| AIPGME Se CW IN Ven| | ANSWERS iz EXPLANATIONS 2010a aa statements that have been asked ay Pee ROT CML Te examinations over the previous years. Te Tore TMM Ra ne ea ana ae Re Late ed fo pay more attention to the entire OR OE aeANATOMY 1. (a) Answer is A (Superior Gluteal Nerve): BDC wol-Il/6%/769 Gluteus medius is supplied by the Superior Gluteal Nerve. Superior Gluteal Nerve supplies the Gluteal medius, Gluteus minimus and Tensor fascia lata, ‘Muscles of Gluteal Region © Gluteus Maximus? Inferior Gluteal Nerve (LS, S1, S2) BG tateus Medius® ‘Superior Gluteal Nerve (LA, LS, S1) © Gluteus Minimus® Superior Gluteal Nerve (L4, LS, S1) Ventral Rami‘of St and S2 Nerve to Obturator Internus (LS, $1. 2) SN Nerve to Quadra femoris (L4, L5, S1) Obturator Internus © Nerve to Obturator Intermus (LS, S1, $2) (Ouiadrates Femoris °°. Nerve to Ouadratus Femoris (14, LS, SI © Obturator Externus® Posterior Division of Obturator Nerve (L2, L3, LA) (BTensor Fascia Lata® Superior Gluteat Nerve (14, L5, SI) 1, (b) Answer is A (Superior Gluteal Artery) : Grays 40"/ 1054, 1087, 1370, 1369; BDC vol-II/ 6/69 Gluteus medius is supplied by the Superior Gluteal Artery. ‘The main blood supply to the Gluteus medius is from the deep branch of the superior gluteal artery. The distal part of the muscle is supplied by the trochanteric anastomosis’ ~ Gray's «Med 3170 ‘Gluteus Maximus ‘¢ Inferior Gluteal artery (Dominant supply) (supplies approx 2/3 of muscle) ‘Superior Gluteal Artery (supplies remainder) ‘+ Superior Gluteal Artery (Deep branch) + Superior Gluteal Artery (Main trnk & Deep branch) ‘© Medial circumflex femoral / First Profunda perforator + Lateral circunfles femoral lateral sacral / ‘Internal pudendal vesels ‘© Trochanteric Anastomosis # Trochanteric Anastomosis (a)Answer is D (Flexor Hallucis longus): BDC vol- I 4"/ 37, 38; Snell's Anatomy 9/494; Last’s Anatomy 11/153 The tendon of the flexor hallucis longus passes along a groove on the under surface of the sustenticulum tali. scala Tall It isa ‘Shelf like’ projection of bone on the medial aspect of calcaneum It is closely related to three tendons forming the medial tendon group ee] Posterior Tendon “Flexor Hallucis Longus Tendon ‘Flexor Digitorum Congus Tendon + Tibialis posterior tendon lies immediately above the (medial side of sustenticulum tali + Tibialis posterior tendon gives a slip which is attached to the sustenticulum tai '« Flexor Hallucis longus tendon lies in a groove on the lower / under surface of the ‘sustenticulum tali |« FHL is most closely related to the base/ attachment of sustenticulum tali to the calcaneum? «Flexor Digitorum Longus tendon crosses the medial surface of the sustenticulum tal ‘s posterior (TP), Flexor Digitorum longus (EDI Flexor Hallucis Longus (FHL) form the medial tendon group. ‘Their arrangement is as follows-2(b). Answer is B (Tibialis Posterior): Gray's 41/142 |AND EXPLANATIONS - 2010 BDC I$" / 38; Anatomy by Mitra vol-II/ 9.138 ‘Sutenticulum Tali provides attachment 10 a slip of Tibialis Posterior Tendon. Tendons of flexor hallucis longus and flexor digitorum longus are closely related to susteticulum tali but do not have ‘any attachments to sustenticulum tal. + Plantar Calcaneonavicular (spring) Ligament. + Slip of Tibialts posterior tendon, «| Superficial fibres of deltoid ligament. + Medial talocalcaneal ligament. Answer is C (Colle’s facia) : BDC vol II 6"/356 Colle’s fascia does not contribute to the Urogenital Diaphragm i Urogenital Diaphragm refers to a triangular musculo fascial diaphragm situated in the anterior part of the perenium filling in the gap of the pubie arch. ‘Urogenital diy is formed a Deep Transverse Perineal muscles Sphincter Urethrae Superior fascia of Urogenital Diaphragm Inferior fascia of Urogenital Diaphragm Perineal membrane) Colte’s fascia is attached posteriorly to the posterior border of the Urogenital diaphragm but does not form part of this diaphragm. eye tani ase ‘Supertcalfascia of wogentaeaphvagm Sphincter ueta & Deep vansvere pre Call's fascia is attached to he Posterior border of Urogenital diaphragm But of penis but des not fom par oe of this diaphragm oe a ‘Cross-sectionAnswer is C (Pelvic fascia): Grant's Atlas of Anatomy 12"/251 Hypogastric sheath is a condensation of the endopelvic fascia (pelvic fascia). “The endopelvic fascia lies between and is continuous with both visceral and parietal layers of pelvic fascia, Hypogastric sheath is a condensation of this fascia and contains the vessels to the pelvic viscera, the ureters and (in the ‘male) the ductus deferens’ ~ Grant's Aas of Anatomy 127251 Answer is C (Deep Inguinal Nodes): BDC vol 11 6%/379 Lymphatics from the spongy urethra pass mostly to the deep inguinal lymph nodes. ae ] * Drain partly to Extemnal Iliac nodes « Drain partly to Superficial Inguinal & External ae nodes Answer is A (Anterolateral to Aorta): Gray's 41/1036; ‘Practical Management of Pain’ by Prithvi Raj 3/251 The celiac plexus lies on the anterolateral surface of Aorta. “The celiac plexus lies on the anterolateral surface of aorta from the T13 0 L, vertebra level “Practical Management of pain ‘© Celiac plexus is the largest major Abdominopelvic Autonomic plexus ‘© Celiac plexus is located retroperitoneally, in the upper abdomen over the anterolateral surface of Aorta at the level of TirL, vertebra + It is posterior to the stomach and lesser sac anterior tothe crura of diaphragm and the beginning of abdominal aorta and lies between the suprarenal glands. Answer is None (All of the above arteries may form channels for collateral circulation) : Gray's 4/"/1025; ‘Radiology of peripheral vascular diseases’ by Zetler, Ammann (2000) /324; ‘Aortic Diseases: Clinical Diagnostic Imaging Atlas’ by Hutchison (Elsevier) 2008/273; ‘Moss and Adams heart disease’ 7th 990; ‘The natural and modified history of congenital heart disease'(Wiley Blackwell) 2003/254 Suprascapular artery, Subscapular artery, Posterior intercostal artery and Vertebral Artery may all form channels ‘for collateral ciculation in coarctation of aorta, ‘The vertebral artery is probably the least prominent pathway for collateral circulation amongst the options provided ‘and hence may be accepted as the single best answer by exclusion (Veriebral artery has also not been mentioned in Gray's textbook of anatomy as a channel for collateral circulation in coarctation of aorta while all other options have been distinctly ‘mentioned )820» AIPGME EXAMINATION ANSWERS AND EXPLANATIONS - 2010 ajonty of collateral blood flow ‘of aorta is provided by the subclavian artery and its branches. The high-pressure arterial branches of the subclavian artery give branches to the low-pressure arteries locate distal to the coarctation ‘Subclavian artery ‘All four branches of the subclavian artery may ‘contribute blood for collateral circulation through ‘various channels © The internal mammary artery is « major pathway of communication via connections ‘of the anterior intercostal branches with the posterior intercostal arteries and via the superior epigastric artery branch with the inferior epigastric artery ‘© The-costocervical unk ofthe subclavian artery supplies the first and second posterior intercostal arteries, which communicate both anteriorly with the intemal mammary artery ‘and posteriorly with the third and fourth posterior intercostal arteries © The:thyrocervical trunk supplies collateral ‘circulation through , transverse cervical, and ‘Suprascapular branches, which ‘communicate with the posterior intercostal arteries and thence into the aorta © The vertebral artery branch of the subclavian artery contributes through the anterior spinel artery which ‘communicates with the intercostal arteries and then to aorta ‘© Branches of the axiallaryanery including the thoracoacromial,, lateral thoracic, and subscapular arteries also participate inthe collateral circulation Posterior Intercostal arteries ‘© The third through the eleventh posterior intercostal arteries and the subcostal arteries arse from the posterior aspect of the descending aorta distal to the origin ofthe left subclavian artery andthe site of coarctation. These posterior intercostal arteries, receive the collateral blood from the subclavian artery branches, thus re-establishing flow into the distal aorta 8 Answer is A (Vertebral Artery): BDC I11/5"/19 Vertebral Arteries are transmitted through the subarachnoid space in the Foramen magnum. [Through Wider Posterior Part Through the Subarachnoid Space [Through narrow Anterior part [+ Lowest Part of Medulla * Spinal Accessory Nerve [+ Apical Ligament of Dens oblongata + Vertebral Arteries + Vertical band of cruciate Three meninges Sympathetic plexus around vertebral | | Ligament Arteries (Not sympathetic chain) | |e Membran tectoria + Posterior spinal Arteries Anterior spinal Artery#_Bamissary vein (cavernous sinus to pterygoid plexus) _ Occasionally anterior rank of middle meningeal vein —" + Midile meningeal artery® & vein (posterior rank) . © Emissary vein : at © Nervus spinosus (meningeal br. of mandibular nerve) ® ‘Structures pasing whole length + Meningeal br. of Ascending Pharyngel artery + Emissary vein Other structures partially traversing + Internal cart artery with venous & sympathetic plexus around it © Greater petrosal neve unites wit Deep ptrosa nerve to form Nerve ofperygold cana. Carotid Canal, ‘© Internal carotid artery & venous and sympathetic plexus around it ® a = a + Mesilary nerve? (Aailary nerve passes through foramen rotund pterygopalatin fora & inferior orbial sure 10 reach the orb) ¢ Facial nerve ® + Posterior duricla anery(splomasol branch) * Facialnene © Vestibulo cochlear nerve (VIP) + Nerves intermedius or pars intermedia of wrisherg.? © Labrihine vessels + Hyposiossal nerve * Meningeal branch of poglossal nerve © Meningeal branch of Ascending Pharyngeal artery © Emissary vein (Sigmoid sinus to internal jugular vein) Jugular Foramen Amerior part Middle part Posterior part «Inferior.» 9 (glossapharyngel) neve» Interna gular vein— Sigmotd smas Petrosal — + 10° agus) nerve? ‘uncon ‘Sims? © 11 (accessory) nerve? ‘© Emissary vein (sigmoid simus to © Meningeal of Ascending ‘ccptal vein) Pharyngeal Artery + Occipital artery (meningeal branch) Mastoidcanaicuus (enter) + Aurcular branch of vagus nerve “Tympanomastold fissure (exit ‘Tympaniccanaicalas Incisive foramen ‘Tympanic br. of glossopharyngeal (0%) nerve sai Generac 4 [Nasopalarine nerves Answer is C (Medial rotation of scapula): Gray's 41"/816; Snells 8°/ 465, 466° Clinical Anatomy for Students’ by Greater polatine vessels Kulkarni (2006)/36' Anatomy and Human movement’ S"/ed 116, 117° Joint Range of motion and Muscle Length Testing’ 2/51 ei. . ‘Midile & Posterior palatine nerve Abduction of shoulder is associated with lateral rotation of scapula and not medial rotation.10, 2010 ‘Lateral rotation of scapula increases the range of humeral elevation by turning the glenoid cavity to face almost directly up’ -Grays “Ar initiation of abduction there is slight There is always some associated There is always some movement at both ‘wuxcior translation of menus while elevation and protraction of scapula SC and AC joint o allow Scapular ‘after about 120° of abduction external rotation at Scapulothorace articulation. etation of humerus is required Motion of scapula isa result of motion that occurs at the scapulathorocic articulation 1s well as atthe acromioclavicular and sternoclavicular joint. © Lateral rotation of scapula is defined in relation to the inferior angle of LATERAL ROTATION scapula, With lateral rotation of scapula the inferior angle of scapula ‘Upper fibers moves laterally such that the glenoid fossa points upwards. of apts ‘© This lateral rotation of scapula is an integral part of abduction of shoulder (especially beyond 90°) ‘+ Apart from the initial approximately 30° of abduction, glenohumeral neccae took joint movement and scapular motion occur simultaneously ina ratio of of wapazas \ If ae, 2 to I (scapulothoracie rhythm) For every 15° of elevation, glenohumeral movements is said o be 10° and scapular movement 5° (Ratio = 2 t0 1) + This movement is brought about by the lower five digitations of serratus anterior along with upper and lower fibres of the trapezius. + Scapular rotation at the scapulothoracic junction requires movement at both sternoclavicular (SC) and acromioclavicular (AC) Lavetor scape + The only true bony articulation of scapula is withthe lateral end of Rhomboid minor Rhomboid clavicle via acromium at the AC joint. As clavicle is anchored to the Acronium and Sternum, movements of the scapula produce movement of at the AC joint & SC joints. Elevation of the lateral end of clavicle at the AC joint and rotation of _—‘i#dustion s astosiated with medial rotation the clavicle along its long axis which takes place both at the SC joint ‘and AC joint have been observed. ‘+ Scapular rotation forces motion of the clavicle, Answer is A (Flexor Carpi Ulnaris): Gray's 41°/849-853; B.D. Chaurasiya 4" ed vol. Il/64; Cunningham's Textbook of Anatomy (Original edition)/671; Grant's Method of Anatomy (Old edition-1971)/353 The existence of more than one nerve to a muscle indicates usually that the muscle is composite. Flexor carpi ulnaris receives a single innervation and is not classified as a Composite or Hybrid muscle. Pectineus, Biceps Femoris and Flexor digitorum Pofiundus are all innervated by more than one nerve and may thus be classified as composite muscles.M1. /AIPGME EXAMINATION ANSWERS AND EXPLANATIONS ~ 2010 * 823 ‘Composite Muscles ‘Composite Individual Muscles Composite Group of Muscles ‘These include muscles that have different origins (two heads) These include a composite of different individual muscles that and different innervations forthe two heads. These muscles function asa single muscle model are also referred to as Hybrid muscles Examples Example © Adductor Magnus? © Quadriceps femoris . es Femoris? (This is considered a composite of four individual muscles 2 Pecdnens? namely the rectus femoris, vastus lateralis all of which : Work in conjunction a to bring about extension at the knee Flexor digitorum profundus? nal The existence of mare than one nerve fo @ muscle Indicates usually that the muscle lx composite ~ Cunningham's Tex Book of Anatomy (Old edition) ‘© Biceps Femoris (Gray's 39° /1469) “Biceps femoris is innervated by the sciatic nerve; the long head through tibial division and the short head through the common peroneal division, which reflects the composite derivation from flexor and extensor musculature’ Grays © Pectineus (BDC 11/4" 64 “The Pectineus muscle is of double origin and soit also has a double innervation. ts anterior fibres are supplied by the femoral nerve and its posterior fibres by the anterior division of the obturator nerve or the acessory ‘obturator nerve. Such muscles are called Hybrid or composite muscles - BDC The Pectineus supplied by the femoral and obturator nerves belongs to the composite class - Grants Hlexer Digitorium Profundus ‘Flexor digitorum Profundus has a dual nerve supply. The lateral part of the muscle is supplied by the anterior interosseus branch of the median nerve. The medial part of the muscle is supplied by the ulnar nerve. The existence of dual nerve supply indicates that this muscle is a composite muscle’ © Adductor Magnus (Gray's 39”/1467) ‘Adductor magnus is a composite muscle and is doubly innervated by the obturator nerve and the tibial division of selatie nerve’ - Gray's Answer is C> A (Coronary Sinus) > (Right Atrium): Langman’s Embryology 12"/ 94 Left Superior Vena Cava drains directly into the coronary sinus and by way of the coronary sinus into the right atrium, Left SVC thus, drains into both, the coronary sinus and the right atrium. ‘Since coronary sinus is the initial / direct portal of drainage and provided in the question as a distinct option, itis the single best answer of choice. Len mperer| ‘Left Superior Vena Cava (Langman's Embryology 11/195) + Left superior vena cava is caused by persistence ofthe left anterior cardinal vein and obliteration ofthe common cardinal and proximal part of the anterior cardinal veins on te right. + Blood from the right is channeled towards the left by way of| brachiocephalic vein. + The left superior vena cava drains into the right atrium by way of the Left sinus horn, thats, the coronary sinus. — Baler od ‘Left superior vena cava draining into the right atrium by way of the coronary sinus (dorsal view)AIPGMEE 2010 - EXPLANATIONS Answer is B (IX and X): Ganong 23/535, Chaudhry physiology 73 Vitamin K dependent coagulation factors include coagulation factor Il, VI, IX and X. + Six proteins involved in clotting require conversion of a number of glutamic acid residues to - carboxyglutamic acid residues before being released into circulation + This process of y (gamma) carboxylation occurs in the liver and requires vitamin k and hence these proteins are called vitamin ~ K dependent + These include coagulation factors I, VII, IX and X as well as protein C and protein S. Sane ictor II® (Prothrombin) actor VIF° (Proconvertin) Gonpaon Fact N° (Chroma actor . aprcneege foter X (Sener Prover Feces ss “© Protein oy Protein? ssa