key:2 1st line of defense: by Tissue macrophages, histiocytes (subcutaneous tissue), alveolar macrophages (lungs) & microglia (brain). Duration: Starts within minutes and lasts for an hour or so. Products of infection / inflammation cause activation of macrophages by their rapid enlargement & they become mobile. (1 mark) 2nd line of defense: by neutrophil invasion. Duration: Within the 1st hour or so. Products of inflammation alter the inner surface of capillary endothelium neutrophils stick to capillary wall (margination). Intercellular attachment between endothelial cells of capillaries & small venules loosen passage of neutrophils from blood into tissue spaces by squeezing through the pores of membrane (diapedesis). Other products of inflammation causes attraction of neutophils towards injured tissue (chemotaxis). Within several hours of injury neutrophils are ready to begin their scavenger function. (1 mark) 3rd line of defense: by 2nd macrophage invasion into the inflamed tissue. Duration: several days to several weeks. Along with neutrophils, blood monocytes enter into inflamed tissue. Immature monocytes develop many lysosomes in 8 hrs & become tissue macrophages. Macrophages phagocytize 5 times more than neutrophil. It can even phagocytize neutrophils. (1 mark)

4th line of defense: by increased production of granulocytes & monocytes by the bone marrow. Duration: 3-4 days to months-years. Stimulation of granulocytic & monocytic progenitor cells of bone marrow leads to initiation of 4th line of defense. (1 mark) Components of RES: Tissue macrophages in skin & subcutaneous tissue (histiocytes). (0.25 marks)

Macrophages in the lymph nodes and Alveolar macrophages in the lungs. (0.25 marks) Macrophages in hepatic sinusoids (kupffer cells). (0.25 marks) Macrophages of spleen & bone marrow. (0.25 marks)

Q.3 Give a brief account of the role of preprocessing in the Thymus and Bone Marrow. What do you understand by Delayed-Reaction Allergy? (4 + 1 marks) Key:3 Preprocessing in Thymus: (0.25 marks each)

Bone marrow develops T lymphocyte which migrate to Thymus where they divide & develop diversity for different specific antigens. 1 thymic lymphocyte develops specificity against 1 antigen. Pre-processed T lymphocytes leave thymus then enter into blood & body lymphoid tissue. Thymus derived T lymphocytes are so processed that they do not react against self proteins or other self antigens. Otherwise leads to autoimmune disease. If a T lymphocyte reacts with self antigens produced by the body, it is destroyed & not allowed to release from thymus. Cells that are finally released are non-reactive against self. Duration: shortly before birth few months after birth. (0.5 marks each)

Preprocessing in Bone Marrow:

Duration: late fetal life after birth. Whole of B-Lymphocytes does not react unlike T-lymphocytes but secrete antibodies which is reactive agents (large proteins) that combine & destroy the antigenic substances. B-Lymphocytes are more diverse in forming specific antibodies than TLymphocytes. After preprocessing, B & T-Lymphocytes, migrate to lymphoid areas. Delayed reaction allergy: (0.25 marks each) Caused by activated T cells, not by antibodies. Example: repeated exposure to poison ivy causes formation of activated Helper and Cytotoxic T cells On subsequent exposure, activated T cells diffuse from circulating blood into the skin & simultaneously they elicit cell mediated immune reaction Release of many toxic substances causes extensive tissue invasion by macrophages results into tissue damage, especially where the specific antigen is present, e.g., skin in case of poison ivy, lung in case of lung edema, asthma & some air borne antigens.

