Notes-Conti..

64. The rise in H+and fall in HCO3− that occurs in type I (distal) renal tubular acidosis (RTA) does not increase the anion gap because the decrease in HCO3−is accompanied by an increase in Cl−. The failure of the distal nephron H+ ATPase causes a reduction in net acid excretion and a reduced H+ secretion, which causes less ammonium to be excreted in the urine. The low HCO3− in the glomerular filtrate reduces Na+ reabsorption by the Na-H exchanger and therefore more Na+
is delivered to the distal nephron. The increased Na+ delivery results in salt wasting and a secondary hyperaldosteronism which, in turn, causes K+ concentration to fall.





65. The ascending limb of Henle’s loop dilutes the fluid within the nephron by reabsorbing Na+
without water. In the absence of ADH, the reabsorption of Na+ without water continues along the collecting duct, making the Na+ concentration lower and lower. In the presence of ADH, water is reabsorbed from the collecting duct making the luminal fluid isotonic in the cortical collecting duct and hypertonic in the medullary collecting duct.

Parathyroid hormone (PTH) increases Ca2+ reabsorption from the thick ascending limb and the distal convoluted tubule. Although most of the filtered Ca2+ is reabsorbed in the proximal tubule, the regulation of Ca2+ excretion occurs in the thick ascending limb and the distal convoluted tubule. PTH regulates the reabsorption of HPO42− in the proximal tubule.

Aldosterone increases the reabsorption of Na+ from the principal cells within the cortical and medullary collecting ducts. Aldosterone increases Na+ reabsorption by increasing the luminal permeability to Na+ on the apical surface and the activity of the Na-K pump on the basal lateral surface of the principal cells. Aldosterone also increases the secretion of K+ and H+ from the collecting ducts.




66. Approximately two thirds of the 40 to 150 mg of protein excreted per day by the kidney is
derived from plasma proteins. The remainder is derived from the tubular secretion of a mucoprotein, the Tamm-Horsfall protein, that is present in tubular casts appearing in urinary sediment. Not all plasma proteins are filtered equally because glomerular permeability is related to molecular size and charge. The larger and negatively charged proteins are poorly filtered. Most of the filtered protein is reabsorbed in the proximal tubule unless the filtered load exceeds the tubular capacity. Such overload would occur following damage to the glomerular basement membrane and breakdown of normal barriers, or following an increase in the plasma concentration of a small protein, such as myoglobin. Protein excretion is also increased by sympathetic stimulation, such as that occurring during exercise. In this situation, renal vasoconstriction reduces the glomerular filtration rate, which, by increasing the transit time of glomerular filtrate, favors diffusion of proteins across the basement membrane. The presence of protein in the urine indicates glomerular dysfunction. RBC casts are indicative of glomerulonephritis. A red color indicates the presence of hemoglobin, myoglobin, or red food.





67. Juxtaglomerular ( JG) cells are sensitive to changes in afferent arterial intraluminal pressure. Increased pressure within the afferent arteriole leads to a decrease in renin release, whereas decreased pressure tends to increase renin release. Angiotensin appears to inhibit renin release by initiating the flow of calcium into the JG cells. Renin release is increased in response to increased activity in the sympathetic neurons innervating the kidney. Prostaglandins, particularly PGI2 and PGE2, stimulate renin release. Stimulation of the macula densa leads to an increase in renin release, and although the mechanism is not fully understood, it appears that increased delivery of NaCl to the distal nephron is responsible for stimulating the macula densa. Aldosterone does not appear to have any direct effect on renin release.




68. The macula densa senses the chloride concentration of the fluid flowing from the ascending limb of Henle’s loop into the distal convoluted tubule. An increase in NaCl concentration occurs when the amount of fluid flowing through the ascending limb increases because there is less time available for the reabsorption of NaCl. The resulting increase in Cl− concentration results in the release of adenosine (and/or ATP) from the macula densa.Adenosine constricts the afferent arteriole, resulting in a decrease in filtraion and a return of the flow rate within the nephron toward normal. This response is referred to as tubuloglomerular feedback. If the NaCl concentration decreases (e.g., when circulating blood volume decreases), the decreased Cl− concentration results in the release of renin from granular cells of the juxtaglomerular apparatus. Spironolactone acts by competitive
inhibition of aldosterone, thereby blocking Na+ reabsorption in the distal tubules and collecting ducts. Potassium-sparing diuretics are relatively weak and therefore are most effective when administered in combination with loop and/or thiazide diuretics.


The juxtaglomerular apparatus (JGA) is responsible for releasing renin when the effective circulating blood volume is decreased. The JGA releases renin when the Cl− concentration in the luminal fluid bathing the macula densa is decreased. The decrease in Cl− (and Na+) concentration
occurs when the flow rate within the nephron decreases and ample time is available for the loop of Henle to remove NaCl from the lumen. Adenosine is released from the macula densa cells when the luminal Cl− concentration increases in response to an increase in luminal flow rate. Adenosine
decreases renal blood flow by constricting the afferent arteriole and, therefore, the blood flow through the glomerular capillary.


69. Increased renin leads to increased production of angiotensin II, which binds to AT1 receptors in the zona glomerulosa, which act via a G protein to activate phospholipase C. The resultant increase in protein kinase C fosters the conversion of cholesterol to pregnenolone and facilitates the action of aldosterone synthase, resulting in the conversion of deoxycorticosterone to aldosterone.

Increased potassium concentration directly stimulates aldosterone secretion. Like angiotensin II, K+
stimulates the conversion of cholesterol to pregnenolone and the conversion of deoxycorticosterone to aldosterone by aldosterone synthase. Potassium exerts effect on aldosterone secretion by depolarizing the the zona glomerulosa cells, which opens voltage-gated Ca2+ channels, increasing
intracellular Ca2+. Adrenocorticotropic hormone (ACTH) stimulates aldosterone synthesis and secretion via increases in cyclic AMP and protein kinase A. The stimulatory effect of ACTH on aldosterone secretion is usually transient, declining in 1–2 days, but persists in patients with
glucocorticoid-remediable aldosteronism, an autosomal dominant disorder in which the 5’ regulatory region of the 11β-hydroxylase gene is fused to the coding region of aldosterone synthase gene, producing an ACTH-sensitive aldosterone synthase.