Answer is A (Increase in the number of open capillaries): Guyton 11°/486, 487; Pulmonary Physiology (LANGE) 6°/95, 96, 97; ‘ Textbook of Medical Physiology’ by Khurana (2006)/422 Pulmonary circulation can accommodate a significant increase in cardiac output (4-5 times) with only a small rise in inflow pressure by the increasing the number of open capillaries (recruitment) and by greater distensibility (distension) in pulmonary vessels. The increased distensibility is however a passive process and is not mediated by sympathetic stimulation and hence an increase in the number of open capillaries is the single best answer of choice ‘amongst the options provided. Effect of heavy exercise on pulmonary circulation + During heavy exercise the cardiac output (CO) increases and accordingly the blood flow through the lungs (pulmonary blood flow) is also increased upto fourfold to seven folds + Despite this increase in the pulmonary blood flow, the pulmonary arterial pressure is relatively maintained and shows very litle rise in anormal person. «This physiological phenomenon is primarily achieved by two passive processes (Recruitment and Distension) that decrease the pulmonary vascular resistance and hence maintain the pulmonary arterial pressure despite an increase in pulmonary blood flow. Recruitment ‘Recruitment is the process of increasing the number of ‘open parallel capillaries that were previously not lized inthe resting state ‘© Atresting cardiac outputs (CO) many ofthe pulmonary capillaries remain unperfused / collapsed without any flow. ‘+ As the cardiac output is increased and pulmonary blood flow begins to rise, these capillaries that were previously closed begin to open and new parallel pathways for blood flow are established ‘+ This lowers the pulmonary vascular resistance and ‘maintains the pulmonary artery pressure over a wide range of cardiac output «This opening of new pathways is called ‘Recruitment’ Recruitment is a passive process Distension isthe process of increasing the radii / caliber of pulmonary capillaries thereby decreasing the resistance to blood flow and maintaining the pulmonary pressure At resting cardiac outputs, pulmonary cepillaries are not distended to their maximal caliber / radii AAs the cardiac output and pulmonary blood flow increases ‘the transmural pressure gradient ofthe pulmonary blood vessels increases causing distension ofthe vessels ‘This lowers the pulmonary vascular resistance and maintains the pulmonary artery pressure over a wide range of cardiac output This increase in radii / diameter /caliber of pulmonary capillaries is called ‘distension’ Distension is a passive process14, te -h Recruitment and Distension are both passive mechanical processes that regulate pulmonary vascular resistance. These processes are not regulated by the autonomic (sympathetic / parasympathetic nervous system) ‘+ Autonomic stimulation isan active process that may influence the pulmonary circulation, ‘+ Normally the effect of autonomic nervous system on pulmonary vascular resistance is minimal (in contrast to systemic circulation) ‘+ Sympathetic stimulation slightly increases vasoconstriction and resistance and hence may lead to slight increase in pulmonary artery pressure, although this effect is minimal + Tedoes not however promote distension of pulmonary capillaries. [Parasympathetic stimulation produces slight vasodilatation and decreased resistance. Vasodilation (active process) is however not synonymous to distension (passive process) Pulmonary arterioles have less smooth muscles and not more smooth muscles than systemic arterioles Thick wall Thin walls ae * Alyeat moot uae + Les sooth mead z Answer is D (Gravitational increase in arterial pressure): Ganong 231/544, 545, 549; Essentials of Anatomy by LB. Singh (2005) / 172; ‘Human physiology: From cells to systems’ by Sherwood 7"/ 374, 373, 376; ‘Cardiovascular system at a Glance’ 2"/ 48,49. Gravitational increase in arterial pressure during standing does not improve /enhance venous return. Gravitational increase in arterial pressure ‘during standing does not enhance /improve ‘enous return as pressure gradient driving the a circulation is not altered + ‘When the upright postion is assumed the pull of gravity increases the absolute pressures hicesage core al extremities «© The increment in arterial pressure of lower limb wee 20 i, | vessels is same asthe increment in venous pressure of lower limb veins and hence the o GE Pressure gradient driving the blood circulation in not affected by an increase in arterial pressure t. during standing. $ Effect of gravity on arterial and venous pressure I 88 8 815. | EXPLANATIONS - 2010 Factors Affecting Venous Return (Venous Return is the blood returning to the right atrium via the great yeins) Fiance ‘Thorasie Pump] (“Caria Suetion 77] (Venoustone —] ‘© Rhythmic + Rhythmic ~ The hear plays arole in its own» The tone or caliber ‘muscles while person is standing help respiratory filing of venous vessels in propelling blood towards the heart. movements ‘* During ventricular contraction during quiet + Venous vaves prevent reverse flow the AV valve are drawn standing also and hence help in propelling blood downwards enlarging the arial contributes to towards the heart cavities, Asa result the atrial venous retum + Tichtsleeve of deep fascia coclosing create annegative pressure drops thus inreasing (Increased venous the muscles and deep veins help the intrathoracic the vein wo atria pressure tone enhances ‘muscle pump by allowing a rise in ‘pressure, which gradient. This creates a suction ‘venous return) pressure within the sleeve on ‘tends to suck effect that sucks blood into the muscular contraction (Essentials of blood from the atria and there by enhances: “Anatomy by LB. Singh (2005) /172) peripheral veins __venous retum '* Pulsations of Adjoining arteries may towards the | Note = also compress veins and enhance heart thereby Ths cardia ction eet becomes _yenous retum promoting significant at increased hear rats. t Venous retum | does not make a significant contin fo venous rena daring que standing in mans Answer is D (Mid diastole): Harrison's Advances in Cardiology ‘by Braunwald (202/227). ‘Multislice CT’ by Becker 3° 197; MD CT: A Practical Approach (2006) / 213; MD CT: From Protocols to Practice (2008) / 213; Computed Tomography of the Cardiovascular System (2007) /110 Mid Diastolic phase of the cardiac cycle is associated with the lowest mean motion of the heart “Imaging for electron beam tomography (EBT) is performed during mid- diastole when the heart motion is at minimum’ ~ Harrison's Advances in Cardiology (2002) /227 “The period in which heart has the least motion is usually (but not always) in mid- diastole" ~ ‘MDCT: A practical approach by Saini, Rubin & Kalra (2006) /213 «Early detection of coronary artery disease is possible with the use of Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) + The application of these tools to cardiac imaging is however severely limited by motion artifacts as the heart is constantly in motion completing an entire cycle of contraction and relaxation in about 1 second. + Application of these tools to cardiac imaging requires a ‘Window’ where cardiac motion is minimum to reduce motion artifacts and achieve meaningful images. ‘+ The optimal trigger point for such imaging is the phase of the cardiac cycle when cardiac motion is minimum. This period where cardiac motion is minimum is usually (but not always) the mid diastolic phase of cardiac cycle, just before atrial systoe. Diastole consists of four distinct phase: isometric relaxation, early rapid filling, diastasis and atrial systole. Of these four phases diastasis has the least mean cardiac motion. ‘© The phase of minimum cardiac motion is however variable and depends on several factors especially the heart rate ‘Mid ~diastole represents the phase of minimum cardiac motion only in patients with low [intermediate heart rates As heart rate increases the duration of diastole is shortened and the minimum mid- diastolic motion increases. Incontrast the duration of systole is less affected by changes in heart rate. The late systolic phase provides another window where cardiac motion is low and at high heart rates the lowest motion may be recorded in late systole rather than during mid — diastole. ‘Optima phase for imaging coronary vessel (nina cardiac motion at owintermedate ar rates Mid aiolcphave Optimum phase for imaging coronary vessels (minimum cardiac motion) at high rates is variable and may occur in lat systole.16. 17. ‘+ This phase of minimum cardiac motion also varies on whether the Left Atrium. Right Atrium, Left Ventricle and Right Ventricle are being specifically imaged, Answer is B (Contribute to gaseous exchange) :Guyton 11"/483; Chaudhuri Physiology 6/137; ‘Lung Function’ by Miller (Blackwell) 6/28; ‘Medical Physiology’ by Rhodes & Bell 3/371 Bronchial circulation does not take part in gaseous exchange. Gaseous exchange takes place from pulmonary circulation and not bronchial circulation, al cire mntributes 2% of systemic circulati Bronchial arteries arise directly from the aorta and carry oxygenated blood to the lungs. Total bronchial blood flow accounts for about 1 10 2 percent ofthe total cardiac output (Systemic circulation) Bronchial arteri ‘The main function of bronchial arteries is to provide oxygen and nutrients to the visceral pleura, pulmonary arteries «and conducting airways down to and including the respiratory bronchioles MEE 2010 - EXPLANATIONS circulation ding of blood The mixing of unaxygenated blood with oxygenated blood is called venous admixture. After supplying mutrients and oxygen 10 supporting tissues of lungs the bronchial circulation (deoxygenated blood) empties into the pulmonary veins. Bronchial circulation thus, leads 10 drainage of bronchial venous deoxygenated blood directly into the pulmonary 2 venous oxygenated blood causing venous admixture of blood (shunt) Answer is B (Sodium balance): Lecture notes on Human Physiology 4°/400; ‘Principles of Physiology’ by Pramanik 1°/134; ‘The Respiratory System’ by Davies & Moores (2003)/ 28, 29; ‘Pulmonary Physiology’ (LANGE) 6%/215-226; ‘Fluids and Electrolytes:Made Incredibly Easy’ 4/33; ‘Portable Fluids and Electrolytes’ (2007) /25, 26 As part of the rennin — angiotensin aldosterone system, lungs play an important role in sodium balance. Angiotensin converting Enzyme (ACE) in the lung converts Angiotensin Io the active form Angiotensin II which in turn regulates sodium balance by a variety of mechanism. See Lungs and Liver as pat of the Rennin-Angiotensin-Aldosterone system help regulate sodium and water balance as ‘well as blood pressure. Angiotensin IL ‘ Aldosterone 1 Na’ - H’ Exchange t Thirst Vasoconstriction | ‘Na’ Reabsorption ‘T Sodium Reabsorption Maintains Blood pressure. ae | ‘AIPGMEE 2010 - EXPLANATIONS ee = The lungs are involved ina numberof functions related to defense by a vary of mechanisms ee Normal Mechanical defenses (Filtration Epithelial bariers/ Macaca clearance et) [Naural phagocytic defenses (Macrophages, PMN, Microbial tives eg. Antiproeass 4. Specific Immune defenses (Humoral ell mediated immunity) Meuaboic and Endocrine functions a ‘© Convemion of Angiotensin [to Angiotensin I by Angotensin converting enzyme (Helps in regulation of sodium / water balance end blood presure) Sumesi/Storge/Removal/ Deactivation of vasoative substances Bradyknin, Serotonin Haine and cern prostaglandins are al produced and or tore inte hngs, and maybe released nto the genera circulation under certtn circumstances e , anaphylactic shock Bradykinin, Norepinephrine and certain prostaglandins are also removed / deactivated inthe lungs ‘Sunthssia of Cran Pepides Certain peptides like subsance and some opiates are syathesized inthe lngs Fbrnolytie function Heparin Langs are believed tobe capable of producing substances necessary to delay cotng and/or dissolve small lt (fibrinolysis) ‘+ Pulmonary endothelium is known tobe chin plasmin activator. This converts plasminogen ino plasm which in tim promotes fibrinolysis {The ngs ich in mast el which sere ‘heparin’ an anticoagulant Synthesis of surfactant ‘Surfactants synthesized by type Il volar epithelial ells Reservoir of blood Pulmonary circulation may act as temporary reservoir of blood ‘Acid base Balance “Langs play an important role in ac base balance Cooling and water Balance (Sodium balance) Answer is B (Jejunum): Ganong 23/44] Maximum water reabsorption / absorption from gastrointestinal tract occurs in Jejunum. 2500 500 +1500 a 1000 7000 i 000 #800 Sejunum 5500 “Meum 2000 Colon 1300 otal 3800 Balance in tool 200 Answer is C (Gastrointestinal smooth muscle relaxation): Ganong 23"/ 564; Physiology: Pre Test Reddy 11*/ed 140 Q-152; Sleisenger and Fordtron's Gastrointestinal and Liver Diseases Nitric oxide in Health & Disease (1997/81) The primary role of Nitric Oxide in the gastrointestinal tract is to mediate relaxation of gastrointestinal smooth muscles.a. Nitric oxide (NO) is an inhit moot Je relax: ‘+ Nitric oxide (NO) is a unique chemical messenger produced from L-Arginine by the enzyme Nitric Oxide Synthetase (NOS) ‘+ Three types of Nitric oxide synthetase (NOS) are known and all three forms are expressed in the intestine | NOS I (Endothetial NOS) i 7 | Constitutive / Caleium dependent “W°72%s! “NOS 2 (Inducible NOS): Inducible / Calcium sate +The two constitutive isoforms are present during normal conditions while the indueible form (NOS 2) i apparent only when cells ‘become activated by specific inflammatory cytokines: + NO (along with VIP and PACAP) is accepted as an inhibitory neurotransmitter in the gastrointestinal tract that mediates ‘gastrointestinal smooth muscle relaxation, via the guanyleyclase pathway. + Unlike most neurotransmiters and hormones, NO doesnot act via a membrane bound receptor®, Instead NO ready diffuses into adjacent target cells to directly activate guanleyclase and mediate smooth muscle relaxation Answer is A (Stimulation of Adrenergic fibers) : ‘Chronic Pain : A Primary Care Guide to Practical Management’ by Mercus 2™/385, Principles and Practice of High Dependency Nursing’ by Sheppard (Elsevier)2000/297 ‘Stimulation of adrenergic fibers appears to be the single best answer amongst the options provided Relief of pain associated with abdominal spasm by the application of hot water bottle can theoretically be best explained by the ‘Gate control theory of Pain’. Heat therapy with a hot water bottle stimulates the ‘A’ and ‘C’ fibers thereby blocking pain impulses transmitted through visceral ‘C’ fibers. Since these fibers are largely sympathetic (adrenergic) stimulation of adrenergic fibers is the single best answer By exclusion Relief of pain by Hot Water f Theory of ikel Relief of pain associated with abdominal spasm by the application of hot water bottle can theoretically be best explained by the ‘Gate control theory of Pain’ lccording to the Gate Control Theory. painful impulses must first pass through a “gate” in the spinal cord before they can be interpreted as ‘pain’ in the brain. Non painful stimuli such as touch and temperature ‘activate other (larger) nerve fibers that block /close the gate to the painful stimuli and thereby inhibit the ception of pain Visceral pain from the gastro intestinal tract is largely mediated by pain relaying ‘C’ fibers that run almost exclusively in the sympathetic (adrenergic) system. These incoming pain signals from gastro intestinal spasm can be inhibited / blocked from reaching the brain (perception of pain) by closing ‘the gate’ at the level of spinal cord. Heat impulses from hot water bottle are transmitted through larger A fibers and C fibers and these may close /block ‘the gate’ to painful impulses transmitted through ‘C’ fibers from the gastro intestinal viscera. Relief of pain with hot water bottle thus involves modulation of sympathetic (adrenergic) pathways through stimulation ofthe ‘A’ and °C’ fibers thereby blocking the pain sensations carried by sympathetic (adrenergic) small °C’ fibers from gastrointestinal viscera. Stimulation of Adrenergic fibers (A and C) is therefore the single best answer by exclusion. Answer is B (Epinephrine): Ganong 23°/326, 327, 382; Greenspon's Clinical Endocrnology 8/115 The net effect of epinephrine / nor-epinephrine is inhibition of insulin secretion ‘Catecholamines (Epinephrine/Norepinephrine) and Insuli Catecholamines have a dual effect on insulin secretion. They inhibit insulin secretion via a2 adrenergic receptors? They stimulate insulin secretion via adrenergic receptors? The net effect of epinephrine and nor-epinephrine on insulin secretion is inhibitory Note /fcatecholamines are infused after administration of a adrenergic blocking drugs the ee Converted into stimulation due to unopposed action via f- adrenergic receptors. Growth hormone stimulates Insulin secretion2. EXPLANATIONS - 2010 Growth hormone does not stimulate beta cells of the pancreas directly but it increases the ability of the pancreas to respond to insulinogenic stimuli such as arginine and glucose Growth hormone inhibits insulin stimulated glucose uptake and use thereby producing