Andrew John Armstrong, MD

• Professor of Medicine
• Associate Professor in Pharmacology and Cancer Biology
• Professor in Surgery
• Member of the Duke Cancer Institute

https://medicine.duke.edu/faculty/andrew-john-armstrong-md

Developing red blood cells become smaller allergy medicine children effective 5 ml fml forte, change their cytoplasm appearance (from blue to red) due to intense accumulation of hemoglobin allergy to zpack symptoms generic fml forte 5 ml on-line, and extrude their nuclei guna-allergy treatment 30ml fml forte 5 ml buy low cost. Bone marrow contains specialized blood vessels (sinusoids) into which newly developed blood cells and platelets are released allergy shots kansas city order 5 ml fml forte mastercard. Bone marrow not active in hemopoiesis contains predominately adipose cells and is called yellow bone marrow allergy drops for eyes buy fml forte mastercard. Red blood cells (erythrocytes), white blood cells (leukocytes), and thrombocytes (platelets) constitute the formed elements. The granulocytes, so named for the character of the granules that they contain in their cytoplasm, consist of neutrophils, eosinophils, and basophils. Each type of white cell has a specific role in immune and protective responses in the body. They typically leave the circulation and enter the connective tissue to perform their specific role. Blood platelets are responsible for blood clotting and consequently have an essential role in incidents of small vessel damage. Blood smears are utilized for microscope examination and identification of relative numbers of white cells in circulating blood. The blood smear is prepared by placing a small drop of blood on a microscope slide and then smearing it across the slide with the edge of another slide. When properly executed, this method provides a uniform, single layer of blood cells that is allowed to air dry and then stained. In examining the specimen under the microscope, it is useful to use a low magnification to find areas in which the blood cells have a uniform distribution like that seen in the smear on the adjacent page. Once this is accomplished, by switching to a higher magnification, one can identify the various types of white blood cells and, in fact, determine the relative number of each cell type. However, at this magnification, the major distinction is in the staining of their cytoplasm. Higher magnification, as in the figures below, would allow for a more precise characterization of the cell type. This low-magnification photomicrograph shows part of a blood smear in which the blood cells are uniformly distributed. Neutrophils exhibit variation in size and nuclear morphology that is associated with age of the cell. The nucleus seen on the left is that of a neutrophil that has just passed the band stage and has recently entered the blood stream. The middle neutrophil is considerably larger and its cytoplasm contains more fine granules. The neutrophil to the right shows greater maturity by virtue of its very distinctive lobulation. The eosinophils seen in these micrographs similarly represent different stages of maturity. The eosinophil at the left is relatively small and is just beginning to show lobulation. The cytoplasm is almost entirely filled with eosinophilic granules that characterize this cell type. The lighter stained area, devoid of granules, probably represents the site of the Golgi apparatus (arrow). The eosinophil shown in the middle is larger and its nucleus is now distinctively bilobed. The eosinophil at the right is more mature in that it displays at least three lobes. By going through focus, the eosinophil granules often appear to "light up" due to their crystalline structure. The cells shown here are basophils and also represent different stages of maturation. The basophilic granules are variable in size and tend to obscure the morphology of the nucleus. The nucleus of the middle basophil appears to be bilobed, but the granules that lie over the nucleus again tend to obscure the precise shape. The difference in lymphocyte size is attributable mostly to the amount of cytoplasm present. However, the nucleus also contributes to the size of the cell but to a lesser degree. Their size ranges from approximately 13 to 20 m, with the majority falling in the upper size range. Small, azurophilic granules (lysosomes) are also characteristic of the cytoplasm and are similar to those seen in neutrophils. In preparations such as this, the lipid content is lost during preparation and recognition of the cell is based on a clear or unstained round space. The megakaryocyte is a polyploid cell that exhibits a large and irregular nuclear profile. At this low magnification, it is difficult to distinguish the earlier stages of the developing cell types. However, examples of each stage of development in both cell lines are presented in the following plates. In contrast, many cells in their late stage of development, particularly in the granulocyte series, can be identified with some degree of assuredness at low magnification. This type of preparation allows for the examination of developing red and white cells. A sample of bone marrow is aspirated from a bone and simply placed on a slide and spread into a thin monolayer of cells. These are very young erythrocytes that contain residual