70. Blood flow through the kidney is controlled by numerous humoral agents. Angiotensin II decreases renal blood flow. It vasoconstricts efferent arterioles more than afferent arterioles, which helps to maintain glomerular filtration rate in the face of decreases in renal perfusion pressure. This may account for the renal failure that sometimes develops in patients with decreased renal perfusion who are taking angiotensin-converting enzyme inhibitors. Nitric oxide dilates the afferent arteriole and constricts the efferent arteriole, producing a rise in glomerular capillary pressure (and glomerular filtration) without having much of an effect on renal blood flow. Dopamine synthesized in the kidney increases renal blood flow and sodium excretion. Acetylcholine and atrial natriuretic peptide also produce renal vasodilation and an increase in renal blood flow.







71. Free water clearance is the amount of water excreted in excess of that required to make the urine isotonic to plasma. It is calculated using the formula: CH2O = V − Cosm. Free water clearance is positive when the urine is dilute (more than a sufficient amount of water is excreted), and free water clearance is negative when the urine is concentrated (not enough water is excreted to make the urine isotonic to plasma). An increase in free water clearance can lead to hypernatremia; a decrease in free water clearance can lead to hyponatremia. In diabetes insipidus, very little water is reabsorbed in the distal nephron, and, therefore, the free water clearance is very high. In heart failure or renal failure, very little free water can be generated even if the urine is dilute because the glomerular filtration rate is decreased. With diuretic therapy, Na+ excretion is increased. Therefore, the increased water excretion is accompanied by an increased Na+ excretion and the amount of free water generated is limited. Although the water loss is proportionally greater than the solute loss in
diabetes mellitus, the amount of water excreted is much less and the solute concentration significantly higher than in diabetes insipidus, so the free water clearance is much less in diabetes mellitus than in diabetes insipidus.






72. Growth hormone (GH) exerts many of its effects on growth and metabolism by stimulating the production and release of polypeptide growth factors called somatomedins from the liver, cartilage, and other tissues. In humans, the principal circulating somatomedins are insulin-like growth factor I (IGF-I, somatomedinC) and IGF-II. GH release is stimulated by growth hormone-releasing hormone (GHRH) and ghrelin and inhibited by somatostatin. All of these peptides are synthesized and released by the hypothalamus, though the main site of ghrelin synthesis and secretion is the stomach. GH increases lipolysis; the resultant increase in free fatty acids, which takes several hours to develop, provides a ready source of energy for the tissues during hypoglycemia, fasting, and stressful stimuli. GH also has a protein anabolic effect. GH is metabolized rapidly; the half-life of circulating GH in humans is 6 to 20 minutes.





73. Hormone-sensitive lipase is a cytoplasmic enzyme in adipocytes that catalyzes the complete hydrolysis of triglyceride to fatty acids and glycerol. It is activated by a cyclic AMP-dependent protein kinase that phosphorylates the enzyme, converting it to its active form. Because no accumulation of monoglycerides or diglycerides is detected in adipocytes following the action of hormone-sensitive lipase, it is the initial hydrolysis of triglyceride to fatty acid and diglyceride that is the rate-limiting step. Hormone-sensitive lipase is sensitive to several hormones in vitro, but it appears to be regulated in vivo primarily by epinephrine and glucagon, which activate it by increasing cyclic AMP, and insulin, which inhibits it by preventing cyclic AMP-dependent phosphorylation. Cortisol enhances lipolysis indirectly by promoting increased enzyme synthesis.





74. Synthesis and secretion of growth hormone (GH) by the anterior pituitary is regulated by a variety of metabolic factors, many of which act to alter the balance between release of growth hormone-releasing hormone (GRH) and somatostatin (SS) from the hypothalamus. Among the stimuli that increase GH secretion are: (1) conditions in which there is a deficiency of energy substrate (e.g., hypoglycemia, exercise, and fasting); (2) stressful stimuli (e.g., fever, various psychological stresses); (3) an increase in arginine and some other amino acids (e.g., protein meal, infusion of arginine); (4) glucagon; (5) L-Dopa and dopamine receptor agonists; (6) estrogens
and androgens; and (7) going to sleep. Stimuli that decrease GH secretion include somatostatin, REM sleep, glucose, cortisol, free fatty acids, and GH itself.




75. The primary action of glucagon is to increase blood glucose concentration, which it accomplishes by promoting gluconeogenesis and glycogenolysis in the liver but not in muscle. These effects are mediated by cyclic AMP, which is produced by hepatic adenylate cyclase
following interaction of glucagon with its plasma membrane receptor. Interaction of glucagon with different hepatic plasma membrane receptors activates phospholipase C, which results in a rise in concentration of intra-cellular Ca2+, which further stimulates glycogenolysis. Although glucagon
opposes the action of insulin, it does not directly affect insulin secretion.





76. Removal of the adrenal glands produces the clinical picture known as Addison’s disease, a disorder associated with deprivation of adrenocortical hormones. A lack of glucocorticoids diminishes the body’s ability to synthesize glucose by gluconeogenesis. Mineralocorticoid deprivation produces diuresis, natriuresis, and decreased potassium secretion leading to
excessive potassium plasma levels and acidosis.



77. Insulin does not promote glucose uptake by most brain cells. Insulin does increase glucose uptake in skeletal muscle, cardiac muscle, smooth muscle, adipose tissue, leukocytes, and the liver. In most insulin-sensitive tissues, insulin acts to promote glucose transport by enhancing facilitated diffusion of glucose down a concentration gradient. In the liver, where glucose freely permeates the
cell membrane, glucose uptake is increased as a result of its phosphorylation by glucokinase. Formation of glucose-6-phosphate reduces the intra-cellular concentration of free glucose and maintains the concentration gradient favoring movement of glucose into the cell.