a profound stimulation of insulin release by hyperglycemia. retin © Cholecystokinins (CCK)? © Gasiric Inhibitory peptide (GIP)® © Glucagon? Answer is A (Estrous cycle): Novak's 14/172; William's obstetrics 23°/36; Biology of Human Reproduction I" (2002)/128 Estrous cycle is not seen in Humans. Humans undergo a ‘menstrual cycle’ which can be divided into the ‘ovarian cycle’ and an ‘endometrial cycle’ depending on the organ (ovary or endometrium) under examination. “The normal human menstrual cycle can be divided into two segments the ovarian cycle and the uterine (endometrial) eyele based on the organ under examination. The ovarian cycle may be further divided into follicular and luteal phases whereas the uterine (endometrial) cycle is divided into corresponding proliferative and secretory phases'-Novak's 149/172 ‘Normal Human Menstrual Cycle I ! Ovarian Cycle _|*—| Hormonal Cycle |—+| Endometrial | | Menstrual Cycle24, 28, There are two types of female cycles, the Estrous cycle and the Menstrual cycle The estrous cycle is typically seen in mammals while the menstrual cycle is typical of human females, Human females undergo a menstrual cycle and not an estrous cycle. The ovarian cycle and endometrial cycle are components of the normal human menstrual cycle and consist of respective jelical changes in the ovary and endometrum during the menstrual cycle. ‘© Seen in ‘Non Menstruating’ species including» Seen in ‘Menstruating' species including most ‘mammals’ humans and higher primates Se es Setoahe/ hoon ed 1 does not occur — eonception does not occur ‘+ Females are sexually receptive fo males only «Females can be sexually receptive to males at around the time of ovulation and this is called any time of the cycle unrelated to time of the ‘Estrous phase’ (being in heat) of the cycle ‘ovulation Answer is C (Resting tremor): Repeat Resting tremor is a feature of a lesion in the basal ganglia such as Parkinson’s disease. Cerebellar lesions are associated with intention tremors and not resting tremors. Answer is B (Hypothyroidism): Neurological Differential Diagnosis : A Prioritized Approach (2005)/ 492, Interpretation of Diagnostic Tests by Wallach 8/315 Hypothyroidism / Myxoedema is associated with elevated CSF protein levels. Decreased CSF protein may be seen in Hyperthyroidism. F Protein G (CSF leaks and Removal of Large CSF volume + Repeated Lumbar Punctures + During Pnewmoencephalography + Traumatic leaks® + Removal of CSF for eytologie studies Acute water Intoxication nts with acute water intoxication may have increased ICP with reduced CSF proteins, Pseudotumor cerebri or Benign intracranial Hypertension ‘+ About one third of patients with pseudotumor cerebri have low CSF protein ‘Hyperthyroidism ‘» Decreased CSF protein may occur in Hyper parathyroidism (Hypothyroidism / Myxoedema is associated with increased CSF proteins) Children between 6 months to 24 months of Age Answer is A and D (Lean body mass and Body surface area): Refer Text for References Basal Metabolic rate depends on both the lean body mass and the body surface area and both ‘Lean body mass’ and ‘body surface area’ correlate closely with the basal metabolic rate. Overall, however, the Basal Metabolic Rate appears to be slightly more closely related to lean body mass than the body surface area, and hence the single best answer of choice amongst the options provided should be Lean body mass26. |AND EXPLANATIONS - 2010 ‘1 box wurface “BMR is more closely related to ‘lean body mass" tha ‘surface area’- Human Nutrition and Dietic's by Davidson “Basal Metabolic Rate is more closely related to the weight of the fat free portion of the body ‘the lean body mass” than to surface area’ ‘Biochemist's handbook” by Long “Basal metabolic rate have been traditionally normalized by expressing them in relation 1o body surface area, but data now show that they are more closely (and more logically) correlated with lean body mass’- ‘Obesity’ by Brodoff “The correlation between BMR and lean body mass (determined by under water weighing) was 0.92, greater than that _for body surface area which was 0.84’ ~ Children’s exercise physiology” by Rowland Energy Expenditure during Resting State Resting Energy Expenditure (REE) Basal Metabolic Rate (BMR) ‘Gender (Males higher than Females) Age (Decreases with Age) Body Temperature (Increases with fever) “Lean body mass refers to fat free tissue ina living Environmental temperature (Increases in cold) ‘organism and gives an estimate of metabolically active Thyroid status (Increases in hyperthyroidism) components (muscles and internal organs) Pregnancy & Lactation (Increased) Body Surf f Fasting/starvation/malnutrtion body mass Siress/emotional state/Sleep Answer is A (Obesity) : Ganong 23/462; Harrisons 17"/462, 467 ‘ Understanding Nomal & Clinical Nutrition’ by Whitney (2008)/255 Obesity may be associated with a decreased Basal Metabolic Rate and isthe single best answer amongst the options provided. ‘An obese individual has a lower basal metabolic rate than a non-obese individual of the same weight Obesity and Basal Metabolic Rate Obesity by definition is an increase in the amount of adipose tissue mass or fat mass. Adipose tissue is relatively inert from a metabolic rate. Basal metabolic rate depends on the amount of metabolically active tissue or the lean body mass. ‘An obese individual has higher proportion of fat relative to lean body mass than a non- obese individual with the same weight, and hence a lower basal metabolic rate. When adjusted for weight, an obese individual (more fat/adipose tissue) has lower basal metabolic rate than a non obese individual ‘Obese individuals have also bee observed to have lower energy expenditure than lean individuals when reduced to near normal weight. There is also a tendency for those who develop obesity as infants or children to have lower resting energy expenditure (Lower BMR) than those who remain lean'- Harrisons 17"/467 Hyperthyroidism is associated with increased Basal Metabolic Rate Thyroid hormones stimulate basal metabolism. Thyroxine is a key regulator of the Basal Metabolic Rate. The higher the thyroxine levels, the higher is the BMR Feeding and Exercise are associated with an increased Metabolic Rate Basal metabolic rate by definition is determined at ‘rest’, '12-14” hours afer the last meal Feeding and Exercise therefore should ideally not be related to the Basal Metabolic rate. Nevertheless, both exercise and recent ingestion of food (feeding) are associated with an increase in the metabolic rate. An increased BMR will be recorded if the BMR is measured after exercise or food intake. Factors Affecting the fLean Body Mass (Body composition) ‘Body surface Area (BSA) (Height / weight / surface area) Age Gender Fasting starvation malnutition Steep Growth Prognancy (Lactation S000 Suesses Entional State Environmental temperature Bauly Temperature (Fever) GM Deereases he ak STN Relative proportion of lean body mass to adipose tissue determines the basal metabolic rate ‘Obese mdi wer basal metabolic rate compared to non obese individuals ofthe same weight as they have lower proportion of lean body mass 1 Women have lower basal metabolic rate compared 1 men ofthe same weight as thes have lower proportion of lean body mass (more ft) can body mass diminishes with age slowing the BMR, Sthe BMR because [BM decreases with age (as lean body mass decreases) BMR is higher for males Wan females (Males have higher proportion of lean body mass relative to adipose tissue /fat) Decreases the BMR The BMR is higher in growing children Increase the BMR ee “Detteated environmental temperature raises the BMR. © Raises the BMR Musclr Excreon/ Exec nes he metabo Rte Rese lneion sind neem the meno Rte SE BIOCHEMISTRY 27. Answer is B (Beta configuration of anomeric C2): ‘Food and Nutrition supplements: Their role in health and disease’ (Springer) 1" (2001)/130; ‘Colonic Microbiota, Nutrition and Health’ by Gibson & Roberfroid 1" (1999)/105 Resistance to digestion of ‘inulin like fructan' prebiotics results from the presence of beta configuration of anomeric C2 in fructose monomers “The beta ~ configuration of anomeric C2 in their fructose monomers makes inulin type fructans resistant to hydrolysis ‘by human digestive enzymes (alpha- glucosidase, maltase ~ isomaltase; sucrose) which are mostly specific for alpha- osidic linkages’. Food & Nutrition Supplements (Springer) 1"/130 Inulin type Fructan Prebiotics + Prebioties are non digestible food ingredients that beneficially affect the host by selectively stimulating the growth or activity of health promoting (advantageous) colonic bacteria such as lactobacilli and bifidobacteria. Prebiotics should pass harmlessly through the upper digestive tract and be a substrate for selective probiotic agents in the large bowel Inuit a rarides - NDO) are by for the most extensively studied compounds and the most widely used prebiotics (presently) They resist hydrolysis by enzymes (and acid) in the upper GIT due to the nature of their glycosidic linkages. “The beta configuration of anomeric C2 in fructose monomers is thought to make inulin type fructans resistant to hydrolysis by human digestive enzymes which are mostly specific for Alpha -osidc linkages they also resis the acid hydrolysis in the stomach’ Enzymes that digest oligosaccharides such as Alpha glucosidase, maltase, isomaltase, sucrose are present in the er GIT, but these are not able to digest inulin like fructans due to the nature of their glycosidic linkages Inulin like fructans pass through the small bowel without degradation and without inhibiting the absorption of nutrients and minerals especially calcium, magnesium & iron (Absorption ofthese nutrients is actually improved) Inulin like fructans thereby reach the colon in an intact form and here they act as substrates for beneficial (probiotic) bacteria that have health promoting activities like lactobacilli & bifidobacteria AIPGMEE 2010 - EXPLANATIONS28. g 2 g z a 5 2 a 8 = = 2 29. Answer is A (Maple Syrup urine disease): Harper 28/258, 259; Harrisons 17/2472, Nelson's 18/540; Ghai 71632; CPDT 19°/ 968 Maple syrup urine disease is caused by a defect in decarboxylation of branched chain ketoacids (derived from branched chain amino acids leucine, isoleucine and valine) due to an inherited defect in branched- chain- ketoacid dehydrogenase enzyme. Condition ‘Maple syrup urine disease Oxidative decarboxylation of branched chain ketoacids due to inherited deficiency of enzyme branched-chain-ketoacid dehydrogenase Hartnup disease Det ne ape ern necro ae So Tay ‘amino acids) by intestinal mucosa and renal tubules Alhaptonuria Defect in the breakdown of Homogentisic acid due to deficiency of enzyme Homogentesic acid oxidase ‘Maple syrup Urine Disease (Branched chain ketoaciduria) + This an autosomal recessive disorder resulting from a defect inthe metabolism of branched chain amino acids Leucine, Isoleucie and Valine®. ‘= It results from deficiency of the enzyme® ‘branched chain ketoacid dehydrogenase’ which catalyzes oxidative decarboxylation of the branched chain keto acid derivatives of leucene, isoleucine and valine. ‘Branched chain AA: Leucine, Isoleucine, Valine “Branched chain ketoacid dehydrogenase" _| (This enzyme uses Thiamine (Vitamin Bl) as coenzyme® | Oxidative decarboxylation of branched chain ketoacid derivatives of _| leucine, Isoleucine & valine ‘This leads to accumulation of branched chain ketoacids and their corresponding aminoacids in the serum, CSF and urine. The characteristic odour of urine (Maple syrup) is believed to result from accumulated ketoacids of leucine & isoleucine Answer is A (Niemann Pick Disease) : Ref: Harper 28/210; Harrison's 17"/2452-2457 ‘Niemann Pick Disease is an autosomal recessive disorder that results from defect in acid sphingomyelinase. Ex dos “Disease “Enzyme Deficiency Tay-Sachs disease Hexosaminidase A GM2 Ganglioside Mental retardation, blindness, muscular weakness all = e@-Galactosidase —__Globotriaosyleeramide ‘Skin rash, kidney ftir” . (ll yrptoms ony in aes Metachromatic _-Arylsulfatase A -—-—3-Sulfogalactosyleeramide ‘Mental retardation and psychologic Teukodystrophy disturbances in adults; demyelination (Krabbe's disease Galactosidase Galuciosyleeramide ____- Mental retardation; myelin almost absent Gaucher's disease B-Glucosidase Glucosyleeramide Enlarged liver and spleen, erosion of long bones, mental retardation in infants } Farber's disease Ceramidase Acyl|-Sphingosine Ceramide Hoarseness, dermatitis, skeletal deformation, ‘mental retardation; fatal in early life A more elaborate tabular description is given in Harrison's 17"ed 2452 Answer is D (Chylomicrons): Chatterjea Shinde 7"/418; Harper 27/212 Chylomicrons do not migrate on electrophoresis and remain atthe origin. (On electrophoresis Chylomicrons remain at the origin, LDL migrate into f- globulin region, VLDL migrate into pre-B globulin region while HDL migrate into a, globulin region.a 32. Classi of Lipoproteins on in El sis ‘+ Classes of lipoproteins may be separated from one another based on their density or on their electrophoretic properties. ‘+ Electrophoretic properties of lipoproteins are based on their charge / size ratio and plasma lipoproteins separated by technique are classified in relation to comparable migration of serum proteins. si Df teins on Electrophoretic mobili [Gilomicron’s Remain at origin (Do not migrate) terse: Pre i Region (Pre - B- Lipoproteins) “B Region (B-Lipoproteins) “HDL a Region (a- Lipoproteins) Answer is B (lon - Exchange chromatography): Harper 27"/21, 22, 23; Chatterjea-Shinde 7/770; Satyanarayana 3/723 Chromatography involving the separation of molecules on the basis of charge is called Ion-Exchange chromatography. Ton Exchange chromatography with anion- exchange resins (anion exchangers) in solid stationary phase will selectively exchange negative ions from the stationary phase with negative ions from the mobile phase. As a result the negative ion from the stationary phase will move into the positively charged ion in the mobile phase while the negatively charged ion from the mobile phase will move into the positively charged ion in the stationary phase. + Ton Exchange chromatography involves the separation of molecules on the basis of their electrical charges ‘+ Chromatography consists of a mobile phase (liquid) and a stationary phase (cation or anion exchange resins) ‘Mobile Phase Ths refers to the mixture of molecules tobe separated dissolved in iguid ‘Sationary phase: | This refers toa porous solid matrix beads made up of cation or anion exchange resins through which the mobile phase percolates «Ton exchange Resins can accordingly be cation exchangers or anion exchangers based on the charge of the exchange ‘Net charge on Resins in Negative and these attract attract anything that has @ negative charge in any thing that has a positive charge in the mobile the mobile phase phase ‘+ These resins exchange their anions (weaker) ‘+ These resins exchange their cations (weaker) with ‘with any other anion (stronger) in the mobile any other cations (stronger) in the mobile phase phase RA + B =RBS A wR =CR+ (Stationary) Negatively Goes towards (Stationary) Positive Goes towards phase Resin changed positive charge phase Resin changed negative charge molecule in mobile phase molecule in mobile phase in mobile in mobile phase phase + Anion exchange Resins thereby exchange + Cation exchange resins thereby exchange positive negative ions from stationary phase with ions from stationary phase with positive ions from the negative ions from the mobile phase mobile phase. sa result the negative ion from the Asa result the positive fon from the stationary stationary phase (A) is released and moves: ‘Phase (H') is released and moves towards negative towards positive charge in the mobile phase. ‘charge in the mobile phase. * The Net charge on molecules varies with pH and hence the binding abilities of ions bearing positive or negative charges are highly pH dependent. + The bound molecules may thus be eluted out one by one with an cluting buffer ofa suitable pH (Buffer with a pH gradient). Answer is D (Ketones): Satyanarayana 3/295; ‘Practical Biochemistry for Students’ by Malhotra 4%/e 43-47, ‘Laboratory Manual of Biochemistry’ by Chary & Sharma (2004) /21 Rothera’s test is used for detection of ketone bodies in urine.