Q.4 Which cell organelles can increase their number by self replication? Give functions of these organelles. (1+4) UHS MBBS SUPPLEMENTARY 2010, Q:1, Goal Ed. 2011 Key:5 Reference: p 16, 17, Organelles with self-replication are: 1. PEROXISOMES: Contain oxidizing enzymes including oxidases & catalases. Oxidases combine oxygen with hydrogen ions different intracellular chemicals to form hydrogen peroxide, a highly oxidizing substance, that oxidizes many substances that may otherwise be poisonous. (1.5) 2. MITOCHONDRIA: Almost all oxidative reactions occur inside the mitochondria & the energy that is released is used to form high energy compound ATP, used for cellular transport, synthesis of chemicals & mechanical work. (1.5) 3. NUCLEUS: Their replication takes place in mitosis to produce a copy of parent cell. (Any 2 = 1)

Q.5 What are 3 major categories of cellular function which utilize ATP? Reference: Q.9 UHS MBBS (I) ANNUAL 2006, Goal Ed. 2011. Key: 5 (Reference: pp 22, 23 Guyton 11th Ed.) Energy from ATP is used to promote three major cellular functions:
1. Transport of substances through multiple membranes in the cell 2. Synthesis of chemical compounds in the cell 3. Mechanical work.

(5)

Transport of substances through multiple membranes in the cell: (1) ATP is used to transport sodium, potassium, calcium, magnesium, phosphate, chloride, urate, hydrogen ions and other organic substances. (0.5) Membrane transport is so important to cell function that some cells use as much as 80% of the ATP formed for this purpose e.g. the renal tubular cells. (0.5) Synthesis of chemical compounds in the cell: In addition to the synthesis of proteins cells synthesize phospholipids, cholesterol, purines, pyrimidines and a host of other substances. (0.5) (1)

Synthesis of almost any chemical compound requires energy. Some cells use as much as 75% of all the ATP synthesized in the cell simply to synthesize new chemical compounds. (0.5)

Mechanical work: (0.5) The final major use of ATP is to supply energy for special cells to perform mechanical work. Other cells perform mechanical work in other ways, especially by ciliary and ameboid motion. The source of energy for all these types of mechanical work is ATP. (0.5)

Q: 6 Briefly mention voltage & Ligand gating of the cell membrane channels. (5) Reference: UHS MBBS (I) ANNUAL 2009, Goal Ed. 2011. Key: 6 Reference: p 48, Guyton 11th Ed. They remain most of the time in closed state, which allows them to regulate the movement of molecules through them. (1 mark) They are divided into two types. 1. LIGAND (CHEMICAL) GATED CHANNELS: (2 Marks) Gates open by binding of a chemical substance (ligand) with the protein channel leading to conformational or chemical bonding change in protein molecule that opens / closes the gate. (0.5) EXAMPLE: Acetylcholine gated channels (0.5) Effect of Acetylcholine on acetylcholine channel leads to opening of gate (negatively charged pore of 0.65 nm diameter) resulting into passage of uncharged molecules positive ions smaller than 0.65 nm. (0.5) Important at: Nerve to nerve junction & Nerve to Muscle junction (0.5)

2- VOLTAGE GATED CHANNELS: (2 Marks) Molecular conformation of the gate or its chemical bonds responds to electrical potential across cell membrane. (0.5) EXAMPLE: Sodium channels & Potassium channels. (0.5) When strong negative charge inside the cell membrane (at Resting membrane potential): Sodium gates remain closed. When inside of membrane loses its negative charge: Sudden opening of sodium gates causes massive sodium influx leading to onset of action potential. (0.5) When inside becomes positive: Potassium gates open leading to potassium efflux & termination of action potential. (0.5)

Q.7 a) Draw and label a neuromuscular junction? b) What is a latch phenomenon in a smooth muscle fiber? Give its significance. How it is regulated? Key:7a) (Reference: Fig. 7.1, Guyton 11th Ed.) (0.5 mark for drawing and 0.5 mark for labeling)

(1) (1+1+2)