78. Thyroid storm is an exaggerated manifestation of hyperthyroidism. Thyroid storm is a medical emergency and mortality is high (20–50%) even with the correct treatment. After primary stabilization of the airway, breathing and oxygenation, circulation, and fluid balance, treatment
includes propylthiouracil (PTU) or methimazole to block the synthesis of new thyroid hormone and β-blockers to block adrenergic effects. Iodine should not be given until after PTU has taken effect (~1.5) or more thyroid hormone will be produced. Aspirin displaces T4 from thyroid binding pro-
tein, and therefore should not be used to treat fever. T3 and T4 inhibit the release of thyrotropin-releasing hormone (TRH) from the hypothalamus, which regulates thyroid-stimulating hormone (TSH) secretion from the anterior pituitary gland.



79. Synthesis and secretion of melatonin are increased in the dark via input from norepinephrine
secreted by postganglionic sympathetic neurons. Melatonin is synthesized in the pineal gland from the amino acid tryptophan. Pinealomas (tumors of the pineal gland) that destroy the pineal gland and reduce secretion of melatonin and cause hypothalamic damage may cause precocious puberty
by removing the inhibitory effect of melatonin on the pituitary response to gonadotropin-releasing hormone. Melatonin causes amphibian skin to become lighter in color but has no role in the regulation of skin color in humans.




80. The islets of Langerhans, which constitute 1 to 2% of the pancreatic weight, secrete insulin, glucagon, somatostatin, and pancreatic polypeptide. Each is secreted from a distinct cell type, A, B, D, and F, respectively. The islets are scattered throughout the pancreas, but are more plentiful in the tail than in the body or head....



81. As a result of insulin deficiency-->Decreased intracellular α-glycerophosphate in liver and fat cells---α-Glycerophosphate is produced in the course of normal use of glucose. In the absence of adequate quantities of α-glycerophosphate, a normal acceptor of free fatty acids in triglyceride synthesis, lipolysis will be the predominant process in adipose tissue. As a result, fatty acids will be released into the blood. The prevailing insulin level is decisive in the selection of substrate by a tissue for the production of energy. Insulin promotes use of carbohydrate, and a lack of the hormone causes use of fat mainly to the exclusion of uptake and use of glucose, except by brain tissue. Indirect depression of glucose utilization due to excess fatty acids is a result, and not a contributing cause, of increased use of fat.



82. Thyroxin-binding globulin (TBG) is increased in estrogen-treated patients and during pregnancy, increasing the total plasma levels of T3 and T4, but with a normal level of the free thyroid hormones, such that the clinical state is euthyroid. Cortisol levels also increase during pregnancy and parturition due to increased production of corticotropin-releasing hormone (CRH) by
the placenta (as well as the fetal hypothalamus). Although tissue renin contributes little to the circulating renin pool, pregnancy is associated with increased renin levels that may arise from components of the tissue renin-angiotensin system found in the uterus, the placenta, and the fetal membranes. Amniotic fluid contains large amounts of prorenin.


Secretion of TSH is regulated primarily by the pituitary levels of T3. As plasma thyroid hormone levels increase, pituitary T3 levels rise and lead to inhibition of TSH synthesis and secretion. TSH stimulates thyroid gland function by binding to specific cell membrane receptors and increasing the
intracellular levels of cAMP. The thyroid gland secretes thyroxine (T4) and triiodothyronine (T3); the latter is the physiologically active hormone. The majority of T3 is formed in the peripheral tissues by deiodination of T4.


84. Growth hormone activates many different intracellular enzyme cascades, including the
JAK2-STAT pathway, which also mediates the effects of various growth factors and prolactin. Secretion of insulin-like growth factor I (IGF-I) increases throughout childhood and stimulate cell proliferation and growth in many different cell types, including chondrocytes within growth plates.
Linear growth ends earlier in girls than in boys. IGF-II is largely independent of growth hormone and plays a role in the growth of the fetus before birth. Thyroid hormones are essential for normal linear growth and skeletal development. The growth-promoting effects of thyroid hormones occur
via a synergistic effect with growth hormone.

Patients with acromegaly have insulin resistance. In addition, they manifest increased lipolysis and increased gluconeogenesis due to their high growth hormone levels. The combination of enhanced glucose production and insulin resistance can produce hyperglycemia and diabetes mellitus.
Protein synthesis increases to support tissue growth and proliferation.



85. Due to their relatively low solubility within the lipid portions of the cell membrane, peptide hormones and catecholamines (epinephrine) must interact with receptors located on the cell membrane. Activation of the receptor is followed by the generation of intracellular second messengers that ultimately mediate the biological response to the hormone. Steroid hormones and thyroid hormones readily pass through the cell surface membrane and interact with intracellular
receptors to produce their effects by regulating gene expression within the nucleus.

Cortisol, like other steroid hormones, diffuses into target cells and interacts with intracellular
receptors. The steroid-receptor complex has a high affinity for the steroid-responsive element of DNA. Once bound to DNA, the hormone-receptor complex acts as a transcription factor to regulate gene expression and formation of specific messenger RNAs.





86. Glucocorticoids lower plasma Ca2+ levels by inhibiting osteoclast formation and activity. Over long periods of time, glucocorticoids cause osteoporosis by decreasing bone formation and
increasing bone resorption. They decrease bone formation by inhibiting protein synthesis in osteoblasts. Glucocorticoids also decrease the absorption of Ca2+ and PO4 3–from the intestine and increase the renal excretion of these ions. Vitamin D formation is facilitated when plasma Ca2+
levels are low.