~~ Ketone Bodies + Foucher's test” + Rosenbach's test + Gmelin’s test Bile salts + Hay'stex® + Ehrlich’s test ‘+ Rothera’s Test” © Gerhardt's Test? Ketone bodies in Urine and their detection + Ketone bodies represent intermediate products of fat catabolism that may accumulate in the blood in certain states like diabetes mellitus and starvation ete ‘+ They are exclusively produced in the liver? + These products of fat catabolism? that are collectively called ketone bodies include acetone®, acteoacetic acid (diacetic acid)? and betahydroxybutyric acid? ‘Acetoacetic Acid Loses CO, Acetone Reduced Beta-hydroxy-butyric acid ‘+ In normal individuals the concentration of ketone bodies in blood is maintained around 1 mg/ 100 ml. Their excretion in urine is very low and they are undetectable by routine tests, + In certain conditions like Diabetes mellitus (Diabetic ketoacidosis) and Starvation, there is overproduction of ketone bodies in the liver due to abnormal fat catabolism. ‘+ These ketone bodies serve as alternate sources of energy for several peripheral tissues especially brain and other parts of CNS. during periods of food deprivation ‘Ketone bodies can meet 50-70% of brain's energy needs®. This is an adaptation for survival of an organism «Excessive ketone bodies in urine can be detected by special tests including Rothera’s test and Gerhardt’s test. eS s ‘Rothera’s test Gerhardt’s test + This is atest to detect acetoacetic acid and acetone ‘© This tes is also called the ‘Nidroprusside test ® Principle ‘itroprussde in alkaline medium reacts with ketones o give permanganate colour (purple / pink) Reagents + Ammonium sulphate (Solid) «+ Sodium Nitroprusside + Concentrated Ammonia Procedure + Saturate 5 ml of urine with ammonium sulphate and sodium nitroprusside (Rothera’s mixture) Add 2 ml of concentrated liquor ammonia by the side of tet tube + Appearance of permanganate ring (purple/ pink) at junction indicates the presence of Ketone bodies in urine ‘© This is atest to detect acetoacetic acid. ‘© This testis also called the ‘Ferrie chloride test ® Principle ‘A ferric chloride reacts with Acetoacetic acid to sive a red — wine colour Reagents ‘Ferric chloride solution cedure © To3:ml of urine at ferric chloride solution drop by drop ‘© Appearance of red wine colour indicates the presence of ketone bodies in urine Note: Benedict's test (Test for presence of reduci is used for di tive Rothera'stest® The urine of a patient with diabetic ketoacidosis will give positive Benedict's test as well as positive Rothera'’s test. The urine of a patient with starvation will give a negative Benedict's test but a positive Rothera’s test33. 38. Answer is A (SGOT /AST): The Textbook of Hepatology 3%/451; ‘Clinical Laboratory Medicine’ by Clatchey 2“/286,287 Inside the liver SGOT / AST is predominantly mitochondiral. SGOT has two isoenzymes ~ cytosolic and mitochondrial. Inside the liver SGOT (AST) is localized mainly in the ‘mitochondria (80%) with the remainder in the cytosol. Liver enzymes Mitochondrial Membrane Bound je SGPT (ALT) [* SGOT (AST) (Mitochondrial isoenzyme) | [+ Alkaline phosphatase + LDH }+ Glutamate Dehydrogenase (GDH) * GGT [+_ SGOT (AST) Cytosolic isoenzyme) J+_5 Nucleotidase ‘Cytosolic & Mitochondrial enzymes are used as evidence of hepatocellular damage. | {Membrane bound enzymes are used as evidence for cholestasis Answer is D (Microarray): Harrison's 17°/390, 406 Microarrays allow the detection of variations in DNA sequences and enable description of gene expression comprehensively for the entire genome. Microarray technique is the most powerful tool for screening gene expression profiles of biological samples. ‘© Microarray tech ue is the most powerful tool for screening gene expression profiles of biological samples ‘+ This technique allows researches to explore expression patterns of thousands of genes (entire genome) in a single analysis ‘+ This technique is based on the principle of nucleic acid hybridization like Southern blot or Norther blot tests, but allows simultaneous study of multiple genes rather than the study of single gene / sequence with the latter. ‘+ Microarrays = Mic 8 it These can be used for Identity diagnostic or prognostic markers ences and a Genetic fingerprinting of different types of diseases / malignancies Classify diseases (that are indistinguishable by microscopic examination) Understanding pathophysiology of diseases especially mechanism involved in genes of disease processes These technigoes in molecular biology ae Eaed on te fundamental pani of bridization” ‘+ Hybridization isthe process by which two complementary strands of nucleic acid, bind or hybridize to one another in accordance with Watson — Crick rules (Adenine (A) binds to Thymine (T) and Cytosine (C) binds to Guanine (G)) ‘+ This DNA Hybridization is the basis for Southern blot analysis, Northern blot analysis as wel as Microarray technology. | [Techniques that allow the study /expression of a single _Bene / sequence within a sample (target) genome [Technique that allow the study /expression of multiple | enes (entire genome) within a semple (target) genome ‘© Southern blot (DNA sequence) ‘= Northern blot (RNA sequence) ‘© Microarray Technique (DNA7 RNA) “These techniques form the basis of the newer microarray technique but are only capable of describing the behavior of a single gene in a population pathway or environment This technique allows researchers fo explore expression patterns of thousands of genes (entire genome) within a ‘sample and allows extensive gene expression profiling. It ‘can be considered as multiple Southern or Northern blots ‘analysis running in parallel. Microarray technology has revolutionized the way genetic information can be used and analyzed Answer is D (Microarray) : Harrison 17"/406 Microarray based techniques are currently not used for detection of Specific Aneuploidies. Microarray is the single best answer of exclusionFluorescent in situ hybridisation (FISH) and Polymerase chain Reaction (PCR) based tests including QF-PCR and RT-PCR are commonly used for rapid detection of common specific chromosomal aneuploidy. Microarray based Array- Comparitive Genomic Hybridization (a-CGA) is a relatively new technique that is complementary to conventional cytogenetic analysis (karyotyping) and fluorescence in situ hybridization (FISH). This technique has the ability 10 detect genomic imbalance including deletions, duplications and aneuploidies at a whole- ‘genome level. This technique may be currently used as a high resolution whole genome scan for the detection / screening of unknown abnormalities rather than for specific aneuploidy detection, Also, a microarray based CGH cannot detect balanced translocations or inversions ‘Microarray based CGH is better suited for screening unknown abnormalities than FISH, which is limited to probing specific chromosomal regions’ Answer is A (PCR): ‘Pediatric Hematology: Methods & Protocols’ by Goulden (2004)/65; UKHCDO Official Publications Guidelines (www. ukhcdo.org); ‘Exploring Genetic Mechanism’ by Singer & Berg (1997); Atlas of Genetic Diagnosis & Counciling” by Chen (2006)/478; ‘Advances in Genetics" by Hall (volume 32) (1995)/121 Prenatal diagnosis of Hemophilia is best done by Direct Mutation Analysis using PCR technique Linkage analysis may be used for prenatal diagnosis, but this has been largely superseded by direct mutational analysis involving PCR techniques. The preferred method of prenatal diagnosis of hemophilia is chorionic villous sampling at between 11 and 13 weeks of _gestation and performance of direct mutational analysis. Direct testing can determine unequivocally whether the proband has inherited the disease causing mutation and has become the gold standard for prenatal Prenatal diagnosis of hemophilia is based on demonstrating causative DNA mutation ‘Two general approaches are used to detect relevant mutations, namely, indirect approaches using linkage analysis and direct approaches identifying specific changes in the DNA sequence (Direct Mutaional anaysis) + Direct mutational analysis is now the method of choice for prenatal diagnosis of Hemophilia al Direct Mutational Analysis =a ‘Tndireet Linkage Analysis sic) ‘© Direct mutational analysis involves identification of the specific mutation / base pair change that is responsible for hemophilia based on the DNA sequence of the gene ‘Analysis of DNA from multiple family members is ‘usualy not required as this method is not based on the segregation of genetic markers «This method involves physical isolation and sequencing of the gene and can unequivocally determine whether the proband has inherited the disease «Direct mutational analysis is now the method of choice for prenatal diagnosis of hemophilia . analysis methods are general ‘based on the Polymerase Chase Reaction (PCR) technique and begin with PCR amplification of regions of the gene in question ‘PCR based methods are favoured for mutational ‘analysis +P if js followed by the use ofa detec technique DNA sequencing is the gold standard detection technique for mutation detection ther techniques for mutation detection include GHPLC (denaluring High Performance Liqui chromatography) , CSGE (Conformation sensitive Gel Electrophoresis) etc, ‘+ Indirect linkage analysis involves segregation of genetic ‘markers known to be linked to a gene responsible for ‘hemophilia and ths is used to determine whether an individual has inherited a chromosome that carries the abnormal gene ‘© Analysis of DNA from multiple family members is required to identity the markers that segregate with the abnormal chromosome in each affected pedigree ‘© This method does not involve physical isolation sequencing ofthe gene ‘Linkage analysis has now been largely super by direct ‘mutational analysis which is currently the method of choice for prenatal diagnosis of HemophiliaDe, PHARMACOLOGY 37, Answer is B (Lithium): ‘FDA: Centre of Drug Evaluation & Research: Guidance’ (Official publication of he FDA) Lithium has a narrow therapeutic index and is included in the list of drugs labeled as ‘Narrow Therapeutic Index’ Drugs (NTI) by the FDA. Therapeutic index is a quantitative measure of the safety of a drug ‘Therapeutic index is defined as the ratio of Lethal / Toxic dose in 50% of population (LDso) over the median ‘minimum Effective dose (ED;o) in 50% of subjects «The FDA has defined Narrow therapeutic Index Drugs (NTI) as drugs where the difference between the minimum effective concentration and minimum toxic concentration is les than 2 fold + The FDA has accordingly named approximately 25 drugs having a narrow therapeutic index (NTI) Lithium is included in the list of NTI drugs Drug Generic i) Amphotericin B Lithium Aminophylline Metaproterenol sulfate Carbamazepine (Tegretol) ‘Minoxidil = Clindamycin Prazosin hydrochloride a Digoxin Primidone | Dimercapro! Procainamide hydrochloride Ethinyl estradiol/progestin oral Quinidine sulfate contraceptives Guanethidine sulfate Theophylline Isoproterenol sulfate Warfarin (Coumadin). 38. Answer is C (Omeprazole): KDT 7/651; KDT for Dentistry 1"/265 Omeprazole is a proton pump inhibitor. Ranitidine and Loxatidine are H2 antihistamines, while Misoprostol is a prostaglandin analogue. ‘Drugs Reducing gastric acid secretion ot, 12 Antihistamines] [Proton Pump Inhibitors | [— Anticholinergic Prostaglandin Analogues + Ranitidine + Omeprazole + Pirenzepine + Misoprostol = Cimetidine + Lansaprazole + Telenzepine + Famotidine + Pantaprazole + Propantheline + Roxatidine + Rabeprazole + Oxyphenonium + Loxatidine + Esmeprazole + etc + Nizatidine 39. (a) Answer is D (Beta-2 Receptor stimulation): Katzung 11/345; Current Review of Asthma (2003)/ 174, 175 Beta -2 Receptor stimulation has not been proposed as a mechanism of action for theophylline. Several mechanisms have been proposed for the actions of methylxanthines (eg theophylline), including Phosphodiesterase inhibition, Adenosine Receptor inhibition, and enhancement of Histone deacetylation. etunet cons gaeetin cs « Inereased Histone Deaceaylose nets (Ted abicncy ef Carcbaerohls) ee ee39. 40. 41. (b)Answer is A (Phosphodiesterase Inhibition): KDT 7/224; Katzung 11/345 Theophylline (Methyl xanthine) is a non selective phsphodiesterase inhibitor. Inhibition of phosphodiesterase is proposed as the most important mechanism of action of theophylline, ‘Theophylline is a non selective phosphodiesterase inhibitor. Phosphodiesterase enzyme is involved in degradation / Indrolysis of cyclic nucleotide (cAMP/GMP). Cyclic nucleotides are responsible for a myriad of cellular function including relaxation of smooth muscles and reduction of inflammatory activity of specific cells. Theophylline increases the concentration of cyclic nucleotides by inhibiting phosphodiesterase and thereby helps Bronchial asthma by relaxation of smooth muscles and ~ reduction of inflammatory activity. Note: Of the various isoforms of phosphodiesterase that have been identified the, PDE 4 isoenzyme appears to be ‘most directly involved in action of methylxanthines n bronchial asthma, Theophylline is anon selective PDE | inhibitor, but selective inhibitors of PDE4 isoenzyme are being developed eg Roflumilast, Cilamilast, Tofimilast) _| T [7 Mast cell] [Anti-lge Antibody Pinte > Sodium [> Omalizumab Cromoglygate J» Bambuterol Aminophylline Je ete le Ketotifen Je Salmeterol Doxophyili Formoterol [Sclestive PDE« inhibitors J+ Ephedrine |» Roflumilast l- ere J+ Cilamilast |» Tofimilast ete SuSE Je Iprapium Bromide | Note J+ Tiotropium Bromide | Several mechanisms offor action of etc ‘methylxanthines have been explained including PDE inhibition Answer is B (Pregnancy Induced Hypertension): KDT 7/566, Goodman Gillman's Manual of Pharmacology (2007)/550 Methyl-dopa is the drug of choice for pregnancy induced hypertension ‘Methyl-dopa is the preferred drug for treatment of hypertension during pregnancy based on its effectiveness and safety ‘for mother and fetus ~ Goodman Gillman’s Manual of Pharmacology (2007)/550 “Methyldopa is infrequently used now except to treat hypertension during pregnancy’ ~ KDT 6/547 Answer is D (Naloxone is more potent than Naltrexone): Kaplan & Saddock’s Pocket hand book of Psychiatric Drug Treatment 4/179, 180; Katzung 11/548; Goldfrank's toxicologic emergencies 8/615; Goodman & Gillman's Manual of Pharmacology (2007)/364, 365 Naltrexone is much more potent than Naloxone. Naltrexone is more potent than Naloxone “Naltrexone is much more potent than nalaxone and 100 mg oral doses given to patients addicted to opioids produce concentrations in tissues sufficient to block the euphorogenic effect of 25 mg intravenous doses of heroin for 48 hrs, = Goodman & Gillman’s Manual of Pharmacology (2007)/365 ‘Naltrexone is three to five times as potent as Naloxone’ ~ Modern Pharmacology with Clinical Applications 6/327 ‘Naloxone can be used for treatment of opioid induced constipation when given orally“Opioid induced constipation that is refractory o laxatives may be treated with oral Naloxone. Oral Naloxone can reverse opioid induced constipation without precipitating withdrawal because ofits extensive hepatic first pass metabolism, which leads to low plasma levels’ - Manual of Clinical Oncology 6"/115 Naloxone Nalrexone Nalfemine 4 4+ + ‘Oral bioavailability minimal (<10%) ] [Oral bioavailability (60%) ‘Oral Bioavailability (50-60%) + + Does not precipitate opioid withdrawal + Precipitates opioid withdrawal Precipitates opioid withdrawal on {in most patients on oral administration on oral administration ‘oral administration Methyleno Dioxy methamphetamine (MDMA, Ecstasy) Sibutramine Serotonin Syndrome «Serotonin syndrome refers to a dangerous / potentially fatal syndrome caused by excess synaptic serotonin levels due to the use of serotonin potentiating drugs + Serotonin syndrome is diagnosed on the basis of recent history of administration of a serotonergic drug and characteristic clinical presentation ‘+ Diagnostic criteria have been devised for the clinical diagnosis of serotonin syndrome based on Mental (Cognitive / Behavioral) symptoms, Autonomic symptoms and Neurological symptoms. (ese Nilo Ea Ss Re ‘Mental Cognitive / Behavioral Confusion / Altered consciousness + Restlessness. ‘Symptoms Elevated mood © Insomnia ‘Neurological Symptoms52. 