USMLE Step 1 Qs (5)

Mast cells and basophils are the key cells in the development of anaphylactic shock, a type of hypersensitivity reaction. In this allergic response, a person who has been sensitized to a particular antigen on first exposure responds with release of secretions (heparin and histamine) from both mast cells and basophils, resulting in smooth muscle contraction (e.g., constriction of bronchioles), increased vascular permeability (dilation of blood vessels), and a reduction in blood pressure. In severe cases, circulatory or respiratory failure may occur. On an initial exposure to an antigen, IgE binds to receptors on the mast cell and basophil surfaces. On second exposure, this bound IgE functions as an antigen receptor. Presence of antigen-antibody complexes on the cell surface induces release of secretion, including release of eosinophil-chemoattractant factor of anaphylaxis (ECF-A), histamine, heparin, and slow-reacting substance of anaphylaxis (SRS-A). In the presence of allergens, allergy symptoms are induced by histamine and heparin, which increase vascular permeability and dilate blood vessels.

The correct diagnosis is Paget's disease, also known as osteitis deformans because of its deforming capabilities (e.g., skull or femoral head enlargement). In this disease the serum calcium is normal, but there is an increase in osteoclastic activity (osteolytic lesions and elevated 24-h urine hydroxyproline) and an increase in osteoblastic activity (elevated osteocalcin and alkaline phosphatase). Patients with Paget's disease exhibit a marked increase in osteoid, and the bone actually enlarges. The osteoid is never normally mineralized in this disease. In this patient, the bone scan shows significant uptake of labeled bisphosphonates, which are incorporated into newly formed osteoid during bone formation. Her proximal femur is enlarged and no longer fits properly into the acetabulum, which results in the hip pain.
There are a number of useful biochemical markers of bone metabolism. Osteoclasts synthesize tartrate–resistant acid phosphatase so that increased osteoclastic activity is reflected in increased serum levels of tartrate–resistant acid phosphatase. Bone resorption fragments of type I collagen and noncollagenous proteins increase as bone matrix is resorbed. Hydroxyproline is a good urinary marker of bone metabolism because hydroxyproline is released and excreted in the urine as collagen is broken down. The presence of pyridinoline cross-links, which are involved in the bundling of type I collagen, is used for measurement of bone resorption. These cross-links are released only during degradation of mineralized collagen fibrils as occurs in bone resorption. Usually, pyridinoline cross-links are measured by immunoassay over a 24-h period to detect excess bone resorption and collagen breakdown in disorders such as Paget's disease.
Markers of bone formation include osteocalcin, alkaline phosphatase, and the extension peptides of type I collagen. Osteocalcin is a vitamin K–dependent gla ( -carboxyglutamic acid) protein that is synthesized by osteoblasts and secreted into the serum in an unchanged state. Serum concentrations of osteocalcin are, therefore, directly related to osteoblastic activity. It is a more specific marker than the marker alkaline phosphatase, because other organs, such as the liver and kidney, produce that enzyme. Radiologic methods such as conventional x-ray can be used to detect osteoporosis, but only after patients have lost 30 to 50% of their bone mass. Dual-beam photon absorptiometry allows a much more accurate diagnosis of loss of bone mass.

The patient is suffering from multiple myeloma. In this disease, there are abnormal changes in the bone marrow indicative of altered plasma cell activity and anemia (hemoglobin data and increasing fatigue). These plasma cells produce elevated levels of interleukin 1 (IL-1), which functions as an osteoclast activation factor. The increased IL-1 stimulates osteoclastic activity and results in elevated serum calcium (12.3 mg/dL). The depletion of bone calcium results in lytic lesions of the skull and pelvis as well as the presence of the compression fracture of the spine. The Bence Jones protein represents free–immunoglobulin light chains, which are a diagnostic feature (Bence Jones proteinuria) found in the urine of patients with multiple myeloma.

DiGeorge syndrome is a congenital malformation that results in the absence of the thymus and parathyroid glands, which arise from the third and fourth pairs of branchial pouches. The absence of the thymus results in a deficiency in T lymphocyte–dependent areas of the immune system. These areas include the deep cortex of the lymph nodes, periarterial lymphatic sheath (PALS) of the spleen, and interfollicular areas of the Peyer's patches. Parathyroid hormone (PTH) stimulates the development of osteoclasts and the formation of ruffled borders in osteoclasts. The absence of PTH results in (1) a drastic reduction in numbers and activity of osteoclasts, (2) reduced Ca2+ levels in the blood, (3) denser bone, (4) spastic contractions of muscle called tetany, and (5) excessive excitability of the nervous system. The parafollicular (C) cells arise from the ultimobranchial body that migrates into the developing thyroid gland and should form normally.

Cytotoxic T cells possess the CD8 cell surface marker. CD8+ T cells recognize foreign antigen in association with class I MHC molecules. Cytotoxic T cells are effective in killing virus-infected cells because these cells express fragments of virus combined with MHC I molecules on their surfaces. In contrast, helper T (CD4+) cells recognize antigen in association with class II MHC molecules. MHC class I is present on the surface of most cells, whereas antigen-presenting cells (including B lymphocytes) and thymic epithelial cells possess MHC class II.

The alveolar macrophage (containing hemosiderin) has been called the "congestive heart failure cell." The presence of these cells is an indicator of edematous lung changes. During congestive heart failure, edema results in leakage of erythrocytes into the alveoli. Transferrin and hemoglobin are also present in the edematous fluid released from the capillaries. These two products are phagocytosed by alveolar macrophages, which convert these products to hemosiderin.