ribosomes in their cytoplasm. Their cytoplasm is basophilic and the nucleus exhibits a dense chromatin structure and several nucleoli. The cytoplasm shows strong basophilia due to the increasing number of ribosomes involved in hemoglobin synthesis. The accumulation of hemoglobin in the cell gradually changes the staining reaction of the cytoplasm so that it begins to stain with eosin. The recognizable presence of hemoglobin in the cell by virtue of its staining signifies its transition to the polychromatophilic erythroblast. With time, increasing amounts of hemoglobin are synthesized and concomitantly, decreasing numbers of ribosomes are present. The nucleus of the cell is smaller than that of the basophilic erythroblast and the heterochromatin is much coarser. At the end of this stage, the nucleus has become much smaller and the cytoplasm more eosinophilic. The next definable stage is the orthochromatophilic erythroblast, also called normoblast. The cytoplasm is considerably less blue leaning more to a pink or eosinophilic coloration. In the next stage, the polychromatophilic erythrocyte, also more commonly called a reticulocyte, has lost its nucleus and is ready to pass into the blood sinusoids of the red bone marrow. Comparison of this cell to typical mature erythrocytes in the marrow smear reveals a slight difference in coloration. The proerythroblast shown here is a large cell, larger than the cells that follow in the developmental process. The greater abundance of cytoplasm is deeply basophilic compared to that of the proerythroblast. The cytoplasm is basophilic but is considerably lighter in color than that of the basophilic erythroblast. The cytoplasm also exhibits some eosinophilia, which is indicative of hemoglobin production. Note how much more dense the chromatin appears as well as how much smaller the nucleus has become. The cytoplasm is predominantly eosinophilic but still possesses a degree of basophilia. Their nuclei have become even smaller Polychromatophilic erythrocyte, bone marrow smear, human, Giemsa, 2,200. Compare the coloration of the polychromatophilic erythrocyte with that of the mature red blood cells. Polychromatophilic erythrocytes can also be readily demonstrated with special stains that cause the remaining ribosomes in the cytoplasm to clump and form a visible reticular network, hence, the polychromatophilic erythrocyte is also commonly called a reticulocyte. The earliest recognizable stage is the myeloblast, which is followed consecutively by the promyelocyte, myelocyte, metamyelocyte, band cell, and finally, the mature granulocyte. It is not possible to differentiate eosinophil, basophil, or neutrophil precursors morphologically until the myelocyte stage is reached-when specific granules characteristic of each cell type appear. The cells of the basophil lineage are extremely difficult to locate in a marrow smear because of the minimal number of these cells in the marrow. The myeloblast is characterized by a large euchromatic, spherical nucleus with three to five nucleoli. Promyelocyte cytoplasm stains similarly to that of the myoblast, but it is distinguished by the presence of large, blue/black, primary azurophilic granules, also called nonspecific granules. The cytoplasm of the neutrophilic myelocyte is characterized by small, pink-to-red specific granules with some azurophilic granules present. The eosinophilic lineage has a similar-appearing nucleus, but its specific granules are large. The nuclear-cytoplasmic ratio is further decreased and the nucleus assumes a kidney shape. There are few azurophilic granules at this stage in cells, and there is a predominance of small, pink-to-red specific granules. The eosinophilic metamyelocyte shows an increased number of specific granules compared to the neutrophilic metamyelocyte. The chromatin of the nucleus exhibits further condensation and has a horseshoe shape. In the neutrophilic band cell, the small, pink-to-red specific granules are the only granule type present. The eosinophilic band cell shows little or no change relative to the specific granules, but the nucleus exhibits a kidney shape. The myeloblast shown here exhibits a deep blue cytoplasm with a lighter region that represents the Golgi area (G). The eosinophilic myelocyte exhibits a nucleus the same as that described for the neutrophilic myelocyte. The cytoplasm, however, contains the large specific granules characteristic of eosinophils, but they are fewer in number. The neutrophilic myelocyte retains the round nucleus, but nucleoli are now absent. The cytoplasm exhibits numerous characteristic eosinophilic granules that are present throughout the cytoplasm. The neutrophilic metamyelocyte differs from its precursor by the presence of a kidney- or bean-shaped nucleus. The small, pink-to-red specific granules are now seen in the cytoplasm and few or no azurophilic granules are present. The band or nonsegmented neutrophil exhibits a horseshoe-shaped nucleus with abundant small, pink-to-red specific granules in the cytoplasm. In contrast, muscle cells contain a large number of aligned contractile filaments that the cells use for the single purpose of producing mechanical work. Two principal types of muscle are recognized: Two types of myofilaments are associated with cell contraction. Each thin