53. ‘AIPGME EXAMINATION + Serotonin syndrome is diagnosed by the presence of atleast 4 major symptoms or 3 major plus 2 minor symptoms following the addition or an increase in dose of a known serotonergic agent. + Therapy essentially involves sedation (benzodiazepines), paralysis, intubation & ventilation. ‘Serotonin blockage with Cyproheptadine or chlorpromazine may be considered. Answer is A > B (Pethidine > Pentazocine): Previous question Concurrent use of either Pethidline (Meperidine) or Pentazocine with MAO inhibitors can potentially precipitate the “Serotonin syndrome’ and hence both Pethidine and /or Pentazocine should not be used with MAO inhibitors However, amongst pethidine (meperidine) and pentazocine, pethidine is more strongly associated with a risk of serotonin syndrome and hence is the single best answer of choice amongst the options provided. * Pethidine / ao +» Pentazocine® + Dextromethorphan Tramadol These agents can inhibit serotonin reuptake and hence precipitate serotonin syndrome. Answer is A (Chloramphenicol): Harrison's 17/2626; Jawetz 24%; ‘Antimicrobial Drug Resistance’ by Mayers (2009)/776 Chloramphenicol is recommended for patients with penicillin and cephalosporin resistance or allergy Penicillin G is the drug of choice for meningococcal meningitis caused by susceptible strains. Third generation cephalosporins (ceftriaxone and cefotaxime) should be substituted if penicillin resistance is found. Chloramphenicol is recommended for patients with penicillin and cephalosporin allergy “Agent "Drug of choice, ‘Meningococcal PenicilinG ‘Third Generation Cephalosporis Chloramphenicol z ‘Meningitis (orAmpicilin) "Ceftriaxone or Cefotaxime eee Answer is D (Platelet count): Goodman & Gillman’s Manual of Pharmacology (2007)/780; Katzung 11"/804; British National Formulary (BNF) Issue 51/294 Platelet count should be monitored in patients receiving linezolid therapy. ‘Platelet counts should be monitored in patients with risk of bleeding, preexisting thrombocytopenia, or disorders of platelet function and in patients receiving therapy for > 2 weeks’ ~ Goodman & Gillman's Pharmacology ‘tt is recommended that Full blood count (including platelet count) should be monitored weekly in patients who receive linezolid’ British National Formulary (BNF Issue 51/294) C ‘Minor Side Effects ] [Relatively Significant Side effects (Rare / Uncommon) ‘Gastrointestinal side effects (most common) ‘> Myelosuppression = Nausea / vomiting / diarrhea = Thrombocytopenia (Most common) = Tongue discolouration = Anemia / Leukemia / Pancytopenia have also been + Headache reported Rash ‘+ Optic & peripheral neuropathy (prolonged course) The principle relatively significant toicity of linezolid is hematologic. Myelosupression including anemia, leucopenia, jopenia and thrombocytopenia have all been reported. Thrombocytopenia is the most common manifestation seen in approximately three percent of treatment courses, particulary when the drug is administered for longer than two weeks. Thrombocytopenia is usually mild and reversible. Parents receiving linezolid should be monitored with weekly ‘blood counts (including Platelet counts) especially in patients with risk of bleeding, preexisting thrombocytopenia, [disorders of platelet function, predisposition to or underlying bone marrow suppression and in patients receiving therapy > 2 weeks.57. -2010 Answer is D (Most common side effects are diarrhea and euphoria): Katzung 11°/1028, 973, 974; Goodman & Gillman’s Manual of Pharmacology (2007) / 897 Most common side effects of Thalidomide are sedation and constipation. “The most common adverse effects reported in cancer patients are sedation and constipation while the most serious one is treatment emergent neuropathy" - Goodnan & Gilman lor hi reintrod ivity in ENI “Thalidomide has been reintroduced in clinical practice as an oral agent for the management of Erythema Nodosum Leprosum (ENL) and in other disease settings most notably Multiple Myeloma’ - Goodman & Gillman of Multi vel (MM) “Thalidomide is used to treat patient with relapsed and refractory MM, as well as early stage disease. The National ‘Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for MM include thalidomide as an option for salvage therapy in patients with elapsed or refractory MM, or as initial therapy in combination with dexamethasone for advanced MM. - Goodman & Gillman lide ws as an antiemetic in ancy but withdrawn when it was found to cause teratogenesis (phacomelia) ‘Thalidomide was initially used during the 1950's as a sedative and an antiemetic during early pregnancy. “Tewas withdrawn from the marked in 1960's because of its disastrous teratogenic effects when used during pregnancy’ = Katzung ‘Thalidomide First ‘+ Phacomelia (shortened or absent fa f + Other intemal malformations. Answer is D (Didonosine): Harrisons 17°/ 1191 Pancreatitis is an established complication of Didanosine. “Pancreatitis may be seen in about 10% of patients treated with high doses of didanosine. Pancreatitis associated with didonosine therapy can be fatal.Didanosine is contraindicated in patients with prior history of pancreatitis. Didanosine should be discontinued if a patient experiences abdominal pain consistent with pancreatitis or ifan elevated serum amylase or lipase level is found in association with an edematous pancreas on ultrasound'= Harrison's ~ 17/1194 Pancreat ot an established adverse effect of Zidovudine, Lamivudine or Abacavir ES ng Zidovudine Reverse Transcriptase © Anemia / Granulacytopenia (Macrocytie anemia / Neutropenia) Inhibitor (frst drug + Mopathy approved for treatment of © Cardiomyopathy HIV infection) = Lactic Acidosis «| Hepatomegaly with fatty liver + Nausea, Malaise, Fatigue, Headache (at initiation) Reverse Transcriptase «Peripheral Neuropathy (Mast commion) Inhibitor (Second drug Pancreatitis (most serious complication) approved fortrestment of ¢ Lactic Acidosis HIV infection) + Hepatomegaly with Fatty liver 2 ih Reverse Transcriptase * Hepatotoxicity Inhibitor Answer is D (Lapatinib): Devita's 8/472; Sabiston 18"/ Chapter 4; Schwartz 9"/Chapter 10; Management of Breast Diseases" by Kaufmann (2009) / 440, 441 Lapatinib is a dual tyrosine kinase inhibitor of HER 1 and HER 2 Receptors. (Devita) Lapatinib has been approved for treatment of HER- 2 pasitive metastatic breast cancer in patients who have already received trastucumab (selective HER 2 receptor inhibitor).Dual HERI HER ‘+ Trastuzumab (Herceptin) | |» Lapatinib (Approved) (approved for Breast (Reversible) + Cetuxmab (Approved) cancer) + Panitumubab (Approved) Pentuzumab (Trial phase) + Matuzumab (Trial phase) Nimotuzumab (Trial phase) Zalutumumab (Trial phase) = Eriotinib (reversible) = Gefitinib (reversible) Lapatinib in treatment of Breast Cancer Lapatinib is an orally bioavailable, reversible dual inhibitor of Epidermal Growth Factor Receptor (EGFR / HERI) and Human Epidermal Receptor 2 (HER — 2) tyrosine kinas activity. 1k does not show cross resistance with Trastuzumab (HER-2 inhibitor) Trastuzumab is an Anti-HER 2 recombinant antibody that has been shown to inhibit the growth of breast cancer cells over expressing HER-2 Lapatinib is indicated in combination with capacetibine for treatment of patients with advanced metastatic breast cancer whose tumors over express HER. Patients should have already received treatment with an anthracycline, a taxane, and trastuzumab. Answer is A (Gastrointestinal stromal tumors (GIST)): Katzung 11*/953, 954, 955 Tyrosine kinase inhibitors imatinib and sunitinib are approved for the treatment of Gastrointestinal Stromal Tumors ee (ISN). Philadelphia chromosome positive ALL Head & Neck Cancers (used in combination with Radiotherapy) ‘Non Small cell carcinoma Lung Colorectal cancer Renal cell cancer Hepatocellular cancer Pancreatic cancer Gastrointestinal Stromal Tumors (GIST) ‘+ Tyrosine kinase signalling pathways play an essential role in carcinogenesis and hence tyrosine kinase inhibitors have been developed for cancer therapy. + Drugs targeting tyrosine kinase can be broadly classified into small molecule tyrosine kinase inhibitors and large ‘molecule monoclonal antibodies targeting tyrosine kinase receptors and their ligands. + Tyrosine kinase inhibitors (small molecule) are broadly classified into Epidermal Growth Factor Receptor EGFR tyrosine kinase inhibitors (HERI), Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitors and Non EGER Tyrosine kinase Inhibitors. imatinib (hese inhibit the protein Tyrosine kinases BeR- AbL, PDGFR and KID) apatinib is dual inhibitor ofboth HERI & HER2 Tyrosine kinase + These small molecule tyrosine kinase inhibitors have been licensed for use in a variety of cancers including CML, Philadelphia chromosome positive ALL, GIST, colorectal cancer, Non-small cell lung cancer, Renal cell cancer, Hepatocellular cancer, Breast cancer.SAND EXPLANATIONS - 2010 sine kinase inhibit “ —{— cmeTrerney an Tnhbits EGFR tyrosine kinase ——-Non-small cell ung cancer, Diarrhea ‘Skin mah, danbes, leading to inhibition of EGFR pancreatic cancer merece ag Renin peels signaling — signaling Gri a st Mata Tnbibis Ber-Abl tyrosine kinase CML, gastroinestinal stro- Nausea and Vomiting Fluid retention with ankle ‘and othe receptor tyrosine kinases, mal tumor (GIST), Philadel- and periorbital edema, including PDGF, stem cell factor, phia chromosome + ALL, = a: Sees Se ee ee teeters totes seoeient Ss aa care sree B invasion, and metastasis as je RT ‘Skin rash, fatigue and asthenia, bleeding ‘complications, cardiac toxicity leading to congestive heat failure in “rastuzumab ‘Monoclonal Atbody agains HER? ‘[Biitimamss = Monoclonal Antibody against HERI (EGFR) Monoclonal Antibody against HER (EGFR) ail 59. Answer is B (Imatinib) : Katzung 11953, 954, 955 Tyrosine kinase inhibitors imatinib and sunitinib are approved for the treatment of Gastrointestinal Stromal Tumors (GIST). Erlotinib ‘Non-small cell lung cancer, pancreatic cancer Gefitinib . — ‘CML, Gastrointestinal stromal tumor (GIST), Philadelphia chromosome + ALL iain | Sorafenib a is 60. Answer is C > D (Using Liposomal delivery systems > By combining with flucytosine): Lippincott’s Pharmacology 4/408; Katzung 11/838, 839, 836, 837 Use of Liposomal Delivery systems (Liposomal Amphoterecin) allows reduction of toxicity without sacrificing efficacy. This is the method of choice for reducing Amphoterecin B toxicity. “Therapy with Amphoterecin B is often limited by toxicity especially drug induced renal impairment. This has led to the development of Lipid drug formulations (Liposomal amphoterecin). Liposomal amphoterecin B (Lipid packaged drug) binds to the mammalian membrane less readily, permitting use of effective doses of drug with lower toxicity. This approach allows for a reduction of toxicity without sacrificing eficacy and permits use of larger doses Katzung 11%/838Combination therapy with Flucytosine is another valid approach for reducing Amphoterecin toxicity but this has limited indications Reducing the dose of Amphoterecin B to reduce taxicity will compromise therapeutic efficacy and hence is not Preferred 61. wee Ua Delivery: ‘* Liposomal formulations of Amphoterecin B are considered the preparations of choice for reducing Amphoterecin toxicity + Liposomal delivery systems serve as Amphoterecin reservoirs reducing the amount of free drug in circulation. Only the infected cells appear to interact with Liposomal Amphoterecin B causing release of drug at the site of action in a sel manner. This allows for a reduction of toxicity without sacrificing efficacy and permits use of larger doses z ‘Using Combination Therapy ‘© Combination therapy with synergistic aniifongal agents (Flucytosine) has been proposed as a method to reduce Amphoterecin toxicity © Combination therapy may permit use of lower doses ‘of Amphoterecin eading to possible lowering of toxicity while maintaining efficacy (This approach is certainly possible but not the approach of choice as it has linited indications, The combination therapy with Flucytosine is however currently considered optimal ‘for eryptococeal meningitis). Answer is A (Most common adverse effect is Nephrotoxicity): KDT 7/883; Goodman & Gillman’s Manual of Pharmacology (2007) 916 Most common adverse effects of mycophenolate mofetil are leucopenia, diarrhea and vomiting. Nephrotoxicity has not been mentioned in association with Mycophenolate and this drug is indicated as an immunosupressant in the ‘management of Renal transplant rejection. tis essentially a prodrug that is rapidly hydrolyzed to mycophenolic acid ‘[BMethanism of Action — ‘© Mycophenolate Mofeti is rapidly hydrolyzed to Mycophenolic acid (MPA) ‘s_ MPA isa reversible inhibitor of Inosine Monophosphate Dehydrogenase (IMPDH) (ae is an important e ‘Therapeutic Uses ‘+ Mycophenolate is mainly used 10 curtail transplant rejections ith Glucocorticoids and Calcineurin in ‘¢ Itis typically used in combination ime inthe de-now pathway of Guanine mcTeoiule sythess (purine sthexs) mT and B calle] Buti should not be combined with Azathioprine Toxicity (Advetse Effects ‘+ Leukopenia, Diarrhea and Vomiting are the principal toxicities ‘+ Predisposition to infections especially CMV (CMV sepsis) ‘Gi bleeds may be seen Answer is B (Lepirudin): Goodman & Gillman's Manual of Pharmacology (2007) 955; ‘Clinical Hematology & Oncology’ by Furie (2003) /488. Lepirudin (direct thrombin inhibitor) is a recommended agent for Heparin induced thrombocytopenia and thrombosis. + Lepirudin (Direct Thrombin Inhibitor) + Argatroban (Direct Thrombin Inhibitor) + Danaparoid (Mixture of Non Heparin Glycosaminoglycans) alternative agents to treat or prevent thrombus formation Bivalirudin (Direct thrombin inhibitor) is under evaluation for HIT. * Heparin Induced Thrombocytopenia isan important complication / adverse effect of Heparin administration that necessitates use of3 3 5 : ‘+ HIT is usually seen as a complication ofthe use of unfractionated heparin but may also be seen with the use of LMWH. HIT may be non inne mediated (Tye, Mik) rime mediated ue to development of antibodies ype 2 Signifcan) as 1 a Type —— Tmmune mediated Benign Severe Mild Thrombocytopenia Significant thrombocytopenia Heparin Therapy may be continued Heparin must be discontinued immediately + Heparin Induced thrombocytopenia Type I isa serious form of HIT that can result in serious complications + The diagnosis of Immune mediated HIT depends on clinical criteria with confirmation by specific laboratory tests '* Thrombocytopenia < 150, 000, or a 50% decrease from pretreatment values ‘+ Thrombocytopenia follows heparin exposure by atleast 5 days (Time taken to form antibodies) ‘+ Reasonable exclusion of other clinical causes of thrombocytopenia ‘+ Onset of new thrombotic event or extension of previous thrombosis, Dirget Thrombin Inhibitors Lepirudin and Argobatran along with Danaparoid are the recommended alternative anticoagulants for patients with Heparin Induced thrombocytopenia. Direct thrombin inhibitors (Lepiradin and Argobatram) are usually preferred but all three drugs are effective anticoagulants and the choice of drug depends n personal experience and patient characteristics lke hepatic or rena insufficiency and desired route “of administration «+ Heparin administration shouldbe stopped immediately. + Low Molecular Weight Heparin (LMWH) should no be substituted because it may eros react with ant-heparin antibodies ‘» Warfarin should not be used until the thrombocytopenia is resolved and the patient is adequately anticoagulated with another agent. ‘Warfarin may precipitate venous limb gangrene or multicentric skin necrosis in patients with HIT Danaproid Lepiruain | Mechanism of action ia aa AA comiplex = with Antitrombin HI : ‘Adinisraion Worsc Vv Half-life 24 hours 3 hours - Reversible No No ‘Monitoring ‘Anti-Xa activity using a danaproid/ aPTT standard Use in pregnancy Several reported cases No reported experience No reported experience Dose adjustment for Yes, monitor Xa activity dosely in Yes, monitor Xa activity closely in No renal faiure ‘Special considerations patients with renal insufficiency Cross: reacts with heparin-induced antibodies in some cases patients with renal insufficiency Antibodies may develop to Jepirudin and protong the half-life All three drugs are anticoagulant in patients with heparin-induced thrombocytopenia. The choice of drug depends on personal ‘experience and patient characteristics such as renal or hepatic insufficiency, desired route of administration Answer is A (More potent than pinicillamine and orally absorbed): Goodman & Gillman’s Manual of Pharmacology (2007) / 1130; Sleisenger & Fordtran’s Gastraintestinal & Liver Diseases 8"/1609; Harrison's 17"/ 2451 Trientine is an orally effective copper chelating agent but it is less potent than penicillamine. Tr ‘an orally apes 1g agent with a mechanism of action similar to penicillamine ‘+ Trientine is a Jess potetnt? chelator than penicillamine but the difference is not clinically important ‘+ Trientine is less toxic® than penicillamine and produces lesser adverse effects + Ithas traditionally been reserved as a second line agent (alternative agent) for treatment of patients intolerant to penicllamine. However Trientine is increasingly been advocated as first line treatment in Wilson's disease when a chelator is indicated - Harrison's '» Trientine may cause iron deficiency (apparently by chelating dietary iron) This iron deficiency ean be over come .with short courses of iron therapy but iron and trientine should not be ingested within 2 hour of each other.6s. “Tetrathiomolybdate ‘Oral zine interferes with ‘+ Penicilamine isthe | J» Tricntine is another copper | J» Tetrathiomolybdate absorption of copper from the | | most potent copper || chelating agent. tis interferes with copper GIT and increases copper chelating agent slightly less potent than absorption from intestine ‘excretion in the stool. It + Penicllamine penicillamine and binds to plasma copper induces hepatic although effective Trientine is saferless toxic | | with high affinity metallothionein synthesis can have serious than penicillamine + Itisemerging as the drug which sequestrates additional | | side effects Trientine is emerging as ‘of choice for severe toxic copper the chelator of choice for | | neurological Wilson's | ++ Zinc is effective in Wilson's Wilson's disease disease (because ofits rapid | disease and is essentially non Trientne is a less toxic action, preservation of toxie chelator ands supplanting | neurological function and + Zinc is the drug of choice for penicillamine when a low toxicity) Prophylactic treatment in chelator i indicated’ ‘resymptomatic patients, for = Harrison | ‘maintainance therapy and is special sub groups of patients like pregnant woman & pediatric patients J Answer is B (Gout): KDT 7/217; Katzung 11/638, current Diagnosis & Treatment