The autonomic nervous system is the primary regulator of salivary gland function in contradistinction to the pancreas, which is regulated primarily by hormones (cholecystokinin and secretin). Parasympathetic fibers carry neural signals that originate in the salivatory nuclei of the medulla and pons. The sympathetic nervous system originates from the superior cervical ganglion of the sympathetic chain and stimulates acinar enzyme production. Elevated aldosterone levels affect the amount and ionic concentration of the saliva, resulting in decreased NaCl secretion and increased K+ concentration. Cholecystokinin (pancreozymin) and secretin are the hormones that regulate acinar and ductal secretions, respectively, in the exocrine pancreas. Antidiuretic hormone can modulate salivary gland production.

Dystrophin, like these other actin-binding proteins, binds actin to the skeletal muscle membrane and, therefore, binds the I and M bands to the cell membrane. The inability to bind actin to the plasma membrane of skeletal muscle leads to disruption of the contraction process, weakness of muscle, and abnormal running, hopping, and jumping. Gowers' maneuver is the method used by persons suffering from muscular dystrophy to stand from a sitting position. Respiratory failure occurs in these persons because of disruption of diaphragmatic function. Dystrophin is found in muscle of all types and is part of a complex that regulates interactions of the sarcolemma with the extracellular matrix through associated glycoproteins (dystrophin-glycoprotein complex). Therefore, loss of dystrophin causes a destabilization of the sarcolemma.

Muscular dystrophy refers to a group of progressive hereditary disorders (1/3500 male births) that involve mutations in the dystrophin gene. Dystrophin is similar in structure to spectrins I and II and alpha-actinin. Dystrophin is absent in Duchenne muscular dystrophy. Becker muscular dystrophy is a less severe dystrophy in which dystrophin is defective. Synthesis of actin is not reduced in skeletal muscle from these patients; in fact, hypertrophy and pseudohypertrophy (replacement of muscle with connective tissue and fat) occurs. Microtubules perform vesicular and organelle transport functions, and intermediate filaments not actin from the intracellular connection in desmosomes.

Immunoglobulin switching normally occurs in the germinal centers during the maturation of B cells. Synthesis of B cell antibody begins as IgM inserted into the cell membrane and then switches to membrane-bound IgM and IgD. After antigen stimulation, a switch to surface IgM, IgA, IgG, or IgE occurs, and these antibodies are secreted. Most antibody production occurs in the germinal centers of the lymph nodes, tonsils, and spleen. It occurs to a lesser extent in the bone marrow, but the bone marrow functions in the education of B cells as well as representing the major site of hematopoiesis in the adult. The thymus is responsible for the education of T cells. The splenic red pulp is the site of red blood cell breakdown.

Recognition of antigen by B cells is accomplished by the expression of IgM molecules on the cell surface. Some investigators use the term pre-B cell, or virgin B cell, to distinguish those B cells that have not yet synthesized IgM from those that have synthesized and inserted IgM into their cell membranes. IgD, which is produced later by maturing B cells, also serves as an antigen receptor.

Commonly, initial low levels of glucuronyl (glucuronysl) transferase in the underdeveloped smooth endoplasmic reticulum of hepatocytes in the newborn result in jaundice (neonatal unconjugated hyperbilirubinemia); less commonly, this enzyme is genetically lacking. The neonatal small intestinal epithelium also has an increased capacity for absorption of unconjugated bilirubin, which contributes to the elevated serum levels.

Bilirubin, a product of iron-free heme, is liberated during the destruction of old erythrocytes by the mononuclear macrophages of the spleen and, to a lesser extent, of the liver and bone marrow. The hepatic portal system brings splenic bilirubin to the liver, where it is made soluble for excretion by conjugation with glucuronic acid. Increased plasma levels of bilirubin (hyperbilirubinemia) result from increased bilirubin turnover, impaired uptake of bilirubin, or decreased conjugation of bilirubin. Increased bilirubin turnover occurs in Dubin-Johnson and Rotor syndromes, in which there is impairment of the transfer and excretion of bilirubin glucuronide into the bile canaliculi. In Gilbert's syndrome, there is impaired uptake of bilirubin into the hepatocyte and a defect in glucuronyl transferase. In Crigler-Najjar syndrome, a defect in glucuronyl transferase occurs in the neonate. The ability of mature hepatocytes to take up and conjugate bilirubin may be exceeded by abnormal increases in erythrocyte destruction or by hepatocellular damage (functional jaundice), such as in hepatitis. Finally, obstruction of the duct system between the liver and duodenum (usually of the common bile duct in the adult and rarely from aplasia of the duct system in infants) results in a backup of bilirubin.

A secondary immune response is more rapid, of longer duration, and more intense than the primary immune response and involves memory cells. Humoral immunity and cell-mediated immunity involve retention of immunologic memory through memory B and T cells, respectively. A secondary immune response may involve memory T cells, helper cells, macrophages, and memory B cells. The proliferation of either T or B cells during the first exposure to antigen results in the production of memory cells. Specificity is retained. For example, the introduction of a different (new) antigen induces a primary rather than a secondary response.

In a tuberculin skin test, T cell proliferation is increased by secretion of interleukins. An extract of tuberculin (an antigen of lipoprotein composition obtained from the tubercle bacillus) is injected into the skin of a person who has had tuberculosis or has been immunized against tuberculosis. Memory helper T cells react to the tuberculin and secrete IL-2, which upregulates IL-2 receptors. IL-2 binding to IL-2 receptors on the same cell is an example of autocrine regulation in which a cell secretes a ligand for a receptor on its own surface. The result of this upregulation and ligand-receptor binding is an increase in T cell proliferation. T cell–derived cytokines such as tumor necrosis factor-alpha and beta (TNF alpha and beta ) induce leukocyte recruitment. Production of gamma-(r )-interferon by helper T cells attracts and activates macrophages (monocytes comprise most of the cellular infiltrate). gamma -Interferon also converts other cells (such as endothelial cells) to antigen-presenting cells by induction of class II MHC expression, which further augments the response. The result of the activity of helper T cells is a dramatic increase in the number of lymphocytes and macrophages at the test site, which produces swelling. IL-1 is only synthesized by antigen-presenting cells and helper T cells are the targets.