filament of fibrous actin (F-actin) is a polymer primarily formed from globular actin molecules (G-actin). The long, rod-shaped tail portion of each molecule aggregates in a regular parallel but staggered array, whereas the head portions project out in a regular helical pattern. The two types of myofilaments occupy the bulk of the cytoplasm, which in muscle cells is also called sarcoplasm [Gr. Actin and myosin are also present in most other cell types (although in considerably smaller amounts), where they play a role in cellular activities · · Skeletal muscle is attached to bone and is responsible for movement of the axial and appendicular skeleton and for maintenance of body position and posture. In addition, skeletal muscles of the eye (extraocular muscles) provide precise eye movement. Visceral striated muscle is morphologically identical to skeletal muscle but is restricted to the soft tissues, namely, the tongue, pharynx, lumbar part of the diaphragm, and upper part of the esophagus. Cardiac muscle is a type of striated muscle found in the wall of the heart and in the base of the large veins that empty into the heart. This low-magnification photomicrograph shows skeletal muscle in longitudinal section. Muscle fibers (cells) are arranged in parallel fascicles; they are vertically oriented, and the length of each fiber extends beyond the upper and lower edge of the micrograph. Note on the left the epimysium, the sheath of dense connective tissue surrounding the muscle. The nuclei of skeletal muscle fibers are located in the cytoplasm immediately beneath the plasma membrane. The cross-striations in striated muscle are produced largely by the specific cytoarchitectural arrangement of both thin and thick myofilaments. The main differences between skeletal muscle cells and cardiac muscle cells are in their size, shape, and organization relative to one another. Smooth muscle cells do not exhibit cross-striations because the myofilaments do not achieve the same degree of order in their arrangement.

The loose connective tissue in the periodontal ligament contains blood vessels and nerve endings allergy symptoms icd 9 code generic fml forte 5 ml overnight delivery. In addition to fibroblasts and thin collagenous fibers allergy forecast vienna austria order fml forte 5 ml with amex, the periodontal ligament also contains thin allergy forecast johannesburg 5 ml fml forte buy, longitudinally disposed oxytalan fibers allergy symptoms from black mold order fml forte on line. The submandibular gland is located under the floor of the mouth allergy forecast georgia trusted 5 ml fml forte, in the submandibular triangle of the neck. The sublingual gland is located in the floor of the mouth anterior to the submandibular gland. The minor salivary glands are located in the submucosa of different parts of the oral cavity. Initially, the gland takes the form of a solid cord of cells that enters the mesenchyme. The proliferation of epithelial cells eventually produces highly branched epithelial cords with bulbous ends. Degeneration of the innermost cells of the cords and bulbous ends leads to their canalization. The gingiva is a specialized part of the oral mucosa located around the neck of the tooth. The gingiva is composed of two parts: · · the major salivary glands are surrounded by a capsule of moderately dense connective tissue from which septa divide the secretory portions of the gland into lobes and lobules. The connective tissue associated with the groups of secretory acini blends imperceptibly into the surrounding loose connective tissue. Numerous lymphocytes and plasma cells populate the connective tissue surrounding the acini in both the major and minor salivary glands. The parotid and the submandibular glands are actually located outside the oral cavity; their secretions reach the cavity by ducts. The parotid gland is located subcutaneously, below and in front of the ear in the space between the ramus of the mandible and the styloid process of the temporal bone. The four major parts of the salivon-the acinus, intercalated duct, striated duct, and excretory duct- are color-coded. The three columns on the right of the salivon compare the length of the different ducts in the three salivary glands. The red-colored cells of the acinus represent serous-secreting cells, and the yellow-colored cells represent mucus-secreting cells. The ratio of serous-secreting cells to mucus-secreting cells is depicted in the acini of the various glands. The term periodontium refers to all the tissues involved in the attachment of a tooth to the mandible and maxilla. These include the crevicular and junctional epithelium, the cementum, the periodontal ligament, and the alveolar bone. A basal lamina­like material is secreted by the junctional epithelium and adheres firmly to the tooth surface. The basal lamina and the hemidesmosomes are together referred to as the epithelial attachment. In young individuals, this attachment is to the enamel; in older individuals, where passive tooth eruption and gingival recession expose the roots, the attachment is to the cementum. The acini of salivary glands contain serous cells (protein-secreting), mucous cells (mucin-secreting), or both. The relative frequencies of the three types of acini are a prime characteristic by which the major