in Rheumatology 2/350 Allopurinol is used in the treatment of chronic gout. Allopurinol is a xanthine oxidase inhibitor that reduces total body uric acid burden by inhibiting the synthesis of uric ‘acid. Allopurinol is the agent of choice for treatment of gout in the intercritical period between acute attacks “The preferred and standard-of care therapy for gout in the intercritical period (the period between acute episodes) is allopurinol” - Karung “The xanthine oxidase inhibitor allopurinol is the agent of choice for most patients with gout Current Rheumatology 24/350 * Corticosteroids (iicosuries Drugs used for Gout ‘Drugs used for Acute Gout (Digs used for chronic Gout / Symptomatic Hyperuricemia + NSAIDs + Colchicine = Probenecid? Inhibitors) + Allopurin® + Febisxostat Febuxostat isa potent new xanthine oxidase inhibitor that appears to have certain benefits compared to allopurinol. Firstly itis metabo by the liver and hence can be used in patient with mild to moderate renal failure. Second, it can be used safely even in ‘Patients with mild to moderate hepatic insufficiency. Finally no hypersensitivity reactions have been reported. Answer is C (Ointment): Ref: ‘WHO Model Prescribing Information: Drags wed in sn Diseases’ by World Health Organization (1997)/117; Manual of Allergy & Immunology (Lippincott) 72 In equivalent concentrations topical steroids are most patent when used as ointments, ‘In general the same steroid will be most potent in an ointment base followed by emollient, gel, cream and lotion’. ‘Ointment > Emollient > Gel > Cream > Lotion = Manual of Allergy & Immunology Oinoments are most occlusive, have the fewest additives, provide beter delivery of medication, and decrease evaporative losses. i MEE 2010 - EXPLANATIONS: | !AIPGMEE 2010 - EXPLANATIONS DD EXPLANATIONS -2010 PATHOLOGY 66. Answer is B (Nuclear compaction): Robbins 9/53; 7"/13, 21, 27 The most charachteristic feature of apoptosis is condensation of nuclear chromatin which corresponds to nuclear compaction (pyknosis) on light microscopy. Cytoplasmic eosinophilia and intact cell membrane are both features of apoptosis; however these are not characteristic of apoptosis. Chrot with nuclear compaction is) is charachteristi tosis Chromatin condensation within the nucleus is the most charachteristic featue of apoptosis (Robbins) © Condensation of chromatin into a solid structureless mass is associated with reduction of nuclear size or nuclear ‘compaction often termed ‘pyknosis’, + Nuclear compaction on light microscopy thus corresponds to chromatin condensation and reflects the charachteristic feature of apoptosis © Dense condensation of Nuclear chromatin ‘© Irregular clumping of nuclar chromatin (Dense aggregation of nuclear chromatin (Loose aggregation of nuclear chromatin) + Naclear compaction (pyknoss) + Karyolysis, ‘* Convolution of nuclear outline and breakdown (Garyorhexs) + Kayolysis Eosinophilic Cytoplasm is a feature of Apoptosis but is not charachteristic Eosinophilic eytoplasm can be seen in both Apoptosis and Necrosis On hisiolgical examination in issues stained with ‘On histological examination in tissues stained with hematoxslin and ‘hematoxylin and eosin, apoptotic cells show intensely eosin, necrotic cells show increased cytoplasmic eosinophilia ‘eosinophilic cytoplasm ‘attributable in part to loss of normal basophila imported by RNA in the cytoplasm and in part tothe increased binding of eosin to denatured intracytoplasmic proteins Intact cell membrane is a feature of. is but is not charachteristic “Plasma membrane integrity is not very useful in apoptosis detection’ ~ Essentials of Apoptosis 1" (2008)/241 Integrity of cell membrane is a charachteristic feature for evaluating cell injury accompanied by membrane damage (eg necrosis). However, the detection of plasma membrane integrity is not very useful in apoptosis. This is because an intact plasma membrane as seen in apoptosis does not differentiate apoptosis from a normal viable cell. 2ellular swelling is not a feature of Apoptosis Apoptosis is associated with cellular shrinkage. The cell is smaller in size, the cytoplasm is dense and the organelles are ‘more tightly packed Ppoptaais 7 TTS Neon ‘Cellular shrinkage Cellular swelling | Cell size reduced "Cell size enlarged”) (b)Answer is A (Cellular swelling): Child Neurology 7*/1027, Basic Neurochemistry 7*/605; ‘Apoptosis’: A Practical Approach 1" (1999)/6, Robbins 7"/chap-1; Robbins 8"/ chap- 1, Fundamentals of Oncology 4/34; Cancer cell metabolism & Cancer Treatment (2001)/134 Apoptosis is associated with cellular shrinkage (reduced cell size) and not cellular swelling. ‘Stimuli ‘Programmed cell death (Genetically dependent) Random cel death (Genetically independent) Physiological (often) (Limited pathological conditions) Pathological (Invariably) Occurance ‘Single cells “Groups of ees Cell sie Reduced (shrinkage) Enlarged (swelling) (Plasma membrane Intact Disrupted a Nucleus Dense aggregation / condensation of chromatin & Loose aggregation of chromatin into Sragmentation irregular clumps ‘Nuclear compaction (pyknosis) and fragmentation Nuclear lysis (haryolysis) (karyorhexis)7. ‘AIPGME EXAMINATION ANSWERS AND EXPLANATIONS -2010 © 855 (Goptesm —Cytplasmic eosinophitia Coplasmic eosinophilia Cytoplasmic compaction / condensation Cytoplasmic swelling Cytoplasmic organelles Morphologically imtact Morphologically disrupted ve _Late stage swelling Very early swelling disruption ‘Enzyme —_Lysosomes intact ron mes Ruptured ~ Enzyme release absent) EE release present) DNA Breakdown __Internucleosomal Random Membrane surface Blebbing and formation of Apoptotic bois Seta ier abate oa (No apoptotic bodies). Energy (ATP levels) Maintained Depleted ATP dependent ATP independet oe __ a i peeased (Net. Ca") Answer is C (Apoptosis): Robbins 7/56; 7/27, 30,31, Cellular Microbiology 2/412 Caspases are the primary agents involved in the execution of Apoptosis. Caspases need to be activated to induce apoptosis ‘+ Caspases are a family of cysteine proteases that play a cental role in the execution of apoptosis ‘+ The term caspase is based on two properties of this family of enzymes °C refers toa cysteine protease “aspase’ refers to their unique ability to cleave aftr aspartic acid residues. ‘+ Caspases exist as inactive proenzymes and must undergo an activating cleavage for apoptosis to be initiated ‘+ Caspases can be divided into two basic functional groups, namely initiator caspases and executioner caspases /itistor caspases once activated set the enzymatic Executioner easpases once activated act on many vital cellular feeeeroenen moe oid sequential ‘components and cleave the nuclear scaffold and cytoskeleton ‘of other caspases bringing about the charachteristic nuclear and cytoplasmic changes seen in apoptotic cells caspases include capsase 8 and capsase 9) (Executioner caspases include caspase 3 and 6) ine = Tntacellular signals indicating that cll death sbould occur Extracellular signals indicating that ell death should eg withdrawl of growth factors / hormones ‘occur eg Activated TNF receptor / Fos Receptor | \ Mitochondria ‘Surface Death Receptors Regulated by Bel 2 Release of adaptor family members proteins J { paaet 8 f a 2 3 f é a co70. + More than 10 caspases have been identified in humans. Caspase 3 has clearly emerged as the single most important caspase during the execution phase of apoptosis.” + The presence of cleaved, active caspases in a marker for apoptosis (Apoptosis may often be blocked by caspase inhibition) (a) Answer is B (Bronchodilatation): KDT 6/491, 492, Robbins Basic pathology 8"V/ed 53 ; 9"/89; Rang and Dale's Pharmacolgy 6"/ed 223 Bradykinin is associated with contraction of bronchial smooth muscles resulting in bronchoconstriction not bronchodilatation. Vasodilatation (Largely mediated by endothelial cell no and PG12) Uterine smooth muscle contraction ‘Mediation of pain (by directty stimulating pain nerve endings and by 1 PG production) ‘Stimulation of epithelial ion transport and fluid secretion in airways and gastro intestinal tract i i () Answer is A (Increasd Vascular Permeabilty): KDT 6491, 492, Robbins Basic pathology &M/ed 53; Robbins Basic Pathology &*ed $3, Rang and Dale's Pharmacol 6"/ed 23; ‘Immunology: a short course” by Sunshine (Witey- Blackwell) 6/16; “Applied basic science for basic surgical raining’ by Raftey 2™/25 Bradykinin causes vasodilatation, increased vascular permeability and pain in acute inflammation. However the single ‘most important function of Bradykinin in acute inflammation should be regarded as an increase in the vascular Permeability since increased vascular permeability is the characteristic hallmark of acute inflammation “The hallmark of acute inflammation is increased vascular permeability’ Robbins ‘Bradykinin is the most important vascular permeability factor’ Raftrey [Role of Bradykinin in acute inflammation 7 © Increased Vascular Permeability “Most important, Bradykinin acts on vascular endothelial cells causing them to contract leading to an increase in vascular permeability = Immunology 6° /16 ‘Bradpkinin isthe mast important vascular permeability factor’ ~ Raftrey 24/25 © Pain Bradykinin isan important mediator of pain during acute inflammation ‘Mediation of pain however, does not play an important role in the process of acute inflammation and hence is not selected as the answer here. * Vasodilatation Although Bradykinin leads 10 vasodilatation this action of Bradykinin may be inconsistent Answer is B (Malaria): Robbins 9/635; 8/387, 645 Heterozygous Sickle Cell Anemia confers protection against Malaria. ‘Sickle cell trait (HbS trait) confers resistance against Malaria in Heterozvgotes (Robbins 7/402, 628) ‘The possession of the sickle cell allele protects these individuals against malaria because the parasite dies when potassium leaks out of RBCs as they become sickle shaped. ‘HOS trait causes parasites to grow poorly or die at low oxygen concentrations perhaps because of low potassium levels caused by potassium efflux from red cells on haemoglobin sickling’ - Robbins ‘In certain populations in Africa the prevalence of Heterozygosity is as high as 30%. This high frequency probably stems from protection afforded by HBS against falciparum malaria’. — Robbins 8/645 (a) Answer is D (All of the above): Wintrobe’s Hematology 12/1002; Horrison's 17"/ed 660, 661 PNH is associated with a deficiency of GPI anchored proteins including DAF and MIRL PNH is associated with a deficiency of GPI Anchored proteins DAF (CDSS) and MIRL (CD59) are the most important GPI Anchored proteins that may be deficient in PNH.‘Since option ‘D allows us to select all the above options and we are not forced to select one single best protein “Option D? becomes the answer of choice. Glycosv! phosphatidvlinositol (GPI) anchored proteins and PNH_ ‘+ PNH is primarily associated with a deficiency of GPI anchored proteins on hemotopoetic cells All proteins that are deficient in PNH are GPI Anchored and all GPI anchored proteins that are expressed by hematopoietic cells are deficient in PNH’ — Wintrobe's ‘+ The most important GPI anchored proteins that are causally related to PNH are the complement regulatory proteins that result in abnormal susceptibility of erythrocytes to complement mediated lysis. ‘Decay accelerating factor (DAF — CD $3) ‘Membrane Inhibitor of Reactive Lysis (MIRL ~ CD59) + However several other GPI anchored proteins may be deficient in PNH and currently the list of proteins deficient in PNH numbers more than 20 '* Leukocyte alkaline phosphatase '* CD66 (formerly CD67) 4 Aceiylcholinesterase © CD66 | 4 Decay accelerating factor (DAF, CDSS) + p50-80 ‘© Membrane inhibitor of reactivity lysis (MIRL, CDS9) + CD24 + FeyRillb (CD16b) + CD48 Lymphocyte function-assoiated antigen 3 (LFA-3,CDS8) © Thy-1 (CD90) Endotoxin-binding protein (CD14) + cp109 © Campath 1 (CDS2) + cpIs7 | + 5*cctonueleotdase (CD73) + GP500 ‘© Urokinase plasminogen activator receptor (CD87) + opi7s ‘+ JMH-bearing protein (CD108) «+ Folate receptor + Cellular prion protein fm atiananeniaRa ra nacemA ML t 10. (b)Answer is C (GPI Anchored Proteins): Wintrobe’s 12"/ 1002; Harrison's 17"/ed 660, 661 Alll of the proteins mentioned as options (DAF, MIRL and LFA) may be deficient in PNH and all of these proteins are GPI anchored proteins. Since we have to chose a single best answer amongst the options provided, GPI Anchored ‘proteins becomes the answer of choice. ‘All proteins that are deficient in PNH are GPI Anchored and all GPI - Anchored proteins that are expressed by ‘hematopoetic cells are deficient in PNH' - Wintrobe's Hematology All proteins deficient in PNH are GPI anchored proteins and hence GPI anchored proteins isthe single best answer of choice TL. Answer is A (t(8:14)): Harrison's 17"/696, 690; Robbins 9"/587 18; 14) is the most common translocation seen in association with Burkitt's Lymphoma ‘Demonstration of very high proliferative fraction and the presence of the t (8; 14) or one of its variants t (2; 8) or (8:22) can be confirmatory of Burkitt's lymphoma / leukemia’ - Harrison's 179696 Burkitt’s lymphoma / leukemias are associated with reciprocal translocations involving the ‘comye gene on chromosome 8 Moai common Translocation (70% cases) [Tess common translocations (8; 22) & mye gene on chromosome 8 and light chain on chromosome 22 - mye gene on chromosome 8 and Tight chain on chromosome -2 £(8; 14): c-myc gene on chromosome 8 and IgH heavy chain on chromosome 14| 2 é & 3 & 3 e g u 2 é 2 2 14. _AIPGE EXAMINATION ANSWERS AND EXPLANATIONS -2010 Answer is D (Burkitt's Lymphoma): Harrison's 17°/696, 690; Wintrobe's Hematology 12/2082, 1604; Atlas of Hematologic Neoplasms by Tsieh Sun/26; Cancer Cytogenetics by Heim, Mitelman 3rd/326; Clinical Malignant Hematology by Sekeres, Kalaycio, Bolwell I" (2007)/114 Translocation 1(2:8)(p12:q24) is associated with Burkitt's lymphoma /leukemia, “The hallmark of Burkitt lymphoma is the (8;14)(q24:932) and its variants, «(2;8)(p12; 424) and 1(8;22)(q24:q11) . “Cancer Cytogenetics by Heim, Mitelman 3rd/326; Clinical Malignant Hematology by Sekeres, Kalaycio, Batwell 1" (2007)/114 ‘Demonstration of very high proliferative fraction and the presence of the (8;14) or one of its variants 1(2;8) or 1(8:22) ‘can be confirmatory of Burkit’s lymphoma / leukemia’ - Harison’s 177696 Bukit 108:14(@24432) most common MIC: lel (heavy chain) 12;8)(p12:q24) Ign: e-MYC (light chain) :22)@24q11) e-MYC gd (light chain) Answer is B (IgM): Harrison's 17/-706 * Surgicla pathology of Head & Neck’ by Barnes 2/1270, 1271 Plasmacytoid Lymphomas may be associated with a monoclonal IgM paraprotein (Waldenstrom’s Macroglobulinemi This is ee is associated with plasmacytoid differentiation of lymphocytes + Plasmacytoid lymphocytes are transitional forms between lymphocytes and plasma cells + These may be associated with a monoclonal IgM paraprotein and are thus considered the histological counterparts of Waldenstrom’s Macroglobulinemia + Synonyms include immunocytoma Kiel Classification : Malignant Lymphoma, Lymphoplasmacytoid immunocytoma REAL Classification: Lymphoplasmacytoid Lymphoma / Immunocytoma + These are low grade lymphoid neoplams® that occur in middle aged or older individuals. Answer is A (Infective endocarditis): Repeat; Refer text below: Robbins 9"/560; 8"/566,567,568; Harsh Mohan 69/447; Paediatric Pathology by Stocker and Dehner (Lippincott) 2" (2001)/552 Most friable vegetations with the highest risk of embolization are seen in infective endocarditis. Fitability of Vegetation and risk of embolization fective Endocardiis> NBTE (Marantic)> Rheumatic endocardis and Libman Sacks endocarditis + Small > Haul (ut inp Gwe > Mafia) + Large, Bulky + Warty, verucous of rheumatic) + Flat, Verrucous regular + lrregular + Usually Firm + Friable + Usually Firm; occasionally friable + Friable (mast friable? May be file (but ess (embolization common) (embolization rare) (embolization common) than those of NBTE) (embolization rae) lines of closure» Alongs of closure + On surfie of cusps + Irregular vegetations s Both surfaces may be involved on valve cusps that ean ‘most common being the extend onto the undersurface, less often on mural _chordae. endocardium + Less often on mural a + Inpockets of valves endocardium + Sterile (v0 organisms)» Sterile + Sterile + Non-sterle (bacteria) destructive + Non destructive + Destructive + Destructive Valve perforation :no Valve perforation : no Valve perforation : no ‘Uleertes or perforate involvement: rare Mural involvement: rare Mural involvement: common underlying valve (or E myocardium) '» Seen in Rheumatic fever» Seen in hyper coagulable + Seem in SLE + Seen in Infective states eg. cancer, endocarditis promyelocytic leukemia increased estrogenic stateMost common site: ‘© Most common site for vegetations in Libman Sack's endocarditis are the A-V values, mitral and tricuspid. Most common site for vegetations in NBTE is mitral and less often aortic and Tricuspid. ‘+ Most common site for vegetations of RF is mitral followed by combined mitral and aortic. 