The histologic sample contains red fibers. The deductive process is based on the fact that the sample must be skeletal or cardiac muscle due to the presence of cross-striations. The presence of peripherally placed nuclei eliminates cardiac muscle as a possibility. Skeletal muscle may be subclassified into three muscle fiber types: red, white, and intermediate fibers. Red muscle fibers have a high content of cytochrome and myoglobin and, beneath the plasmalemma, contain many mitochondria required for the high metabolism of these cells. Mitochondria are also found in a longitudinal array surrounding the myofibrils. The presence of numerous mitochondria provides a strong staining reaction with the use of cytochemical stains such as that for succinic dehydrogenase.

Physiologically, red fibers are capable of continuous contraction (high concentrations of myosin ATPase) but are incapable of rapid contraction. The term red (type I) fibers is due to the presence of large concentrations of myoglobin, the colored oxygen-binding protein. White (type IIB) muscle fibers are fast-twitch in function, stain very lightly for succinic dehydrogenase, myosin ATPase, and few mitochondria would be visible at the ultrastructural level. White fibers are capable of rapid contraction but are unable to sustain continuous heavy work. They are larger than red fibers and have more prominent innervation. The white fibers contain relatively little myoglobin. Human skeletal muscle fibers are composed of red, white, and intermediate-type fibers. The intermediate (type IIA) fibers possess characteristics including a size and innervation pattern intermediate between red and white muscle fibers. The intermediate fibers contain a concentration of myoglobin between white and red muscle fibers.

Atherosclerosis is initiated by damage to the endothelial cells, which exposes the subjacent connective tissue (subendothelium). The loss of the antithrombogenic endothelium results in aggregation of platelets.

Atherosclerosis is one form of arteriosclerosis (hardening of the arteries) that involves deposition of fatty material primarily in the walls of the conducting arteries. The intima and media become infiltrated with lipid. Intimal thickening occurs through the addition of collagen and elastin with an abnormal pattern of elastin cross-linking. Platelets release mitogenic substances that stimulate proliferation of smooth muscle cells. The thickening of the intima is also called an atheromatous plaque and worsens with repeated damage to the endothelium. It is most dangerous in small vessels, particularly the coronary arteries, where occlusion can result in a myocardial infarction. Atherosclerotic plaques also lead to thrombi and aneurysms.

The cell bodies (perikarya) of neurons carrying sensory information, such as pain and proprioception, from the body wall, are found in the dorsal root ganglia of spinal nerves. They are pseudounipolar neurons, in contrast to the large multipolar neurons with eccentric nuclei and coarse granular Nissl bodies that characterize neurons of the autonomic ganglia. Large pyramidal neurons that innervate skeletal muscle are found in the ventral horns of the spinal cord. Pain from facial structures, including the teeth, is carried in the fifth cranial (trigeminal) nerve. Visual stimuli are carried in the second cranial (optic) nerve. Satellite cells can be observed surrounding the neuronal perikarya and are similar to Schwann cells in function (e.g., insulation and metabolic regulation) but do not produce a myelin sheath.

The patient suffers from osteomalacia, a disease related to malnutrition, specifically vitamin D deficiency. On the basis of the first bone biopsy in which the tissue was decalcified, one could make a diagnosis of osteoporosis. The second, nondecalcified bone biopsy indicates that osteoid is being formed but is not undergoing mineralization. This correlates with the low 25-hydroxyvitamin D levels. Vitamin D replacement and calcium supplementation would be prescribed for this patient.

Darkening of the skin in the presence of UV radiation occurs through the darkening of melanin plus an increase in the synthesis and subsequent transfer of melanin (cytocrine secretion). Melanin is responsible for the pigmentation of the skin and protects the nuclei of dividing keratinocytes in the stratum basale and stratum spinosum from UV light. In general, skin color is determined by the number of melanin granules in the skin and not the number of melanocytes per unit area, which is relatively uniform from region to region and between different races.

In melanocytes, melanin is synthesized from tyrosine by the action of tyrosinase forming 3,4-dihydroxyphenylalanine (DOPA). The DOPA is subsequently transformed to melanin. This process occurs in melanosomes (immature granules that contain tyrosinase). Mature granules are transferred to keratinocytes by phagocytosis of part of the melanocyte; this process is called cytocrine secretion and occurs in the stratum basale and stratum spinosum (malpighian layer). Melanin granules remain relatively intact in persons with black skin; in caucasian individuals, there is degradation of the granules by lysosomal systems.

Mucociliary action is critical in protecting the respiratory system, which is exposed to constant assault from the environment. To protect the distal portions of the lung, which under normal conditions are considered a sterile environment, extensive defense mechanisms have evolved. Nasal clearance of material occurs through sneezing, whereas other material located posteriorly may be swept into the nasopharynx. The mucociliary action within the trachea and bronchi is often called the mucociliary, or tracheobronchial, escalator. At the distal end of the system, the alveolar macrophages phagocytose foreign material and secrete and respond to an array of cytokines. The type II pneumocytes resorb as well as secrete surfactant and surfactant associated proteins that have some antiviral and antibacterial function.
In the bronchi, there is extensive associated lymphoid tissue (BALT), which is analogous to the mucosa-associated lymphoid tissue (MALT) of the gut and the skin-associated lymphoid tissue (SALT). There are B and T cell areas throughout the BALT. The B cells are precursors of plasma cells and synthesize immunoglobulins such as IgA associated with the bronchial secretion. Helper T cells recognize foreign antigen in association with class II major histocompatibility complex (MHC) molecules. Cytotoxic T cells recognize fragments of antigen (specifically viral fragments) on the surface of viral-infected cells in association with class I MHC. Antigen-presenting cells (i.e., alveolar macrophages) also function in a similar fashion to those found elsewhere in the body; they present antigen to helper T cells in conjunction with class II MHC.