salivary glands are distinguished. Thus, three types of acini are described: · · · Serous acini, which contain only serous cells and are generally spherical Mucous acini, which contain only mucous cells and are usually more tubular Mixed acini, which contain both serous and mucous Digestive System I cells. In routine H&E preparations, mucous acini have a cap of serous cells that are thought to secrete into the highly convoluted intercellular space between the mucous cells. Because of their appearance in histologic sections, such caps are called serous demilunes [Fr. Sections prepared from the same specimen by conventional methods show swollen mucous cells with enlarged secretory granules. The serous cells form typical demilunes and are positioned in the peripheral region of the acinus with slender cytoplasmic processes interposed between the mucous cells. The process of demilune formation can be explained by the expansion of mucinogen, a major component of secretory granules, during routine fixation. This expansion increases the volume of the mucous cells and displaces the serous cells from their original position, thus creating the demilune effect. A similar phenomenon is sometimes seen in the intestinal mucosa, in which swollen goblet cells displace adjacent absorptive cells. As noted above, each mixed acinus, such as those found in the sublingual and submandibular glands, contains serous and mucus-producing cells. In routine preparation for both light and electron microscopy, serous cells have traditionally been regarded as the structures that make up the demilune. Recent electron microscopic studies now challenge this classic interpretation of the demilune. Rapid freezing of the tissue in liquid Serous cells have a pyramidal shape, with a relatively wide basal surface facing the basal lamina and a small apical surface facing the lumen of the acinus. Carious lesions generally occur under masses of bacterial colonies referred to as "dental plaque. These bacterial colonies metabolize carbohydrates, producing an acidic environment that demineralizes the underlying tooth structure. Frequent sucrose ingestion is strongly associated with the development of these acidogenic bacterial colonies. Fluoride improves the acid resistance of the tooth structure, acts as an antimicrobial agent, and promotes remineralization of small carious lesions. Resistance to acid breakdown of enamel is facilitated by the substitution of fluoride ion for the hydroxyl ion in the hydroxyapatite crystal. Microbial invasion of tooth structure can reach the "pulp" of the tooth and elicit an inflammatory response. The enamel (E) has been undermined and weakened, causing fracture and a resulting cavity. At this point, bacteria can invade and penetrate down the exposed dental tubules, resulting in destructive liquefaction foci in the dentin (D) and, ultimately, exposure of the pulp. This drawing indicates the relationship of the mucous and serous cells as observed in the electron microscope after the rapid freezing method. In this drawing, serous cells are shown occupying the periphery of the acinus to form the so-called serous demilune. The swollen mucous cells have forced out the serous cells, leaving small remnants of the cytoplasm between the mucous cells. As in other mucus-secreting epithelia, the mucous cells of the mucous salivary acini undergo cyclic activity. During part of the cycle, mucus is synthesized and stored within the cell as mucinogen granules. When the product is discharged after hormonal or neural stimulation, the cell begins to resynthesize mucus. After discharge of most or all of the mucinogen granules, the cell is difficult to distinguish from an inactive serous cell. As indicated by the box in the orientation photomicrograph, only the apical portions of parotid gland serous acinus are shown in this electron micrograph. Many of the granules have coalesced to form larger irregular masses that will ultimately discharge into the lumen (L) of the acinus. The apical portion of the mucous cell contains numerous mucinogen granules and a large Golgi apparatus, in which large amounts of carbohydrate are added to a protein base to synthesize the glycoprotein of the mucin. Mucous cells possess apical junctional complexes, the same as those seen between serous cells. Myoepithelial cells are contractile cells that embrace the basal aspect of the acinar secretory cells. Salivary Ducts the lumen of the salivary acinus is continuous with that of a duct system that may have as many as three sequential segments: · · · Intercalated duct, which leads from the acinus Striated duct, so-called because of the presence of "striations," the infoldings of the basal plasma membrane of the columnar cells that form the duct Excretory ducts, which are the larger ducts that empty into the oral cavity Myoepithelial cells are contractile cells with numerous processes. Myoepithelial cells also underlie the cells of the proximal portion of the duct system. In both locations, the myoepithelial cells are instrumental in moving secretory products toward the excretory duct. The nucleus of the cell is often seen as a small round profile near the basement membrane. The contractile filaments stain with eosin and are sometimes recognized as a thin eosinophilic band adjacent to the basement