75. Answer is A (Fibrous endocardial thickening of Right ventricle, Tricuspid valve & Pulmonary valve): Robbins 71599, Braunwald 8/297, Hurst 11"/2092; ‘Pathology Pre test’ 11/211 Fibrous enodocardial thickening involving the right ventricle, tricuspid valve and pulmonic valve is the ‘charachteristic pathological finding in carcinoid heart disease. + Carcinoid heart disease is the cardiac manifestation of systemic syndrome caused by carcinoid tumors and results primarily from the bioactive products elaborated by carcinoid tumors at other sites. ‘+ Cardiac involvement predominantly affects the endocardium and valves on the right side of heart® (because bioactive tumor substances are inactivated by the lung) and usually occurs in patients with hepatic metastasis? (This bypasses the inactivation by the liver & exposes right heart to high levels of bioactive products) ‘+ This consists of firm plaque like (endocardial) fibrous thickening of the right ventricle tricuspid and pulmonic valves composed predominantly of smooth muscle cells and sparse collagen fibres®, embedded in an acid mucopolysacharide rich matrix material. Elastic fibres are not present. + Right sided cardiac lesions are common and include involvement of the tricuspid valve, pulmoary valve and the right ventricular endocardium. ‘+ Tricuspid valve thickening “Tricuspid Regurgitation is the primary lesion “ Tricuspid stenosis is minimal + Pulmonic valve thickenning Pulnonic Regurgitation (variable degree) Pulmonic stenosis (variable degree) ‘© Right ventricular endocardial thickening ‘Restrictive cardiomyopathy may be seen ‘+ Left sided cardiac lesions are uncommon but may be seen when blood containing the responsible mediator enters the left heart in certain specific circumstances. = Incomplete inactivation in lung due to very high blood levels = Incomplete inactivation due to ‘right to lef” intra-cardiac shunt from a patent foramen ovale = Pulmonary carcinoid /pulmonary metastasis Note: Endocardial thickening of Tricuspid valve with Tricuspid stenosis may be seen, but is not a characteristic feature of carcinoid heart disease. The charachteristc valvular pathology affective the tricuspid valve is tricuspid valve regurgitation “Tricuspid stenosis is usually minimal '- Braunwald 89297; ‘Pure tricuspid stenosis is rare'~ Essel of dnatomle Pathology 2121-8 76. — Answer is C (Usual Interstitial Pneumonia): Harrisons 17"/1647; Robbins 7"/686; Diffuse Lung Diseases (Springer) 1" (2006)223; ‘Imaging in Diffuse Lung Diseases’ by Lynch & Lee (2000/61 Presence of heterogenous, patchy fibrosis with fibroblastic foci is characteristic of Usual Interstitial Pneumonia “The histologic hallmark and chief diagnostic criterion of UIP is a heterogenous appearance, interstitial inflammation, foci of proliferating fibroblasts (fibroblastic foci) dense collagen fibrosis and honey-comb changes. The interstitial inflammation is usually patchy and the histopathological changes affect the peripheral sub-pleural parenchyma most severely’ ~ Harrisons 17/1647 Idiopathic Interstitial ses / I Interstitial Pneumonias © Idiopathic Interstitial Pneumonias are interstitial lung diseases of unknown etiology that share similar clinical and radiological features and are distinguished primarily by the hstopathological pattern on lung biopsyEXPLANATIONS - 2010 Idiopathic pulmonary fibrosis (Coyprogenic fbrosing alveolitis) Desquamative interstitial ‘pneumonia ‘Aeuie interstitial pnewanonia (Hamman-Rich syndrome) ‘Ghptogenic organizing pneumonia, Temporally and spatially heterogeneous pattern with areas of normal lung. fibroblastic foci, and patchy sub-pleural fibrosis Homogenous intra-alveolar macrophage ‘accumulation. Mild alveolar septal thickening Homogenous, diffuse tg injury with hyaline ‘membranes, fibroblast proliferation Mulifocal organizing pneumonia, with (diopathic BOOP) Nonspecific interstitial pnewmonia granulation tissue and polyps in alveolar ducts ‘and bronchioles Temporally and spatially homogenous cellular inflammation with mild fibrosis Respiratory Bronchioltis Associated pDisease(RBILD) Interstitial Lumg Disease ‘* Detailed Histopathological features are often required to distinguish various forms of Idio Pneumonias and hence these have been listed in a tabular form in the following table. ES __ Pathologic features of Idiopathic Interstitial Pneumonias ic Interstitial DIP ‘RBLLD uP NSIP-Celluler _NSIP-Flbrosing Diffuse Mild focal Patchy, Sub-pleural Diffuse Difise/panacinar Homogenous Homogenous Herterogenous——_Homogenous_—‘Homogenous Wariegated) Scant None Sean, patchy Prominent Scant. diffuse Variable Scant Characterisite Absent Diffuse Diffuse Patchy Patchy Absent Absent Fibroblastic Absent Fibroblastc Foci prominent Foci Rare Absent Absent Characteristic Absent Rare Diffise __Peribonchiolar Occasional | Occasional —_Oceasional ‘Absent Absent ‘Absent Absent ‘Absent 77. Answer is (Monosomy of 1 and y): Harrison's 17"/592, Urological Surgical Pathology’ by Bostwick & Chang 2/96, “The kidney’ by Vize, Woolf & Bard 1” (2003)/454, ‘Renal cell carcinoma’ by Campbell & Rini I" (2009)/42,43 (Chromophobe variants of renal cell carcinoma are charachterized by widespread / extensive chromosomal losses resulting in monosomy or hypodiploid DNA index. This includes loss of chromosome 1 and ¥. “The abnormalities most consistently observed have been multiple losses of whole chromosomes, most frequently 1, 2, 6, 10, 13, 17, 21 and the Y chromosome’ — Urological Surgical Pathology Classification of epithelial neoplasms arising from the kidney. [eaciooma Type Cell of Origin Clear cell Proximal tubule 3p deletions (3p-), VHL gene mutations, 5q gains Papillary Proximal tubule Trisomy of chromosome 7 and 17 (+7, +17) Loss of Y chromosome (-Y) iChromephobe Cortical collecting duct __‘Hypodiploid/ Monosomy Loss of multiple chromosomes 1, 2, 6, 10, 13, 17,21.& Y¥ Oncoeytic Conical collecting dust Undetermined Either karyotypically normal or contain limited number of nryotypic abnormalities inloding 1, -¥ and translocations involving chromosme II Collecting duct Medullary collecting duct ‘Undetermined Losses of multiple chromosomes 1, 6, 14, 15 & 222.13 63. 4g, 109 12.420 2 Z gS i & x 6 =I 8 g ‘Grip coy = Answer is A (Loss of Antithrombin III): Harrisons 174/272; Robbins #/912 Loss of Antithrombin III contributes to the hypercoagulable state in Nephrotic syndrome ‘A hypercoagulable state frequently accompanies severe nephrotic syndrome due to urinary losses of antithrmbin IIL, ‘reduced serum levels of protein C and S, hyperfibrinogenemia and enhanced platelet aggregation’ — Harrison 174272 | Hypocalcemia and Secondary ‘Due to loss of transfer defi vn to lss of wansferin Due fo Vitamin D deficiency Dealorronee | 3.6 Fed winery sof AT secondary to Turinary loss of. _ dari cholecaeiero binding PET). Reduced levelsctvty ot (LEA SRACBTAVADTAHONT] proven. ‘Due 1 increased poten &S Due to urinary loss of eG Aepate Ippon ‘© Hyperfibrinogenemia due to _ and increased catabolism) iypotiyreidiom is Ted synthesis, h ) + Impaired fibrinolysis Due to loss of Thyroid binding «fed platelet aggregability slobulin Answer is A (CD 117) : Robbins 9/776; ‘Oncology:An Evidence Based Approach’ (2006) / 413, 414; Sternberg's Diagnostic Surgical Pathology 4/1590 The expression of CDI17 is the most specific marker for Gastrointestinal stromal tumors (GIST). (MARKER in GIST "Approximal Percentage 771 €D 117 (cKit) = 95% (Most specific marker) D4 = 70% Smooth Muscle Actin = 5% ‘© Gastrointestinal stromal tumors are mesenchymal neoplasms of the gastrointestinal tract ‘© GIST represents a distinct group of gastrointestinal tumors that originate from the interstitial cells of Cajal which control gastrointestinal peristalsis.al. Cajal cells normally express the cKit (CD 117) which is a tyrosine kinase growth factor receptor ‘© This cKit (CD 117) Immunoreactivity is the best defining feature of GIST distinguishing them from true smooth ‘muscle tumors (leiomyomas) and tumors arising from neural crest derivatives The cKit (CD 117) is considered the most specific marker for the diagnosis of GIST and is expressed in more than 95% of tumors ‘© The most common site of GIST is the stomach followed by the small bowel ‘Stomach <70% Su 320% Colon __=10% Note Although CD 117 (eKit) is considered the most specifi marker for GIST, itis not pathognonomic of GIST as other tumors may also express CD 117. These tumors include mast cell tumors, germ cell tumors (seminomas), leukemias, ‘malignant melanoma, angiolipomas, and some sarcomas. Answer is C (Polyarteritis Nodosa (Classic PAN)): Harrison's 17/2125; Current Rheumatology 2/297; Robbins 9/506; Vasculitis" by Ball & Bridges 2™/286 Polyarteritis Nodosa or Classic PAN is not associated with a granulomatous pathology “Gramulomas are charachteristically not found in PAN’ Harison “Absence of granulomatous inflammation is charachteristic feature of PAN’ ~ Current Rheumatology Wegener's Granulomatosis, Takavasu Arteritis and Giant cell arteritis are all granulomatous vasculitis Classification of Vasculitis into Granulomatous & Non-Granulomatous > Giant Cell (Temporal) Arteritis? Polyarteritis Nodusa (classic PAN® © Takayasu Arteritis + Kawasaki Disease® ‘+ Wegener's Granulomatosis? ‘Microscopic Polyangitis® © Churg- strauss syndrome® ‘© Henoch— Sehonlein Purpura® + Essential Cryoglobulinemic vasculitis q + Cutaneous Leucocytoclastic Angiitis? Answer is B (Alport’s syndrome) : Rubin's pathology 5"/711; Current Diagnosis & Treatment Nephrology & Hypertension (2008) /423 Electron microscopy is diagnostic in cases of Alport’s syndrome. “The diagnostic histological changes of Alport's syndrome are only seen on Electron microscopy" = Essentials of Nephrology / Rubin's pathology. Electron Microscopy is diagnostic i 58 ‘+ Electron microscopy of renal tissue is the best means for confirming a diagnosis of suspected Alport’s syndrome ‘+ The cardinal pathologic findings of Alport's syndrome are seen on Electron microscopy which shows longitudinal splitting of the glomerular basement membrane with clear areas in between resulting in a laminated appearance. (Bread crumbs pattern / Net like pattern of lamina densa) + Diffuse or widespread spliting, splintering and lamellations of the lamina densa and GBM with rarefactions are the ‘most charachteristic findings and their presence is diagnostic of Alport’s syndrome, “The most diagnostic morphologic lesion of Alport’s syndrome is seen only an electron microscopy as an irregularly thicknned GBM with spliting of the lamina densa into interlacing lamellae that surround electron luscent areas’. = Rubin’s pathology 5*/711 “The presence on electron microscopy of diffuse thickening of GBM with multilamellar splitting of lamina densa is diagnostic of Alport's syndrome’ - Current Nephrology & Hypertension (Large) 1"/42382. ‘AIPGME EXAMINATION ANSWERS AND EX! 790; Pathology of Head and Neck (Springer- 127, 428 Answer is D (Dense core neuroendocrine granules) : Robbins 7”/78' 2006)/274; ‘Head and Neck surgical pathology’ by Pitch (Lippincott Presence of dense core neuroendocrine granules is a charachteristic feature of neuroendocrine tumors including paragangliomas. Presence of. ules is a characteri wdocrine t “Electron microscopic identification of dense core neurosecretory granules in chief cells is characteristic of paragangliomas' - Head and Neck cancer by Harrison 3%058 ‘Note: idenfication of dense core neurosecretory granules isa ch teria no pathogronomic ature of paragangionas. yf ondria, Inconspicuous Golgi bodic “Tumor cells have granular eytoplasm and round nuclei with prominent nucleioli. Nuclear pleomorphism may be present but mitosis is rare. Electron microscopy studies show the tumor cells to contain membrane-bound dense-core neurosecretory granules. The cytoplasm contains abundant large mitochondria and inconspicuous Golgi apparatus, smooth and rough endoplasmic reticulum’ — Pathology of Head & Neck (Springer ~ 2006) /274 ‘GPRS ParapaGieasied 12 SRA PE in I AE TL Paragangliomas are defined as neoplasms that embryologially aise from paraganglia of neural crest origin (Tre adrenal medulla and paraganglia have a common embryological origin from the neural crest). ow are Paragangliomas classified? + Paragangliomas are usually classified as adrenal paragangliomas (called pheochromocytomas) and extaadrenal aragongliomas (usually called paragangliomas) Bo The term ‘parcgangliomas"is generally resered for extra-adrena paraganliomas ; Paragangliomas Extradrenal paragangliomas ‘Paraganglion tumors arising from ‘The Term Paragangliomas’ is usually reserved for paraganglion tumors ‘adrenal medulla are called as arising from extra adrenal tissues *Pheochromocytomas" ———— ‘Paragangliomas of the Head & | Neck aay (chemodectoma) Jugulotympanie paraganglioma Vagal paraganglioma Laryngeal paraganglioma Miscellaneous paragangliomas + Paragangliomas may be further classified as sympathetic or parasympathetic derived paragangliomas ‘What are the microscopic / histological features of Paragangliomas? 25 ‘+ Most paraganglia presenta typical mieroscopic / histological appearance Display an organized clustering or nesting pater called “Zellbalien” | [© This consists ofa cluster of round or oval chief cells (Type 1) surrounded by elongated sustenicular cells (ype U) [| embedded ina web of smal vessels © | © Chief cels rumor cells are neuroectodermal in origin and have large round or oval nuclei and abundant finely ‘granular cytoplasm and round nucle with prominent nucleoli © | Nuclear pleamorphin may be present but mitosis is rare Cytoplasm contains abundant large mitochondria and inconspicuous Golgi apparatus, smooth and rough || endoplasmic reticulum. “The granules within chief cells on ultrastructural examination under electron microscope appear as dense core, ‘membrane bound granules that store catecholamines and are referred to as ‘dense core neuroendocrine / ‘neurosecretory granules’. Presence ofthese dense core neuroendocrine granules i hallmark of neuroendocrine tumors andis charachtristc feature of paragangliomas || These chief cells stain strongly fr neuroendocrine markers such as chromogranin, synapiophysin and neuron specific [| caolase ‘© Sustenticular cells are elongated, have dense ovoid nuclei. These have no neurosecretory granules and do not stain positive for neuroendocrine markers. These cells are however positive for S-100 protein.2 Answer is A (CD1a): Robbins 9"/622; Cancer in children 1" (2009)/246 | CD1a is a specific marker for Langerhan’s cell histiocytes “Tumor cells in Langerhan’s Cell Histiocytosis express HLADR, S100 and CD1a' - Robbins Demonstration of ‘Birbeck’ Granules in the cytoplasm Dla + (Pentalaminar rod like tubular appearance with adilated © « HLADR + ‘terminal end - tennis racket appearance)? © CD68 +H = S100 + + Langerin ++ (cb207) Langerhans Cells typically express high levels of CDla and Langerin (CD207) and positivity of these two markers now defines Langerhan cell Histioeytes. Answer is A (Maternal Nondisjunction): Robbins 9/161; Genetic Basis of Common Diseases 2/766 The most common cause of trisomy 21 (Down's syndrome) is maternal nondisjunction in meisosis 1. ‘In most cases the meiotic non disjunction of chromosome 21 occurs in the ovum. Studies in which DNA polymorphism hhave been used to trace the parental origin of chromosome 21 have revealed that in 95% of the cases the extra ‘chromosome is of maternal origin’ ~ Robbins 7°/176 ‘There are three mechanisms by which three copies of genes on chromosome 21 that cause Down's syndrome may be present in somatic cells Now Duan Toco aes '* This is the most common mechanism |} This is an uncommon mechanism © This is another coma he Hoang oouming rs fener comceeek ne '* Most often Down’s syndrome results from Trisomy 21 accounting for 1-2% of ‘maternal non dysjunction in meiosis 1 1s Thisis caused by Robertsonian cases of Trisomy 21 eee en aetna | |" romioctonottctngarmat | |e Tsiscanel by won {Eamckonosone 21 isofmaemacigins | | Srmosme itsaetermeanic || ductor sirae cca en] | Sonesame sts of oma cell event in the first meiotic division) J+ Such cases are frequently (but not carly in embryogenesis, |e Down's syndrome may rarely be caused by always) familial and the translocated ‘meiosis Il non disjunction (from either paren!) chromosome is inherited from one of ‘or mitotic non disjunction in zygote or early the parents (usualy the mother) who is poke optic es een Answer is C (1/4): Refer text below : Robbins 9"/141 The fact that one child of a normal couple is affected by an autosomal recessive condition (cystic fibrosis) indicates ‘that both parents are carriers of this condition. The recurrence risk of autosomal recessive disorders in siblings is 25% (1/4) for each birth.86. [AIPGME EXAMINATION ANSWERS AND TIONS -2010 = 865 ‘Autosomal Resesiveinberianse + Parents are normal and sully at aware that hey | cary the gen, because they donot show any sigs of the disease or condition ‘First noticed when they have hil aete with the disease or condition '* The occurrence of the disorder is not affected by the sexo the cid Siblings have 4 One chance in four of being affected (28%) (The risk of recurrence s 25 percent for cach birth) 4+ Thrce chances in four of being nomal (78%) ie. 0t showing sins of