The capillary endothelia in the brain and thymus are continuous, as is the basal lamina. The blood-thymus barrier provides the appropriate microenvironment for education of T cells without exposure to self. The capillary is further surrounded by perivascular connective tissue and epithelial cells and their basement membrane. In the blood-brain barrier, there is also a continuous endothelium with a basal lamina and an absence of fenestrations. Surrounding the basal lamina in the brain are the foot processes of astrocytes, which form the glia limitans; however, it is important to note that the blood-brain barrier is formed specifically by endothelial cell occluding junctions with many sealing strands. Other capillary endothelia in the body are fenestrated or discontinuous (sinusoids). The fenestrae are transcellular openings that occur in many of the visceral capillaries. In hematopoietic organs, there are large gaps in the endothelium, and the capillaries are classified as discontinuous. Diaphragms (thinner cell membrane) are present in some fenestrated capillaries and produce an intermediate level of molecular transit.

The photomicrograph shows several types of blood or lymphatic vessels. Frequently, peripheral nerves are found in association with blood vessels (neurovascular bundle). In this section, a small peripheral nerve is labeled "A." It is characterized by an outer covering of perineurium consisting of two or three layers of fibroblast-like cells. The dark nuclei visible within the cross section belong to either Schwann cells or fibroblasts. Neuronal cell bodies (perikarya) are not found within peripheral nerves. The structure labeled "B" is a small lymphatic vessel. Small lymphatic vessels are characterized by a wall consisting only of an exceedingly thin, single layer of endothelium. The lumen is usually larger than that of comparable venules. As observed in the photomicrograph, valves are also present in lymphatic vessels. A small muscular artery (C) and comparable vein (D) are also present in the field.

Accumulation of mucus in the airways is a common finding in children with cystic fibrosis (CF). CF is a frequent occurrence in white children (1 in 200 births). It is a genetic disease in which the defect has been determined to occur in the CFTR protein that functions as a chloride channel. In the sweat glands, a decrease in sodium transport results in increased chloride levels in the sweat (the original detection test for CF). In the airways, decreased chloride secretion occurs in conjunction with active sodium absorption, resulting in loss of water from the lumen as water follows sodium. The result is increased viscosity of mucous secretions and obstruction of the airways and other organs. The pancreas and salivary gland secretions are affected in a similar way, although these abnormalities do not occur in all cases. In the case of the lungs, the loss of the mucociliary escalator action results in susceptibility to opportunistic lung infections.

Oxygen moving from the alveolar air to the capillary blood and carbon dioxide diffusing in the opposite direction pass through a three-component blood-air barrier. This barrier consists of type I pneumocytes, endothelial cells, and their fused basal laminae. Pulmonary capillaries are sometimes in direct contact with the alveolar wall, whereas in other locations, the alveolar wall and capillaries are separated by cells and extracellular fibers. The areas of direct contact are the location of gas exchange, whereas the other areas represent sites of fluid exchange between the interstitium and air spaces. Macrophages are present for the phagocytosis of debris and surfactant. The pores of Kohn are connections from one alveolus to another, and macrophages travel through these passageways. The pores normally equalize air pressure between alveoli and can, in the disease state, provide collateral circulation of air in the event that a bronchiole is blocked. However, they also provide a passageway for the spread of bacteria.

Plasmalemmal vesicles and channels are neutrally charged and rich in galactose and N-acetylglucosamine. Vesicular and channel pathways are required for transport of anionic proteins such as insulin, transferrin, albumin, and low-density lipoprotein (LDL).

Capillary endothelia are continuous, fenestrated, or discontinuous (sinusoids). Transcellular openings known as fenestrae occur in many of the visceral capillaries. In hematopoietic organs, there are large gaps in the endothelium, and the capillaries are classified as discontinuous. Diaphragms contain proteoglycans with particularly high concentrations of heparan sulfate. This results in numerous anionic sites that repel anionic proteins. The diaphragms facilitate the passage of water and small molecules dissolved in fluid. Fenestrations do not permit the passage of cells. Except under pathologic conditions, intercellular junctions do not allow the passage of large proteins. The paracellular pathway through the intercellular junctions is a mechanism for passage of water and small dissolved molecules.

The multinucleate organization of skeletal muscle is derived from the fusion process and not by amitosis (failure of cytokinesis after DNA synthesis). Mitotic activity is terminated after fusion occurs. In the development of skeletal muscle, myoblasts of mesodermal origin undergo cell proliferation. Myocyte cell division ceases soon after birth. Myoblasts, which are mononucleate cells, fuse with each other end to end to form myotubes. This process requires cell recognition between myoblasts, alignment, and subsequent fusion. Satellite cells are supportive cells for maintenance of muscle.

The cells in the region labeled A synthesize pepsinogen, acid, and gastric intrinsic factor. Region A is the fundus of the stomach. Its mucosa is comprised of gastric glands containing mucous cells, chief cells that synthesize pepsinogen, and parietal cells that synthesize hydrochloric acid and gastric intrinsic factor. Gastric intrinsic factor is required for absorption of vitamin B12 from the small intestine. The diagram shows the anatomic relationship between the esophagus, stomach, and duodenum. The esophagus (C) joins the stomach in the cardiac region (D). The pylorus (F) contains shorter glands with deeper pits than those of the fundus and body. These glands contain more mucous cells and many gastrin-secreting enteroendocrine cells. Food entering the pylorus stimulates the release of gastrin, that stimulates HCl production by the parietal cells. The pylorus connects with the duodenum (G), which contains the mucus and bicarbonate-neutralizing secretion of the Brunner's glands. The wall of the stomach consists of the mucosa (epithelium, lamina propria, and muscularis mucosa), submucosa, muscularis externa, and serosa (B) lined by a mesothelium.