Cortisol is defined as a glucocorticoid because it promotes the conversion of amino acids to glucose (gluconeogenesis). It also decreases glucose uptake by muscle and adipocytes by decreasing the sensitivity of the cells to insulin. The net result is to provide more glucose to non-insulin-requiring cells. Cortisol retards wound healing. It also decreases CRH and ACTH secretion by feedback inhibition.





87. Phenylethanolamine-N-methyltransferase (PNMT), the enzyme that catalyzes the formation of epinephrine from norepinephrine, is found in appreciable quantities only in the brain and the adrenal medulla. Adrenal medullary PNMT is induced by glucocorticoiods and glucocorticoids are necessary for the normal development of the adrenal medulla. Circumstances that increase sympathetic nerve input to the adrenal medulla increase catecholamine secretion. Major stressors include decreased intravascular volume or pressure, fear or rage, a change in posture from supine to standing, and hypoglycemia.




88. Atrial natriuretic peptide (ANP) is synthesized, stored, and secreted by cardiac atrial muscle, the latter in response to increased central venous pressure or increased plasma sodium concentrations. ANP increases glomerular filtration by simultaneous dilation of afferent and constriction of efferent renal arterioles. It decreases salt and water reabsorption along the entire length of the kidney. The excretion of water is enhanced by inhibition of ADH.






ANATOMY



89. The maximum number of oogonia occurs at about the fifth month of development. Primordial germ cells arrive in the embryonic gonad of a genetic female during the 7th to 12th week where they differentiate into oogonia. After undergoing a number of mitotic divisions, those fetal cells
form clusters in the cortical part of the ovary. Some of those oogonia differentiate into the larger primary oocytes (not to be confused with primary follicles). The primary oocytes begin meiosis. At the same time, the number of oogonia continues to increase to about 6,000,000 by the fifth month. At this time, most of the surviving oogonia and some of the oocytes become atretic. However, the surviving primary oocytes (400,000 to1,000,000) become surrounded by epithelial cells and form the primordial follicles by the seventh month. During childhood there is continued atresia, so that by puberty only about 40,000 primary oocytes remain.



90. On fusion of the first sperm with the oocyte cell membrane, the contents of secretory granules stored just beneath the oocyte membrane (cortical granules) are released (the zona reaction). Enzymes stored in those granules cause biochemical and electrical changes in the zona pellucida and the oocyte membrane that prevent the binding of additional sperm.

Primitive female germ cells (oogonia) enter the first meiotic division during fetal development . This process becomes arrested in prophase I until individual primary oocytes are hormonally induced to resume the first meiotic division during puberty and early adulthood (menarche to menopause). Fusion of the sperm and oocyte membranes initiates the resumption of the second meiotic division, resulting in the formation of a haploid pronucleus in the oocyte and extrusion of the second polar body .

Capacitation is a process by which enzymatic secretions of the uterus and oviducts strip glycoproteins from the sperm cell membrane. This is required for penetration of the layer of cells surrounding the oocyte (corona radiata). The release of enzymes from the sperm acrosomal cap (an enlarged lysosome) results in digestion of the zona pellucida surrounding the oocyte, allowing penetration by sperm.

Primary oocytes have developed by the time of birth. From puberty to menopause, these germ cells remain suspended in meiotic prophase I (diplotene or dictyate stage). A midcycle surge of LH triggers the resumption of meiosis and causes the FSH-primed follicle to rupture and discharge the ovum. Under the influence of LH, the ruptured follicle is transformed into a corpus luteum, which
produces progesterone. FSH and LH produced in the adenohypophysis result in growth and maturation of the ovarian follicle. Under FSH stimulation, the theca cells proliferate, hypertrophy, and begin to produce estrogen.


The secondary oocyte enters the second meiotic division just before ovulation and arrests at metaphase. Fertilization by a spermatozoon provides the stimulation for the division of chromatin to the haploid number. By the time the fertilized ovum reaches the uterus, the progesterone produced by the corpus luteum has initiated the secretory phase in the endometrium. Once implantation occurs and the chorion develops, human chorionic gonadotropin (hCG) is synthesized and the corpus luteum is maintained . Expulsion from the follicle and the environment of the oviduct and
uterus do not induce the second meiotic division



91. Capacitation, the acrosome reaction and penetration are required for the hamster sperm penetration assay (SPA). Capacitation prepares the sperm for fertilization and requires an increase in fluidity of the sperm plasma membrane. Sperm must reside in the female reproductive tract or under appropriate in vitro conditions for about 1 hour for capacitation to occur. During capacitation there is a loss of decapacitation factors that have been added to the sperm by epididymal cells and accessory male reproductive organs. Cholesterol is removed from the sperm plasma membrane during this period, which results in the increased fluidity of this membrane that is required for the fusion of the acrosomal membrane with the sperm plasma membrane. Next, there is release of the acrosomal enzymes , which are required for the breakdown of the corona radiata and the zona pel-
lucida of the oocyte to facilitate sperm penetration. Sperm formation and maturation occur in the testis and epididymis.


The formation of the acrosome, a specialized secretory granule, is one of many maturation events
occurring during spermiogenesis (the process by which mature sperm are formed from the spermatids). Acrosome formation involves lytic enzyme maturation and occurs after division of secondary spermatocytes. It involves no mitotic or meiotic activity . The acrosome develops from
Golgi vesicles just like any other secretory granules. It contains acrosin, a serine protease, hyaluronidase, and neuraminidase, responsible for the penetration ability of the sperm. The developing cells are in contact with Sertoli cells for all of the stages of spermiogenesis. At the end of spermiogenesis, spermatids are released by Sertoli cells in a process called spermiation .
Decapacitation factors are not involved in acrosomal maturation.

Spermatogenesis, the processby which spermatogonia undergo mitotic division to produce primary spermatocytes, occurs at 1°C (2°F) below normal body temperature. Subsequent meiotic divisions produce secondary spermatocytes with a bivalent haploid chromosome number and then spermatids with a monovalent haploid chromosome number. Spermiogenesis, the maturation of the spermatid, results in spermatozoa. Morphologically, adult spermatozoa are moved to the epididymis, where they become fully motile.