disease or condition + Two in four hance to being nomal but a carir 60%) * One in four chance of beng nomal and unflested ese) operas” t eT See Inheritance isnot influenced by sex as the affected allele is ‘not carried on the sex chromosome Males and Females can both be affected by disease and have ‘an equal chance to be affected. Answer is D (X-Linked Recessive): Robbins 9"/141-142; 7°/150, 151, 152 X Linked Recessive disorders are primarily expressed in males (and only rarely in females) ‘Male is said to be hemizygous for X-Linked mutant genes so these disorders are expressed in males (XY). The heterozygoose female usually does not express the condition because of paired normal allele (XX)'- Robbin's Tnheritance in influenced by sex asthe affected allele carried on the sex chromosome (X chromosome). ‘Males and Females can both be affected by disease but the chance of being affected varies with sex. ce | X Linked Dominant X Linked Recessive ‘+ Inheritence is influenced by sex asthe affected allele is| carried on the X chromosome ‘© Males and females can both be affected by disease ‘These disorders manifest in homozygous as well as. heterozygous/ hemizygous states ‘+ Both males (XY) and females (XX) contain atleast one X chromosome and will be affected whenever this single Xallele is affected Both mates and females will manifest this condition by * Inberitence is influenced by sex asthe affected allele is carried on the X chromosome ‘© Males and females can both be affected by disease ‘These disorders manifest only in a homozygous state when both X alleles are affected or in @ hemizygous state where mutant alleles are not paired (e.g. XY males) ‘Males will manifest the condition by a single affected X chromosome while females will express the condition only when both X chromosomes are affected. These asingle affecied X chromosome ‘disorders are therefore more commonly expressed in males. By an affected heterozygous | By an affected heterozygous By an affectd heterozygous | By an affected heterozygous female these disorders are | male these disorders are male Hemizygous) these | female these disorders are transmitted to half her sons | transmitted to all his disorders are neither transmitted only 1 sons(S0 and halfher daughters | daughers but none of his transmited to sons or Yechance for sons) and none sons daughters to daughters = es ee ee XY XY XX XxX ‘XY XY ¥ XX XY Dominant Patern Dominant Patern Recessive Patern Recessive Pattern X¥ Affected daughter XX Affected daughter XX: Normal daughter Xx; Normal daughter XX : Normal Daughter —_| XX Affected daughter _ (Carrier) (Carrier) XY: Afected son eee corte XX : Normal Daughter Vs Monatoon formal son carrier 2 XY: Normal son RY: Afected fh XY : Normal son (Hemizygous) XY : Normal son87. MICROBIOLOGY EXPLANATIONS - 2010 Answer is B (Distal domain of a subunit): Ananthnarayan 9/140; ‘immunity’ by Defrance, Locksley & Robertson I" (2007)/100 Peptide binding site on class I MHC molecules is located in a grove between the distal domains of a subunits (between ay & a; domains). epie binding sti Pepe binding sites Jocated between dita leented between distal agen petite domains of apa cain Bown achan domains of apa chin 1 @, (alpha! and alpha 2) C) and beta chain (alpha! & a a nn and beta 1) % oe & * cecum '* Class IL molecules are heterodimers consisting of an Hes sebelah pce pips Shs can pal and apa ands Set chon (bat 2 microglobulin) and beta 2) * The rom on ‘consist of three domains (alpha Jalpha2 Each chain has two domains the proximal domain (alpha and alpha 3) such that alpha | and alpha 2 form the distal 2 and beta 2) being the constant region and the distal ‘domains and alpha 3 forms the proximal domain ‘domain (alphal and beta 1) being the variable region. distal domains of he alpha chain (alphal and alpha 2) + The distal domains ofthe alpha and beta chains (alpha 1 highly variable amino acid sequences and are folded and beta 1) forma groove between them which constitute form a cavity or grove between them. This constitutes the antigen binding ste for recognition by C4 T cells antigen presenting site for recogition by CD8 T Cells ‘binding site is located between distal domains of Peptide binding site is located between distal domains of (alphal and alpha 2) alpha chain and beta chain (alphal and beta 1) (a)Answer is A (PBP’S are localized on the outer face of cell wall): Katzung 11/776, 777; Lippincott’s Pharmacology 4/360; Current Medicinal Chemistry (1995) / 443 Penicillin Binding Proteins (PBP) are localized on the outer face of cell membrane (cytoplasmic membrane) and not on the outer face of bacterial cell wall. Peni 1d on the cell membrane (Not cell w © The cell envelope of bacteria consists of the cell membrane (cytoplasmic membrane) and cell wall ‘The cell wall is made up of peptidoglycans in gram. positive bacteria and peptidoglycans plus an outer ‘membrane in gram negative bacteria + Penicillin binding proteins are membrane proteins localized to the cytoplasmic membrane of the bacterial envelope and notin the cell wall (shown in the figure). Penicillin binding proteins (though located inthe cell membrane) are functionally enzymes involved in the synthesis of cell wall. These enzymes are involved in cross linking of peptidoglycans, and hence give cell wall is structural rigidityPenicillin Binding bo} nd Transpeptis The major activities associated with PBPs are peptidoglycan transpeptidase which is believed to be essential and D,D carboxypeptidase which is believed to be dispensible’ - Current Medicinal Chemistry ‘+ Transpeptidase (Essential) + Carboxypeptidase © Endopeptidase eS | Alteration in PBP’s is the primary bases of resistance in MRSA ‘Alteration in target PBPs provides the organism with resistance to penicillins. Methicillin Resistant Staphylococcus Aureus (MRSA) apparently arose because of such an alteration’ - Lippincott's Pharmacology 4"/360 ‘Altered target PBPs are the basis of methicillin resistance in staphylococci (MRSA) and penicillin resistance in pneumococci and enterococii’ = Katzung 11/776 (b) Answer is B (Alteration in target PBPs is an important resistance mechanism in Gram negative bacteria): ‘Antimicrobial Resistance: A crisis in Health Care" (1995) by Jungkind / 17 Alteration in target PBPs is an important resistance mechanism in Gram positive bacteria and not in Gram negative bacteria. I: is very unusual to encounter Gram Negative bacteria that have acquired Resistance to f-Lactam Antibiotics due to an alteration in target Penicillin Binding Proteins.- ‘Antimicrobial Resistance: A crisis in Health Care” (1995) by Jungkind / 17 wolv ‘Normal mechenism of action of ‘Normal mechanism of action of ‘Belactam antibiotics Belactam antibi i ‘+ Antibiotic entry through cell wall Antibiotic enters cell where it binds (penetration) Penicillin binding proteins and causes ‘© Antibiotic binding to Penicillin disruption of cell wall synthesis and binding proteins (Normal PBPs) cell growth Antibiotic survival throughout ‘the process (absence of B- lactamases) Production of Beta Lactamases ‘Alteration in PBP: Trnpaired penetration This causes lysis of Beta- lactamase _| This causes failure ofthe antibiotic to bind_| This causes failure of antibiotic to ring of antibiotic and thus inactivates | tothe target PBP and hence failure of |_| penetrate the cell and hence failure of the antibiotic (Resistance) action (Resistance) action (Resistance) ‘llraion of BPS This is the most common mechanism | This mechanism is primarily seen with | This mechanism is seen only in Gram of penicilin resistance in both Gram | Gram positive bacteria negative bacteria Positive and Gram negative bacteria | (Ir i easier for Gram negative bacteria to | (Never seen in Gram positive bacteria) (Beta lactamases are elaborated by | alter permeability to these drugs and hence | (Gram negative bacteria contain an Several rom pocve ed gram itis very unusual o encounter gram ‘outer membrane outside the negative bacteria) rnegative bacteria that have acquired peptidoglycan layer which is not present resistance by alteration in PBP. MayThowever rarely be seen in highly fastidious ‘gram negative genera like Neisseria and Hemophillus) This isthe basis for methicillin resistance in MRSA and of Penicillin resistance in {in gram positive bacteria. Antibiotics enter G ~ve bacteria through pores ‘protein channels located within the outer membrane. Downregulation or alteration of these channels impairs the ‘entry of antibiotics into the cell. Pneumococeii and Enterococci (This mechanism isnot seen in Gram ‘positive bacteria) Answer is A (Most common source of infection is cross infection from infected people): Harrison 17/873-879; Jawetz 24°/224-230 ‘Most common source of infection is endogenous infection from individuals own colonizing strains & not infection ‘from other infected people. Most common source of infection is endogenous colonizing strains of staph. “Most individuals who develop staphylococcus aureus infections are infected with their own colonizing strains. However, S. aureus may also be acquired from other people or from environmental exposures '— Harrison 179/873 Approximate 10% of general population are he carriers of staphyloccus aureus Staphylococeus aureus is part of the normal human flora and 25 to 50% of healthy persons may be persistently or transiently colonized (Harrison) “The major habitat for Staph aureus on healthy human is anterior nares (30% of individuals) followed by the perenium (15% of individuals) ’— ‘The Desk Encyclopedia of Mirobiology’ (2004/904 ‘Staphylococci are part of the normal human bacterial flora with about 30% of general population being nasal carriers and another 10% carrying it on the perineal skin’ — ‘Essential Surgery by Burk & Read (Churcil Livingstone) I* (2007V/41 ‘Toxic Shock Syndrome Toxin (TSST-1) is a superantigen Toxic Shock Syndrome Toxin (TSST-1) and other staphylococcal enterotoxins belong to the class of superantigens. Epidermolytic toxin is generally not considered a ‘superantigen’. Jawetz textbook however has clearly mentioned ‘epidermolytic toxin as a superantigen. (For the purpase ofthis question we have therefore accepted ‘option Cas tru). “Epidermolysin’ is an exfoliative toxin that causes the ‘generalized desquammation ofthe Staphylococcal Scalded Skin Syndrome Epidermolytic toxin (epidermolysinjare ‘Superantigens - Jawetz Toxic shock syndrome Toxin ~ | (TSST-I) is the most ‘common toxin isolated from patients with Staphylococcal ‘Toxic Shock Syndrome (TSST-1 is same as Enterotoxin F) “TSST-1 isthe protypical superantigen’ —Jawetz Note: Like TSST-1, Enterotoxins are also superantigens (Jawetz) ‘Methicillin Resistance is chromosomally mediated (Harrison/Jawetz) Resistance to Methicillin is due to chromosomally mediated alteration in the Penicillin Binding Proteins (PBPs). Penicillin Binding Protein — 2a (PBP 2a) synthesized by mec gene is most closely responsible for methicillin resistance. Answer is B. (S. Agalacitae): Ananthanarayan 9/216, 210 5. Agalacitate is a beta-hemolytic streptococcus that has a Group B Lancefield Antigen, Iti resistant to bacitracin and shows a positive CAMP test. ‘S. Agalacitae may be identified by the CAMP reaction (Christie, Atkins and Munch-Peterson) which can be demonstrated as an accentuated zone of hemolysis when S. agalacitae is inoculated perpendicular to streak of staph, ‘aureus grown on blood culture’. - Ananthanarayanon. 92. [AIPGME EXAMINATION ANSWERS AND EXPLANATIONS -2010 © 869 = Ten _| ‘Alpha Bets “Gamma Haemolysis Haemolysis Hacmolysis (No Haemolysis) SPoesnonia Veen) [Sao see a D Seopcsock ‘S Agelaciue | | OberB Temaie Streptococi Optochicin sensitive Bile soluble Insulin Fermentation Answer is D (Enterotoxin can have direct effect on other tissues besides intestinal epithelial cells): Park The cholera enterotoxin has no effects on any other tissues except intestinal epithelial cells. Cholera Exotoxin (Enterotoxin) affects only intestinal epithelial cells “The exotoxin has no effect on any other tissues except the intestinal epithelial cells ~ Park 207/202 “There is no evidence the V. cholera invades any tissue nor the enterotoxin to have any direct effect on any organ other than the small intestine'- Park 20/203 ‘Humans are the only reservoir for V. cholera “The human being is the only known reservoir of cholera infection (classical or El-tor). He may be a case or carrier’ ~ Park 20/202 Y. Cholera are killed by boiling for 30 seconds “V. cholera are killed within a few seconds by boiling’ — Park 20"/202 ‘The WHO recommends that wate be heated until it reaches the boiling point. Some other organization like CDC however recommenda olin boil (of | minute, bu this isto ensure that users donot stop heating the water before true boiling point is reached. Both recommendations are acceptable a boiling water for more than afew seconds isnot necessary to kil the pathogen. ‘Y. cholera can survive in ice cold water for 2-4 weeks “They remain in ice for 4-6 weeks or longer’ ~ Park 20°/202 Answer is B (Yolk sac inoculation): Ananthanarayan 9/418; Jawetz 24/720; Harrison 17/1074; Textbook of Microbiology by Vasanthakumari 1" (2007)/32-35; Refer Q71 AIPGME 2004 Inoculation into Yolk sac of embryonal eggs is an established method for isolating Chlamydia.93. PCR is used for detection of Chlamydia genes/nucleic acid while DFA & ELISA are used for detection of Chlamydia antigens. None of these tests however are capable of isolating Chlamydia. Isolation of Chlamydia (Tissue culture/ Yolk sac inoculation / Animal inoculation) Although Chlamydia are bacteria, they are obligate intracellular pathogens. They can only be isolated by methods similar to those used for isolation of viruses. ee [Friese Curae /Cettecuture | [__Yotksseinoculation | [Animal inoculation (mice) — | This is the method of choice for isolating ‘Specimen inoculated into Intranasal, Intraperitoneal or Chlamydia Yolk sac of embryonated ege _Intracerebral inoculation can be # Cyclohexamide Treated Me Coy cells are grows in the endothelial cells carried out in mice ‘most commonly used HeLa or HeP2 or Monkey Kidney cells may be used. Laboratory diagnosis of Chlamydia lly Four Types of Laboratory Procedures are available) T 1 ‘Demonstration of Clamydial Demonstration of Antigen and Nucleic acid tests || Chlamydial Antibodies Ichi le Tissue culture [Antigen Detection test Serology is of limited value in diagnosis of > Di infections t Immunofluorescent |chlamydi Atethod of choice) Antibody (DFA) test ‘Me Coy and HeLa cet tines are ||, ‘commonly used. ELISA _| Methods include ‘i Yolk sac inoculation [Nucleic Acid Detection tests_}/_” Complement Fixation, Giesma stained (most (Embryonated ege) ‘Nucleic Acid Amplification tests|| Tests (CFT) wed stain commonly wed sn) Animal inoculation (Mice) | (NAAT |- Microimmunofluorese ane 1+ PCR (Polymerase Chain ence test (Micro-IF) J+ Microscopic examination Reaction) er Iodine staining or of pad, s le LCR (Ligase chain reaction) J+ TMA (Transcription “This method is only useful for Mediated Amplification) examination of conjunctival Serapings to diagnose inclusion |Non-NAAT secivts ent Thc l+ Non-Amplified DNA Probe Note®: The most sensitive and specific methods for establishing diagnosis of chlamydial infection today are Nucleic Acid Amplification Tests (NAAT)°. NAAT's may use PCR, LCR, TMA or other techniques Harrson Answer is A (Trigeminal ganglion): Harrison 17/1102, 1103, 1084; Jawetz Microbiology 24/399, 430, 437; Rubin's Pathology 5"/156; Ophthalmology Secrets 2"/87 Varicella Zoster Virus remains latent in sensory ganglia including dorsal root ganglia of the spinal cord (most frequently) and other ganglion including trigeminal ganglion and /or geniculate ganglion. Trigeminal ganglion is analogous to the dorsal root ganglion of the spinal cord and varicella zoster virus may remain latent in this ganglion. Reactivation of latent virus from the trigeminal ganglion may result in lesions on the face, in the ‘mouth, on the tongue or in the eye. Herpes zoster ophthalmicus represents reactivation of latent virus from the trigeminal ganglion with retrograde infection along first division (ophthalmic division) of trigeminal nerve.Zoster Views) v Non immune ini (usually child) 4 Virus enters sensory nerve endings and travels in retrograde fashion to + Vir ravels back from ganglia along sensory nerves tothe peripheral nerves ‘of sensory dermatomes causing “Shingles! Or | Iniateral vesicular Eruption within a dermatome associated with severe pain. (The dermatomes from T3 10 L3 are ‘most frequently involved) sensory ganglia whe ittremains latent. + Virus travels back from trigeminal ganglia, most often along first division of cranial nerve V causing Zoster Ophthalmicus. Other divisions may also be involved & lesions may appear on the face, inthe mouth or on the tongue. 94. Answer is B (Herpes): Reference with text + ‘Virus travels back from the geniculate ‘ganglion along the sensory distribution Of facial nerve causing Herpes Zoster Oticus or the ‘Ramsay Hunt Syndrome” Pain and vesicles appear inthe external cudtory canal. Potiens lose their sense

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