Pyramidal neurons are labeled with the arrows in the photomicrograph. Axons are evident in the histologic section accompanying the question. The axon arises from the axon hillock. Neither the axon nor axon hillock contains Nissl substance (rough ER), which is dispersed throughout the soma and dendrites. Dendrites generally are wider than axons, are of nonuniform diameter, and taper to a point. Motor neurons, such as the one illustrated, usually display large amounts of euchromatin and a distinct nucleolus characteristic of high synthetic activity.

The structure in the photomicrograph is a corpus luteum. In the absence of the hormones necessary for maintenance of the corpus luteum [luteinizing hormone (LH) or human chorionic gonadotropin (hCG)], the corpus luteum regresses to form a corpus albicans, which consists primarily of fibrous connective tissue. Without LH or hCG, the uterine epithelium, which has undergone glandular proliferation in preparation for implantation, collapses and degenerates as part of menstruation. The corpus luteum forms from the granulosa and theca layers of the follicle following ovulation. The luteal phase is the second half of the menstrual period and follows the follicular phase during which follicles mature. The corpus luteum synthesizes progesterone in response to high LH levels. In each reproductive cycle, the production of LH stimulates development and maintenance of the corpus luteum, that is well formed by 12 to 14 days following ovulation. In the case of fertilization and subsequent implantation, the corpus luteum of pregnancy is maintained by human chorionic gonadotropin (hCG) produced by the embryo.

Myofibrils are composed of sarcomeres, which are repeating units that extend from Z disk ("A" on the TEM) to Z disk in the transmission electron micrograph (TEM). With the use of polarizing microscopy the A (anisotropic) bands ("E" on the TEM) are visible as dark, birefringent structures, and the I (isotropic) bands are visible as light-staining bands ("C" on the TEM). The I band (labeled "C") consists of thin filaments without overlap of thick filaments. At the center of the myofibril and consisting of thick filaments is the A band, which interdigitates with the I band. Each I band is bisected by the Z disk. The Z disk is composed mostly of the intermediate filament protein desmin and other proteins such as -actinin, filamin, and amorphin, as well as Z protein. In the center of the A band is a lighter staining area that consists only of thick (rodlike portions of myosin) filaments and is known as the H band ("D" on the TEM). Lateral connections occur between adjacent thick filaments in the region of the M line ("B" on the TEM), which bisects the H zone and is composed primarily of creatine kinase, an enzyme that catalyzes the formation of ATP.

The blood-brain barrier is formed primarily by occluding junctions (zonulae occludentes) between endothelial cells that compose the lining of brain capillaries. The capillary endothelium is nonfenestrated, which also adds to the barrier. In addition, astrocytes form foot processes around the brain capillaries. Surrounding the CNS is a basement membrane with a lining of astrocyte foot processes; this forms the glia limitans, which also contributes to the integrity of the blood-brain barrier. Oligodendrocytes function in myelination of CNS axons. Microglia function as brain macrophages and are involved in antigen presentation and phagocytosis.

The cytoplasmic inclusions labeled with the arrows in the transmission electron micrograph are glycogen. The hepatocyte, under the regulation of insulin and glucagon, stores glucose in its polymerized form of glycogen. In electron micrographs, glycogen appears as scattered dark particles with an approximate diameter of 15 to 25 nm. Lipid droplets appear as spherical, homogeneous structures of varying density and diameter, although their diameter would be considerably larger than that of the glycogen granules. Ribosomes are found on the rough endoplasmic reticulum or as free structures, in which case they are not found in clusters like glycogen. Mitochondria contain distinctive cristae and are much larger (0.5–1.0 m in diameter) than glycogen. Chylomicra are located at the basal surface of the hepatocytes and are less dense than glycogen. Secretory granules would also show polarity in their location.

The arrow indicates a single intramural parasympathetic ganglion cell distinctly characterized by its large, euchromatic nucleus and prominent nucleolus. Several small satellite cells surround the ganglion cell. Other structures within the field include serous acini from an exocrine gland, a small peripheral nerve, a venule, and several skeletal muscle fibers.

The Meissner corpuscle is found in glabrous (hairless) skin in areas such as the lips and palms, and responds to low-frequency stimuli (i.e., fine touch). The other listed sensory receptors are all found in the skin and subserve a variety of functions. Free nerve endings are unencapsulated receptors that function in the reception of many different modalities. Pain receptors in the skin are all free nerve endings. The Ruffini endings are the simplest encapsulated receptor and are associated with collagen fibers. Mechanical stress results in displacement of the collagen fibers and stimulation of the receptor. The Pacinian corpuscle is specialized for deep pressure in areas such as the dermis and internal organs (e.g., the pancreas). Its structure resembles an onion with concentric fluid-filled layers surrounding a centrally placed unmyelinated nerve fiber. Displacement of the layers results in the depolarization of the axon. The Merkel corpuscle consists of a Merkel cell, a modified keratinocyte specialized for acute sensory perception, and a neuron terminal that forms a disk apposed to the Merkel cell. Merkel cells are attached to neighboring keratinocytes by desmosomes

The organ in the photomicrograph is the pancreas, and the cells labeled are the islets of Langerhans. The pancreas functions as both an exocrine (secretion of pancreatic juice) and endocrine (secretion of insulin and glucagon) gland. The islets (A) have a heterogeneous distribution within the pancreas (i.e., they decrease from the tail to the head of the gland) and may be used to distinguish the pancreas from the parotid gland. The submandibular and sublingual glands can be ruled out because of the purely serous nature of the acini within the exocrine portion of the gland. The centroacinar cells (B) are modified intralobular duct cells, specifically from the intercalated duct, and are present in the lumen of each acinus. The duct (C) can be distinguished by the presence of a cuboidal epithelium, the absence of blood and blood cells from the lumen, and the absence of a characteristic vascular wall. A pancreatic artery (D) and a vein (E) are shown within the interlobular connective tissue (F).