92. Cells of the inner cell mass (embryoblast) of the blastocyst differentiate into the epiblast and hypoblast. Cells of the epiblast migrate toward the primitive streak during the second week and
become internalized, forming the mesodermal and endodermal germ layers. Remaining cells of the epiblast become the ectodermal germ layer (epidermis, epidermal appendages, and the nervous system). Cells of the hypoblast will contribute to the yolk sac. Cells of the outer cell mass of the blastocyst will differentiate into the cytotrophoblast and syncytiotrophoblast , which will contribute to formation of the placenta. The yolk sac is incorporated into the embryo as the primitive gut during embryonic folding.
Formation of most internal organs occurs during the second month, the period of organogenesis. The first month of embryonic development generally is concerned with cleavage, formation of the germ layers, and establishment of the embryonic body. The period from the ninth week to the end of intrauterine life, known as the fetal period, is characterized by maturation of tissues and rapid growth of the fetal body.

93. During the second week of fetal development, lacunar spaces develop between cells of the syncytiotrophoblast, particularly in the region of the embryonic pole as the conceptus invades the endometrium. Endometrial capillaries in this region become dilated and engorged with blood to form sinusoids. The syncytial cells direct erosion of the endothelium of the maternal capillaries, allowing maternal blood to enter the lacunae and bathe the syncytial cells. During the second week, primary villi consist of projections of syncytial cells surrounding a core of cytotrophoblast cells. During the third week , the villus core is invaded by mesodermal cells to form a secondary villus. Cells of the mesodermal core will then differentiate to form capillaries and blood cells by the end of the third week (tertiary villus). Those vessels become connected to the fetal circulation early in the fourth week establishing the functional uteroplacental circulation.



94. The presence of a murmur could be indicative of any of the conditions. The presence of a continuous machine-like murmur is indicative of a patent ductus arteriosus (PDA). The ventilator requirements are increased due to increasing pCO2 (as the lungs become “wet,” the pCO2 increases). The diastolic blood pressure usually drops and there is a widened pulse pressure (usually greater than 20). The PDA was always there, it is just that her pulmonary vascular resistance relaxed enough to allow more left-to-right shunting and more blood flow to the lungs (less to the body).

An atrial septal defect (ASD), such as a persistent foramen ovale, could be eliminated from the diagnosis because the murmur would be heard as an abnormal splitting of the second sound during expiration.

A patent foramen ovale is a common echo finding in premature babies and is usually not followed up unless it appears remarkable to the pediatric cardiologist or there is a persistent murmur. A patent foramen ovale might result in only minimal or intermittent cyanosis during crying or straining to pass stool.

A murmur caused by a ventricular septal defect (VSD, answer c), occurs between the first and second heart sounds (S1 and S2) and is described as holosystolic (pansystolic) because the amplitude is high throughout systole.

Pulmonary stenosis would be heard as a harsh systolic ejection murmur. Coarctation of the aorta would result in a systolic murmur.

PDA refers to the maintenance of the ductus arteriosus, a normal fetal structure. In the fetus, the ductus arteriosus allows blood to bypass the pulmonary circulation, since the lungs are not involved in CO2/O2 exchange until after birth. The placenta subserves the function of gas exchange during fetal development. The ductus arteriosus shunts flow from the left pulmonary artery to the aorta. High oxygen levels after birth and the absence of prostaglandins from the placenta cause the ductus arteriosus to close in most cases within 24 hours. A PDA most often corrects itself within several months of birth, but may require infusion of indomethacin (a prostaglandin inhibitor) as a treatment, insertion of surgical plugs during catheterization, or actual surgical ligation.



95. IgA deficiency, the most common immunoglobulin deficiency. IgA functions in several ways, one of which is to coat pathogens with a negative charge that repels the polyanionic charge on the cell surface. In IgA deficiency, pathogens can more easily attach to the cell surface leading to persistent infections. The carbohydrate of biological membranes is found in the form of glycoproteins and glycolipids rather than as free saccharide groups. The polyanionic charge of the membrane is produced by the sugar side chains on the glycoproteins and glycolipids. Glycoproteins often terminate in sialic acid side chains, which impart a negative (polyanionic) charge to the mem-
brane. Similarly, the glycolipids (also called glycosphingolipids), particularlythe gangliosides, terminate in sialic acid residues with a strong negative charge. Cholesterol alters membrane fluidity (see figure below and question 34) and is amphipathic (hydrophilic and hydrophobic properties). It
reduces the packing of lipid acyl groups through its steroid ring structure and hydrocarbon tail and cements hydrophilic regions of the membrane through interactions with its hydroxyl (OH) region. Peripheral membrane proteins are found primarily on the cytosolic leaflet of the membrane
bilayer. Integrins (answer e) are heterodimeric receptors that bind with extra-cellular matrix (ECM) molecules such as laminin and fibronectin.