Key:1b) (Reference: p 94, Guyton 11th Ed.) LATCH MECHANISM: Once smooth muscle has developed full contraction, the amount of continuing excitation usually can be reduced to far less than the initial level, yet the muscle maintain its full force of contraction. (0.5) Further, the energy consumed to maintain contraction is often minuscule, sometimes as little as 1/300 the energy required for comparable sustained skeletal muscle contraction. This is called the latch mechanism. (0.5) SIGNIFICANCE: The importance of the latch mechanism is that it can maintain prolonged tonic contraction in smooth muscle for hours with little use of energy. Little continued excitatory signal is required from nerve fibers or hormonal sources (1) REGULATION: When the myosin kinase and myosin phosphatase enzymes are both strongly activated, the cycling frequency of the myosin heads and the velocity of contraction are great. (0.5) Then, as the activation of the enzymes decreases, the cycling frequency decreases, but at the same time, the deactivation of these enzymes allows the myosin heads to remain attached to the actin filament for a longer and longer

proportion of the cycling period. Therefore, the number of heads attached to the actin filament at any given time remains large. (0.5) Because the number of heads attached to the actin determines the static force of contraction, tension is maintained, or latched; yet little energy is used by the muscle, because ATP is not degraded to ADP except on the rare occasion when a head detaches. (01)

Q.8. Ahsanullah a 20 year old marathon runner complains of inability to sustain muscular contraction while fasting during Ramzan a) Give the etiology for this limitation (1+2) b) Which energy system is utilized for sustained muscular contraction for 5 to 8 seconds? (1) c) Mention the energy system that is utilized for muscular contraction for one minute? (1) Key: 8 (p 79 Guyton 11TH Ed) a) Final source of energy is oxidative metabolism. This means combining oxygen with the end products of glycolysis and with various other cellular foodstuffs to liberate ATP. (1) More than 95 per cent of all energy used by the muscles for sustained, longterm contraction is derived from this source. The foodstuffs that are consumed are carbohydrates, fats, and protein. (1) For extremely long-term maximal muscle activityover a period of many hoursby far the greatest proportion of energy comes from fats, but for periods of 2 to 4 hours, as much as one half of the energy can come from stored carbohydrates. (1) b) To reconstitute the ATP is the substance phosphocreatine, which carries a highenergy phosphate bond similar to the bonds of ATP. (0.5) Therefore, the combined energy of both the stored ATP and the phosphocreatine in the muscle is capable of causing maximal muscle contraction for only 5 to 8 seconds. (0.5) c)

Glycolysis of glycogen previously stored in the muscle cells. Rapid enzymatic breakdown of the glycogen to pyruvic acid and lactic acid liberates energy hat is used to convert ADP to ATP (0.5) ATP can then be used directly to energize additional muscle contraction and also to re-form the stores of phosphocreatine. However, so any end products of glycolysis accumulate in the muscle cells that glycolysis also loses its capability to sustain maximum muscle contraction after about 1 minute. (0.5)

Q9. Define end plate potential (EPP). How is it produced? In which pathological condition it is produced. Discuss briefly.

(1+2) (2)

Key .9 (p 87 Guyton 11th Ed) DEFINITION: Local area of the motor end plate, due to increase in potential in the positive direction creates a local potential which is called the End plate potential (1) PRODUCTION: The sudden insurgence of sodium ions into the muscle fiber when the acetylcholine channels open causes the electrical potential inside the fiber at the local area of the end plate to increase in the positive direction as much as 50 to 75 millivolts, creating a local potential called the end plate potential. (1) Sudden increase in nerve membrane potential of more than 20 to 30 millivolts is normally sufficient to initiate more and more sodium channel opening, thus initiating an action potential at the muscle fiber membrane. (1) EPP IN MYASTHENIA GRAVIS: In myasthenia gravis there is muscle paralysis because of inability of the neuromuscular junctions to transmit enough signals from the nerve fibers to the muscle fibers. Pathologically, antibodies that attack the acetylcholine- gated sodium ion transport proteins have been demonstrated in the blood of most patients with myasthenia gravis. (1) Regardless of the cause, the end plate potentials that occur in the muscle fibers are mostly too weak to stimulate the muscle fibers. If the disease is intense enough, the patient dies of paralysisin particular, paralysis of the respiratory muscles. (1)