The photomicrograph illustrates the structure of the gallbladder that stores and concentrates the bile. Although the finger-like extensions resemble villi, they represent changes that occur in the mucosa with increasing age. The thinness of the wall is the notable characteristic of the gallbladder. The bile is synthesized by hepatocytes and transported from the liver to the gallbladder. The colon absorbs water from digested material in the colonic lumen. The placenta is responsible for exchange of waste and nutrients between the fetus and the mother. The small intestine absorbs monosaccharides, glycerol, and amino acids.

To a minor extent, the uterine cervical stroma changes during each reproductive cycle; however, during pregnancy (especially parturition) there is a thinning of the uterine stroma. This results in eversions (mistakenly called "erosions"), which are sites of exposed uterine columnar epithelium in the acidic, vaginal milieu. These sites often become reepithelialized as stratified epithelium (squamous metaplasia) and are believed to be the location of cancerous transformation in the cervix. As part of the process of reepithelialization, the openings of cervical mucous glands are obliterated, which results in the formation of nabothian cysts.

The neural crest forms most of the peripheral nervous system, in contrast to the neural tube, which is the embryonic source of the central nervous system. The sensory neurons of the cranial and spinal sensory ganglia (e.g., dorsal root ganglia), sympathetic chain ganglia, postganglionic sympathetic and parasympathetic fibers of the autonomic nervous system, cells of the pia and arachnoid, Schwann cells, and satellite cells of the dorsal root ganglia are neural elements derived from neural crest. Nonneuronal structures formed from neural crest include melanocytes of the skin, odontoblasts in teeth, derivatives of the branchial arch cartilages (e.g., pinnae of ear), and the adrenal medulla (not the adrenal cortex, e.g., zona granulosa). The adrenal medulla represents postganglionic sympathetic fibers that respond to inputs from preganglionic sympathetic fibers in splanchnic nerves. Ventral horn cells are derived from the neuroepithelium of the neural tube.

Passage of lymphocytes from the lymphoid compartment of the lymph node to the bloodstream involves passage from the efferent lymphatic vessel to the thoracic duct and eventually into the venous system (at the juncture of the left brachiocephalic and subclavian veins). The region of the lymph node marked with the asterisk in the photomicrograph is the hilus of the lymph node. Passage from the blood to the lymphoid compartment involves specific homing receptors on lymphocytes, which are complementary to addressins on the postcapillary high endothelial venules (HEVs) and explains the specificity of lymphocyte homing. The cells that line the HEVs permit the selective passage of lymphocytes by diapedesis through the intercellular junctions. Lymphocytes have specific homing receptors on their cell surfaces that provide entry for mucosal (versus lymph node) seeding. High endothelial venules (HEVs) provide a mechanism for lymphocytes to leave the bloodstream and enter specific areas of the lymph nodes. HEVs are also found in Peyer's patches and during inflammation of tissues (e.g., the synovium in rheumatoid arthritis). Under normal conditions, HEVs are found in the T-dependent areas, i.e., the deep cortex (paracortex) of the lymph nodes and the interfollicular regions of the Peyer's patches. T cells home to T-dependent areas of the lymph nodes, spleen, and Peyer's patches. The circulation and recirculation of lymphocytes is a constant process that allows lymphocytes to continuously monitor the presence of antigen. The circulation process also allows augmentation of the immune response to infection. Plasma cells never enter the bloodstream under normal conditions but secrete antibodies into the circulation from the medulla of the lymph nodes or the marginal zone of the spleen. Lymphocytes and other cells (e.g., monocytes and neutrophils) that leave the blood never pass through the endothelial cells.

In the histologic section of a lymph node, there is a distinctive cortex and medulla with a connective tissue capsule. The organ possesses the classic bean shape with a hilus (marked by an asterisk in the figure). Afferent lymphatics enter the lymph node on the convex side, and lymph percolates through the subcapsular, cortical, and medullary sinuses. The medullary sinuses converge on the hilus, where the efferent lymphatic vessel drains the node. The hilus also contains an artery and a vein.

Differentiation of type II pneumocytes (shown in the electron micrograph) occurs late in gestation and is, therefore, incomplete at birth in premature infants. These newborn "premies" have a deficiency of surfactant because of the immaturity of the type II pneumocytes. The deficiency of surfactant inhibits normal expansion of the alveoli and results in idiopathic respiratory distress syndrome [(RDS); hyaline membrane disease]. The lecithin/sphingomyelin ratio is a test that can be performed on a sample of amniotic fluid obtained by amniocentesis. It is used to determine whether the type II pneumocytes are mature and are synthesizing and secreting surfactant. Maternally administered glucocorticoids may be used to induce surfactant production prior to birth, and surfactant may be given intratracheally to premature infants to reduce the severity of RDS. The surfactant is produced by type II pneumocytes in the lung and is stored in the form of lamellar bodies (the whorls seen in the electron micrograph). Surfactant consists of an aqueous layer, or hypophase, that contains proteins and mucopolysaccharides. That layer is covered by a functional layer of phospholipid that consists predominantly of dipalmitoyl phosphatidylcholine (lecithin). The release of lamellar bodies by exocytosis is followed by their general unraveling to form tubulomyelin figures. The tubulomyelin consists of a crisscross lipid bilayer that covers the type II pneumocytes. Surfactant-associated proteins (SAP) stabilize surfactant, activate surfactant recycling, enhance surfactant-induced reduction of surface tension, and possess antiviral and antibacterial activities. Turnover occurs by both endocytosis (type I and II pneumocytes) and phagocytosis (macrophages); 90% of surfactant is recycled.

The blood-air barrier is formed by the type I pneumocyte, the capillary endothelial cell, and their fused basal laminae.