96. In its anion exchanger role, band 3 protein exchanges bicarbonate ion for chloride ion. Bicarbonate is transported by band 3 out of the RBC in exchange for chloride, permitting the highly efficient transport of CO2 to the lungs as bicarbonate. In the absence of band 3 protein, the bicar-
bonate buffering of the blood is reduced, leading to acidosis or lowering of blood pH. The result is reduced capacity to carry CO2. In addition to its functional, bidirectional anion exchanger role, band 3 plays a key membrane structural role, since the cytoplasmic domain of the protein interacts with spectrin through an ankyrin bridge. Spectrin exists as dimers and trimers; the trimers are bound together by actin, thus providing a connection to the cytoskeleton maintaining the shape and stability of the RBC. The result of a null mutation in band 3 is the formation of erythrocytes that are small and round instead of biconcave (spherocytosis). Spherocytes are osmotically fragile because of their decreased surface area per unit volume. The defective RBCs do not readily pass through the small sinusoids of the spleen, resulting in destruction and further membrane conditioning, which leads to accelerated destruction and, eventually, enlargement of the spleen (splenomegaly). The
accelerated hemolysis leads to increased bile production and jaundice. Hemoglobin production is also increased, as exemplified by an increase in mean corpuscular hemoglobin concentration (MCHC) by about 35 to 40%. The bone marrow compensates for the increased destruction of RBCs with hyperplasia of erythroid precursors in the bone marrow and increase in the number of reticulocytes (polychromasia)





97. The patient in the scenario is suffering from cirrhosis in which there are alterations in plasma
lipoproteins. Binding of an antibody to a cell surface receptor results in lateral diffusion of protein in the lipid bilayer, resulting in increased membrane fluidity—patching and capping. Rotational and lateral movements of both proteins and lipids contribute to membrane fluidity. Restriction reduces
membrane fluidity. Phospholipids are capable of lateral diffusion, rapid rotation around their long axis, and flexion of their hydrocarbon (fatty acyl) tails. They undergo transbilayer movement, known as “flip-flop,” between bilayers in the endoplasmic reticulum; however, in general thisdoes not occur in the plasma membrane. Other factors reduce membrane fluidity. An increase in the amount of cholesterol relative to phospholipid has been shown by a variety of physicochemical techniques to decrease fluidity in both biological and artificial membranes by interacting with the hydrophobic regions near the polar head groups and stiffening this region of the membrane. Association or binding of integral membrane proteins with cytoskeletal elements on the interior of the cell and peripheral membrane proteins on the extracellular surface limit membrane mobility and fluidity.


Asymmetry of the lipid bilayer is established during membrane synthesis in the endoplasmic retic-
ulum before reaching the Golgi apparatus. Carbohydrates are associated with the N terminals of transmembrane proteins that extend from the extracellular surface, not the cytoplasmic surface. Cholesterol is different from proteins and phospholipids that are asymmetrically distributed within the bilayer. Cholesterol is found on both sides of the bilayer. The small polar head group structure
of cholesterol allows it to flip-flop from leaflet to leaflet and respond to changes in shape. In contrast to cholesterol, most proteins and phospholipids are capable of only rare flip-flop. For example, transbilayer movement of phospholipid is limited mostly to the endoplasmic reticulum.


98. Albuterol binds to β-receptors, which are multipass G-protein-linked receptors. Binding to G-protein-linked receptors activates or inactivates enzymes bound to the plasma membrane (adenylyl cyclase or phospholipase C) or opens or closes ion channels using G proteins. A table of G proteins and their functions appears below. The β-receptors, as well as muscarinic cholinergic receptors and rhodopsin, are multipass transmembrane proteins consisting specifically of seven hydrophobic
spanning segments of the single polypeptide chain. The peptide bonds of the spanning segments are polar. In the hydrophobic environment of the lipid bilayer, in the absence of water, they form hydrogen bonds with eachother. There is a remarkable homology between the cell-surface receptors
linked to the G proteins. Ligand binding occurs on the extracellular surface. Receptors with intrinsic enzyme activity belong to a separateclass of single-pass transmembrane proteins. All of these trans-
membrane proteins show a carboxyl terminus on the cytosolic side and N-linked glycosylation sites on the extracellular surface.







99. Anti-vimentin is specific for mesenchymal cells such as fibroblasts, macrophages, endothelial cells, and smooth muscle of the vasculature. In the salivary glands fibrous stromal tissue is derived from mesenchyme.
The acini and ducts are derived from epithelium.
The parasympathetic ganglia will stain with pan-neuronal markers such as peripherin.
The type of intermediate filament protein is relatively specific for cells derived from the three embryonic germ layers. Antibodies to intermediate filament proteins have been used by pathologists to determine the origin of tumors. Intermediate filament proteins have a structural role but also are involved in the anchorage of the proteins that form ion channels.
Cytokeratins (also known as keratins) are specific for epithelial cells.
Neurofilament proteins (NFL, NFM, and NFH) are found in neurons. In Alzheimer’s disease, extensive plaques of neurofilament proteins occur.
Desmin is found in striated and most smooth muscle, except vascular smooth muscle.
Glial fibrillary acidic protein, GFAP, is specific for astrocytes, not microglia or oligodendrocytes





100. The large subunit of the ribosome catalyzes peptide bond formation by activation of peptidyl transferase. The small ribosomal subunit contains the peptidyl-tRNA-binding (P) site that binds the tRNA molecule attached to the carboxyl end of the growing end of the polypeptide chain.
The small subunit also contains the aminoacyl-tRNA-binding (A) site that holds the incoming tRNA and amino acid. The initiation factors are loaded on the small ribosomal subunit that must locate the AUG (start) codon to initiate protein synthesis. This occurs before binding of the large subunit. In addition, the initiator tRNA containing methionine provides the amino acid necessary to start protein synthesis. The initiator tRNA is also located on the small subunit. It resides at the P site (the normal peptidyl site) even though it is an aminoacyl-tRNA. This occurs before binding to the mRNA. Therefore, the initiation phase of protein synthesis is regulated by the small subunit of the ribosome.
Ribosomes are composed of both protein and RNA (predominantly rRNA, but also mRNA and
tRNA). Single ribosomes are involved in synthesis of cytosolic proteins. Polyribosomes, linked by mRNA, synthesize proteins that are translocated into the cisternal space of the rough endoplasmic reticulum (RER) and destined for export or specific organelles.



101. Histochemical stains, such as acid phosphatase and nucleoside diphosphates, show that the Golgi apparatus is topologically compartmentalized. It presents two faces: a cis face, which is the point of entry of transport vesicles (COP-II-coated), in transit from the rough endoplasmic reticulum (RER) to the Golgi, and a trans face, which is the exit point associated with
granule formation and the maturation of proteins. Both proteins and lipids are transported from the transitional elements of the ER to the Golgi apparatus. Packaging is not the sole function of the
Golgi. This organelle is also involved in the processing of proteins (e.g.,addition and trimming of oligosaccharide chains) that was initiated in the RER as well as sulfation.