The electron micrograph includes matrix vesicles that are derivatives of osteoblast, hypertrophied chondrocyte, ameloblast, and odontoblast cell membranes. After budding off from the plasmalemma, matrix vesicles accumulate calcium and phosphate in the form of hydroxyapatite crystals and serve as seed crystals for calcification. Exposure of these crystals to the extracellular fluid leads to seeding of the osteoid between the spaces in the collagen fibrils located in the matrix. Matrix vesicular alkaline phosphatase results in local increases in the Ca2+/PO42– ratio. Adult lamellar bone contains very few matrix vesicles, suggesting that mineralization in adult bone occurs by other mechanisms. The three-dimensional arrangement of collagen with the presence of holes or pores where hydroxyapatite crystals form is involved in the mineralization of adult bone.

The neurohypophysis containing the Herring bodies is formed from neuroectoderm as an extension of the developing diencephalon. The pars nervosa consists of pituicytes (supportive glia) and the Herring bodies, dilated axons that originate in the supraoptic and paraventicular nuclei. These nuclei produce oxytocin and vasopressin that are stored in the Herring bodies.

Overall, the pituitary gland (hypophysis cerebri) is formed from two types of ectoderm. An outgrowth of the oral ectoderm, Rathke's pouch, forms the structures that compose the adenohypophysis: pars distalis, pars intermedia, and pars tuberalis. The pars distalis includes the classic histologic cell types: chromophils (acidophils and basophils) and chromophobes (acidophils and basophils that are depleted of secretory product). Since the development of immunocytochemistry, the classification scheme for pars distalis cell types has been changed to include acidophils: lactotrophs (prolactin), somatotrophs (growth hormone), and basophils: corticotrophs (ACTH, -lipotropin, -MSH and -endorphin), thyrotrophs (TSH), and gonadotrophs (FSH and LH). The pars intermedia is also formed from the oral ectoderm, is rudimentary in humans, and may produce preproopiomelanocortic peptide. The pars tuberalis forms a collar around the pituitary stalk and is also derived from the oral ectoderm. The pars nervosa (including Herring bodies) and the remainder of the pituitary stalk (infundibular stem and median eminence) are formed from a downgrowth of the diencephalon. The posterior pituitary (pars nervosa and stalk) retains this close relationship with the brain (i.e., hypothalamus) throughout life.

The large pores (50 to 70 nm in diameter) are represented by the pinocytotic vesicles. Endothelial cells are joined together by tight junctions (zonula occludens) with a rare desmosome (macula adherens) observed between the cells. Gap junctions may be present between adjacent endothelial cells and permit transfer of information between adjoining cells. Intercellular junctions, particularly the tight junctions, function as the small endothelial pores (approximately 10 nm in diameter) observed in physiologic studies. Coatomer-coated vesicles shuttle material between the rough ER and cis-Golgi.

In deep wounds, new epithelial cells are obtained from the epithelium of the hair follicles and sweat glands located in the dermis. Reepithelialization is inhibited in wounds that remove all epithelial cells and require skin grafts to enhance the repair process. In those cases there is only minor wound healing by migration from the margins of the wound. Repair of epidermal wounds requires chemoattraction of macrophages to the wound site and removal of damaged tissue by those monocyte-derived infiltrating cells. Repair is mediated by the proliferation of endothelial and smooth muscle cells for the repair of blood vessels and angiogenesis. Proliferation of basal keratinocytes and fibroblasts occurs in small wounds for the repair of the epidermis and dermis, respectively.

The white matter of the adult CNS is derived from the marginal zone of the developing neural tube. The other layers of the neural tube are the mantle zone, which forms the gray matter, and the ventricular zone from which astrocytes, oligodendrocytes, and neurons differentiate. Ultimately, the cells that remain in the ventricular zone become the ependymal cells that line the central canal.

The first stage of neural tube development involves cell proliferation and occurs before neural tube closure. The second stage involves the differentiation of neurons from the germinal (ventricular) layer of the epithelium and is initiated after closure of the neural tube. Differentiation of three distinct layers of the wall is observed. Mitotic activity occurs in the ventricular zone, closest to the lumen. The next zone is the mantle (intermediate) zone, where cell bodies of differentiating motor neurons are located. The most peripheral zone is the marginal zone, which contains the myelinated axons of the developing motor neurons (adult white matter).

In the central nervous system, neural tissue is separated into two types. White matter contains a predominance of myelinated fibers. The gray matter contains mostly cell bodies of neurons. The formation of three layers in the developing neural tube results in the pattern of peripheral white matter with a central H-shaped region of gray matter, which is seen in the spinal cord. Astrocytes and oligodendrocytes, the macroglia, arise from the neural epithelium and not from neural crest cells. Microglia (the macrophages of the brain) are bone marrow-derived arising from monocytes.

It is important to note that the cerebral and cerebellar cortex are areas of peripheral gray matter. CNS cortex is formed through a second wave of cell proliferation. In the cerebellum this occurs from the external granular layer that is present during development. In the cerebral cortex, the layers (I to VI) are formed by waves of proliferation and migration from deep to superficial layers

The dura mater ("tough mother") contains the venous sinuses and is composed of dense connective tissue and possesses very limited osteogenic potential. The dura mater is one of the three protective layers that comprise the meninges surrounding the brain and spinal cord. In the spinal cord, the dura is separated from the periosteum by the epidural space. The thin subdural space lies between the dura mater and the arachnoid. The arachnoid is composed of a weblike avascular connective tissue that forms villi for the reabsorption of cerebrospinal fluid (CSF) into the venous sinuses found in the dura. The subarachnoid space contains the CSF, which is formed both by ultrafiltration of the blood and transport across the epithelial lining of the choroid plexuses. The pia covers the brain and spinal cord as a delicate, vascular connective tissue. It lines the perivascular spaces through which blood vessels penetrate the CNS. The periosteum is an important connective tissue layer surrounding the bone of the skull. This layer retains osteogenic potential even in the adult.

Platelets (thrombocytes) are involved in the conversion of fibrinogen to fibrin through the action of phospholipids. In thrombocytopenia, fibrinogen will not be converted to fibrin in sufficient quantity to allow normal clotting. The absence of platelet aggregation interferes with normal endothelial maintenance and repair after injury. The endothelium becomes increasingly leaky and eventually may permit thrombocytopenia purpura with seepage of blood from the vessel.

Platelets (thrombocytes) are fragments of megakaryocytes that function in aggregation, coagulation, clot retraction, and removal. The cytoskeleton of the platelet is extensive and facilitates changes in shape of the platelet as well as contractions, which assist in the release of secretory granules. Platelet-derived growth factor (PDGF) is released by platelets and stimulates the proliferation of endothelial cells, vascular smooth muscle cells, and fibroblasts. Thrombin is involved in conversion of fibrinogen to fibrin, but it is a plasma protein, not a platelet secretory factor. Platelets are not required for the initiation of the blood-clotting cascade, but they are required for the adherence and normal formation of a clot. Plasmin is not secreted by platelets but is formed by the conversion of plasma-derived plasminogen under the influence of plasminogen activator secreted by endothelial cells. Plasmin is involved in dissolution, not formation, of blood clots.

The smallest functional unit of the lung is the respiratory bronchiolar unit, which contains a respiratory bronchiole and the alveoli associated with it. This unit allows for air conduction and gas exchange. The alveolus is only associated with gas exchange, and the bronchi form part of the conduction system. The bronchopulmonary segment is a functional unit of lung structure, but it is not the smallest unit. Bronchopulmonary segments are particularly important in surgical resections of the lung because they represent functional units with connective tissue boundaries and individualized vasculature, including pulmonary and bronchial arteries, pulmonary lymphatics, and pulmonary nerves, all of which follow the air-conducting system of the bronchial tree and its branches.

The development of the testis from an indifferent gonad depends on the presence of the testis-determining factor, a gene on the short arm of the Y chromosome. During fetal development, the production of androgens by the developing testis results in masculinization of the indifferent gonadal ducts and the indifferent genitalia. In the absence of androgens, female genitalia and female ducts (vagina, oviducts, and uterus) develop. In the mature male, testosterone is required for the initiation and maintenance of spermatogenesis as well as the structural and functional integrity of the accessory glands and ducts of the male reproductive system. Testosterone is bound to androgen-binding protein (ABP), which is synthesized by the Sertoli cells under the influence of follicle-stimulating hormone (FSH). ABP is important for both the storage and delivery of androgens in the male ducts and accessory glands.

Hirschsprung disease (congenital megacolon) and Chagas disease have different etiologies, but both inhibit intestinal motility by affecting the myenteric (Auerbach's) plexus located between the layers of the muscularis externa (labeled "e") in the figure. The submucosal (Meissner's) plexus is more involved in regulation of lumenal size and, therefore, will affect defecation, but will be less involved in peristalsis. Vascular smooth muscle, the muscularis mucosa, and enteroendocrine cells do not play a major role in the regulation of peristalsis, which is observed even after removal of the gut and placement in a nutrient solution. Hirschsprung disease, also known as aganglionic megacolon, results from failure of normal migration of neural crest cells to the colon, resulting in an aganglionic segment. Although both the myenteric and submucosal plexuses are affected, the primary regulator of intrinsic gut rhythmicity is the myenteric plexus. Chagas disease is caused by the protozoan Trypanosoma cruzi. Severe infection results in extensive damage to the myenteric neurons.

The wall of the GI tract contains four layers: mucosa, submucosa, muscularis externa, and serosa. The structure labeled "a" in the photomicrograph is the lamina propria, a loose connective tissue layer immediately beneath the epithelium. Also part of the mucosa is a double layer of smooth muscle cells (b) comprising the muscularis mucosae. In the photomicrograph, an inner circular and outer longitudinal layer of smooth muscle cells is discernible. A thick layer of dense irregular connective tissue, the submucosa (d), separates the muscularis mucosae from the muscularis externa. The structure labeled "c" is a nest of parasympathetic postganglionic neurons forming part of Meissner's plexus. The muscularis externa (labeled "e") generally consists of inner circular and outer longitudinal layers of smooth muscle cells. Slight variations in these components may occur in specific organs of the GI tract. The respiratory, urinary, integumentary, and reproductive systems differ from the gastrointestinal system in their epithelia and arrangement of underlying tissue.

The cells of the stratum granulosum contain numerous keratohyalin granules. This layer also produces lamellar granules, which form a bidirectional lipid bilayer barrier to penetration of substances. The skin or integument is composed of an epithelial layer (epidermis) and underlying connective tissue (dermis). The epidermis consists of four to five strata (from the basement membrane to the skin surface): stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and stratum corneum. The basal layer contains most of the mitotic cells and is attached to the basement membrane with hemidesmosomes. The stratum spinosum contains the prickle cells, which have numerous cytoplasmic tonofilaments and intercellular desmosomes. This layer is often classified with the stratum basale as the malpighian layer. The stratum basale and stratum spinosum contain mitotic keratinocytes, and these are the two layers that show a hyperproliferative state in psoriasis. In that disease, increased cell proliferation leads to a thickening of the epidermis with a shortening of the epidermal turnover period. Under normal conditions, there is a gradual replacement process in the epidermis with the production of new cells in the stratum basale and stratum spinosum and their migration toward the surface as they gradually differentiate. The stratum lucidum is a translucent layer typical of thick skin. The stratum corneum contains as many as 20 layers of flattened cells and is filled with keratin.

The photomicrograph shows the pylorus of the stomach. The pylorus differs from the fundus of the stomach in the length of the pits of the glands compared with the length of the gland. In the fundus there are short pits and long glands (pit/gland ratio of about 1:4) compared with a pit/gland ratio of 1:2 in the pylorus. There is also an absence of parietal cells in the pylorus. The small intestine contains crypts and villi, the colon has crypts without villi, and the esophagus is lined by a stratified squamous epithelium.