102. Oxidative metabolism by cytochrome p450 enzymes in hepatocytes is a primary mechanism for drug metabolism. Barbiturates are modified in the liver by oxidative demethylation through the P450 oxidase system found in the smooth endoplasmic reticulum (SER) (the structure shown in the electron micrograph). The SER in hepatocytes responds to Phenobarbital ingestion by increasing its volume. The proliferation (hypertrophy) of the SER facilitates metabolism of drugs. There is a concomitant increase in enzymatic activity, however, the synthesis of those enzymes occurs in the
rough endoplasmic reticulum (RER) not in the SER (answer d). The purpose of drug metabolism is to make drugs more water soluble so they can be more easily excreted from the liver through the bile. Increase in enzymatic activity following Phenobarbital ingestion catalyzes reactions that increase the solubility of various xenobiotics including toxins, alcohol, steroids, eicosanoids, carcinogens, insecticides, and other environmental pollutants. Lysosomes not the SER contain acid hydrolases. The P450 system and the SER are involved in drug interactions. Hepatocytes adapted to metabolize one drug may develop increased capability to metabolize other drugs. For example, if patients taking Phenobarbital for epilepsy increase their alcohol intake they may be ingesting subtherapeutic levels of the antiseizure medication because of induction of smooth ER in
response to the alcohol.



103. The woman in the sce nario suffers from retinitis pigmentosa. Vesicles and organelles move
unidirectionally along microtubules from the inner segment to the outer segment of the photoreceptor. Opsin, which is needed to sense light, is transported to sites of utilization in the disks of the outer segment. Transport occurs through the connecting, non-motile cilium, driven by the microtubule motor, kinesin, an ATPase. Microtubules are composed of tubulin and are involved in motility as the principal protein in the composition of the axoneme (the core of the cilium or flagellum). Micro-filaments (thin filaments) are composed of actin, the most abundant protein in cells of eukaryotes. They are involved in cell motility and changes in cell shape. Myosin is the main constituent of the thick filament that binds to actin and functions as an ATPase activated by actin. Intermediate filaments that are “intermediate” in diameter (8 to 10 nm) between thin and thick filaments are of five different types. Type I and type II are the acidic and basic keratins (cytokeratins) respectively and are found specifically in epithelial cells. Type III intermediate filaments are composed of vimentin, desmin, and glial fibrillary acidic protein (GFAP). Vimentin is found in cells of mesenchymal origin, desmin in muscle cells, and glial fibrillary acidic protein in astrocytes. Type IV intermediate filaments are neurofilament proteins found in neurons. Type V intermediate filaments include the nuclear lamins A, B, and C and are associated with nuclear lamina of all cells. Spectrin heterodimers stabilize the plasma membrane and connect the membrane to actin.





104.














105. The common fibular (peroneal) nerve bifurcates into superficial and deep branches. The deep fibular nerve innervates all muscles of the anterior compartment of the leg. The lateral sural cutaneous is a cutaneous branch of the common fibular nerve. The superficial fibular nerve
emerges from the deep fascia and descends in the lateral compartment, where it innervates the fibularis (peroneus) longus and brevis muscles before dividing into median dorsal cutaneous and intermediate dorsal cutaneous nerves, which supply the distal third of the leg, dorsum of the
foot, and all the toes. The saphenous nerve [ the terminal branch of the common femoral nerve] distributes cutaneous branches to the anterior and medial aspects of the leg as well as to the dorsomedial aspect of the foot. The sural nerve follows the course of the lesser saphenous vein and becomes the lateral sural cutaneous nerve to supply the anterolateral aspect of the foot.



106. All of the listed choices are branches of the internal iliac artery. The inferior vesical artery in the male supplies the seminal vesicle, prostate, fundus of the bladder, distal ureter, and the vas deferens. In the female, the vaginal artery supplies the vagina, urinary bladder, and pelvic portion of the urethra. The obturator artery (Br of post division) gives off muscular and nutrient branches within the pelvis and then leaves the pelvis via the obturator canal to supply the thigh. The internal pudendal artery crosses the piriformis muscle, exits the pelvic cavity via the greater sciatic foramen, and enters the ischiorectal fossa via the lesser sciatic foramen. It supplies the external genitalia (penis and clitoris). The middle rectal artery supplies the inferior rectum and forms important anastomoses with other rectal arteries. The umbilical artery (Br of Ant division of Internal iliac artery) gives off the superior vesical artery in both sexes. Its distal portion degenerates to form the medial umbilical ligament.





107. The Celiac Plexus (Plexus Cœliacus; Solar Plexus) —The celiac plexus, the largest of the three sympathetic plexuses, is situated at the level of the upper part of the first lumbar vertebra and is composed of two large ganglia, the celiac ganglia, and a dense net-work of nerve fibers uniting them together. It surrounds the celiac artery and the root of the superior mesenteric artery. It lies behind the stomach and the omental bursa, in front of the crura of the diaphragm and the commencement of the abdominal aorta, and between the suprarenal glands. The plexus and the ganglia receive the greater and lesser splanchnic nerves of both sides and some filaments from the right vagus, and give off numerous secondary plexuses along the neighboring arteries

The Celiac Ganglia (ganglia cæliaca; semilunar ganglia) are two large irregularlyshaped masses having the appearance of lymph glands and placed one on either side of the middle line in front of the crura of the diaphragm close to the suprarenal glands, that on the right side being placed behind the inferior vena cava. The upper part of each ganglion is joined by the greater splanchnic nerve, while the lower part, which is segmented off and named the aorticorenal ganglion, receives the lesser splanchnic nerve and gives off the greater part of the renal plexus.
The secondary plexuses springing from or connected with the celiac plexus are the
Phrenic.

Renal.
Hepatic.

Spermatic.
Lienal.

Superior mesenteric.
Superior gastric.

Abdominal aortic.
Suprarenal.

Inferior mesenteric.




The Hypogastric Plexus (Plexus Hypogastricus)—The hypogastric plexus is situated in front of the last lumbar vertebra and the promontory of the sacrum, between the two common iliac arteries, and is formed by the union of numerous filaments, which descend on either side from the aortic plexus, and from the lumbar ganglia; it divides, below, into two lateral portions which are named the pelvic plexuses.

The Pelvic Plexuses—The pelvic plexuses supply the viscera of the pelvic cavity, and are situated at the sides of the rectum in the male, and at the sides of the rectum and vagina in the female. They are formed on either side by a continuation of the hypogastric plexus, by the sacral sympathetic efferent fibers from the second, third, and fourth sacral nerves, and by a few filaments from the first two sacral ganglia. At the points of junction of these nerves small ganglia are found. From these plexuses numerous branches are distributed to the viscera of the pelvis. They accompany the branches of the hypogastric artery.

The superior mesenteric plexus (plexus mesentericus superior) is a continuation of the lower part of the celiac plexus, receiving a branch from the junction of the right vagus nerve with the plexus. It surrounds the superior mesenteric artery, accompanies it into the mesentery, and divides into a number of secondary plexuses, which are distributed to all the parts supplied by the artery, viz., pancreatic branches to the pancreas; intestinal branches to the small intestine; and ileocolic, right colic, and middle colic branches, which supply the corresponding parts of the great intestine. The nerves composing this plexus are white in color and firm in texture; in the upper part of the plexus close to the origin of the superior mesenteric artery is a ganglion (ganglion mesentericum superius).


The inferior mesenteric plexus (plexus mesentericus inferior) is derived chiefly from the aortic plexus. It surrounds the inferior mesenteric artery, and divides into a number of secondary plexuses, which are distributed to all the parts supplied by the artery, viz., the left colic and sigmoid plexuses, which supply the descending and sigmoid parts of the colon; and the superior hemorrhoidal plexus, which supplies the rectum and joins in the pelvis with branches from the pelvic plexuses.



The Hypogastric Plexus (Plexus Hypogastricus)—The hypogastric plexus is situated in front of the last lumbar vertebra and the promontory of the sacrum, between the two common iliac arteries, and is formed by the union of numerous filaments, which descend on either side from the aortic plexus, and from the lumbar ganglia; it divides, below, into two lateral portions which are named the pelvic plexuses.

The superior gastric plexus (plexus gastricus superior; gastric or coronary plexus) accompanies the left gastric artery along the lesser curvature of the stomach, and joins with branches from the left vagus.

The suprarenal plexus (plexus suprarenalis) is formed by branches from the celiac plexus, from the celiac ganglion, and from the phrenic and greater splanchnic nerves, a ganglion being formed at the point of junction with the latter nerve. The plexus supplies the suprarenal gland, being distributed chiefly to its medullary portion; its branches are remarkable for their large size in comparison with that of the organ they supply.

The renal plexus (plexus renalis) is formed by filaments from the celiac plexus, the aorticorenal ganglion, and the aortic plexus. It is joined also by the smallest splanchnic nerve. The nerves from these sources, fifteen or twenty in number, have a few ganglia developed upon them. They accompany the branches of the renal artery into the kidney; some filaments are distributed to the spermatic plexus and, on the right side, to the inferior vena cava.

The spermatic plexus (plexus spermaticus) is derived from the renal plexus, receiving branches from the aortic plexus. It accompanies the internal spermatic artery to the testis. In the female, the ovarian plexus (plexus arteriæ ovaricæ) arises from the renal plexus, and is distributed to the ovary, and fundus of the uterus.




108. Preganglionic parasympathetic neurons to the lower colon arise from the spinal cord at sacral levels two to four and reach the wall of the colon via pelvic splanchnic nerves. The nucleus ambiguus is the source of preganglionic parasympathetic neurons that innervate the heart via the vagus nerve and cardiac plexus. Neurons arising in the cervical intermediolateral cell column are sympathetic preganglionics. Preganglionic parasympathetic neurons arising from the motor nucleus of the vagus innervate the upper GI tract. Neurons arising from the ventral horn are primary somatic motor neurons to skeletal muscle.



109. The lower thoracic and upper lumbar portion of the spinal cord tend to receive a single major
radicular artery (of Adamkiewicz), which supplies blood to the anterior longitudinally running spinal artery. The anterior spinal artery mainly supplies the anterior two-thirds of the spinal cord in this region, which includes motor neurons that control the lower limbs. Because the metabolic needs of the spinal cord nerves are so great, the lack of blood during the surgery can lead to nerve cell death and thus paraplegia. Both muscle and peripheral nerves generally can survive the temporary disruption in blood flow. A process of cooling the spinal cord, by perfusing ice cold saline into the extradural space (called epidural cooling), is often performed to reduce the metabolic needs of the spinal nerves, thus often preventing central nervous system cell death during the surgical procedure. Muscles and nerves of the lower limb can survive reduced blood flow for an hour.





110. The lateral umbilical folds are produced by the underlying inferior epigastric arteries as they course from the external iliac artery in the inguinal region toward the rectus sheath. A direct inguinal hernia starts medial to the lateral ambilical fold and an indirect inguinal hernia starts lateral to the same fold. The medial umbilical folds are peritoneal elevations produced by the obliterated umbilical arteries. In the midline, the median umbilical ligament is formed by the underlying urachus, a remnant of the embryonic allantois. The Falx inguinalis represents infero-medial attachment of transversus abdominis with some fibers of internal abdominal oblique, also known as: conjoint tendon. The lateral border of the rectus sheath forms the medial edge of the inguinal triangle.