membrane. Serous glands have well-developed intercalated ducts and striated ducts that modify the serous secretion by both absorption of specific components from the secretion and secretion of additional components to form the final product. Mucous glands, in which the secretion is not modified, have very poorly developed intercalated ducts that may not be recognizable in H&E sections. Intercalated ducts are lined by low cuboidal epithelial cells that usually lack any distinctive feature to suggest a function other than that of a conduit. Low-magnification electron micrograph of the sublingual gland, prepared by the rapid freezing and freeze-substitution method, shows the arrangement of the cells within a single acinus. Electron micrograph of the sublingual gland prepared by traditional fixation in formaldehyde. Note the considerable expansion and coalescence of the mucinogen granules and the formation of a serous demilune. This electron micrograph shows the basal portion of two secretory cells from a submandibular gland. Note the location of the myoepithelial cell process on the epithelial side of the basal lamina. The cytoplasm of the myoepithelial cell contains contractile filaments and densities (arrows) similar to those seen in smooth muscle cells. Having migrated through the basal lamina, it is also within the epithelial compartment. In mucus-secreting salivary glands, the intercalated ducts, when present, are short and difficult to identify. Striated ducts are lined by a simple cuboidal epithe- Large amounts of adipose tissue often occur in the parotid gland; this is one of its distinguishing features (Plate 52, page 564). Digestive System I lium that gradually becomes columnar as it approaches the excretory duct. The infoldings of the basal plasma membrane are seen in histologic sections as "striations. Basal infoldings associated with elongated mitochondria are a morphologic specialization associated with reabsorption of fluid and electrolytes. The striated duct cells also have numerous basolateral folds that are interdigitated with those of adjacent cells. The nucleus typically occupies a central (rather than basal) location in the cell. Striated ducts are the sites of: Submandibular Gland the submandibular glands are mixed glands that are mostly serous in humans. The large, paired, mixed submandibular glands are located under either side of the floor of the mouth, close to the mandible. A duct from each of the two glands runs forward and medially to a papilla located on the floor of the mouth just lateral to the frenulum of the tongue. Some mucous acini capped by serous demilunes are generally found among the predominant serous acini. When secretion is very rapid, more Na and less K appear in the final saliva because the reabsorption and secondary secretion systems cannot keep up with the rate of primary secretion. Striated ducts are located in the parenchyma of the glands (they are intralobular ducts) but may be surrounded by small amounts of connective tissue in which blood vessels and nerves can be seen running in parallel with the duct. Sublingual Gland the small sublingual glands are mixed glands that are mostly mucous secreting in humans. The sublingual glands, the smallest of the paired major salivary glands, are located in the floor of the mouth anterior to the submandibular glands. Their multiple small sublingual ducts empty into the submandibular duct as well as directly onto the floor of the mouth. Intercalated ducts and striated ducts are short, difficult to locate, or sometimes absent. As the diameter of the duct increases, stratified columnar epithelium is often seen, and as the ducts approach the oral epithelium, stratified squamous epithelium may be present. Saliva Saliva includes the combined secretions of all the major and minor salivary glands. A smaller amount is derived from the gingival sulcus, tonsillar crypts, and general transudation from the epithelial lining of the oral cavity. The volume (per weight of gland tissue) of saliva exceeds that of other digestive secretions by as much as 40 times. The large volume of saliva produced is undoubtedly related to its many functions, only some of which are concerned with digestion. The parotid duct travels from the gland, which is located below and in front of the ear, to enter the oral cavity opposite the second upper molar tooth. The secretory units in the parotid are serous and surround numerous, long, narrow intercalated ducts. The parotid gland in the human is composed entirely of serous acini and their ducts. The lower portion of the figure reveals an excretory duct within a connective tissue septum. The mucus-secreting acini are readily discernible at this low magnification because of their light staining. Higher magnification of an acinus revealing a serous demilune surrounding mucus-secreting cells. Critical examination of the mucous acini at this relatively low magnification reveals that they are not spherical structures but, rather, elongate or tubular structures with branching outpockets. The ducts of the sublingual gland that are observed with the greatest frequency in a section are the interlobular ducts.

Photomicrograph of brown adipose tissue from a newborn in an H&E­stained paraffin preparation allergy medicine 2014 purchase fml forte 5 ml fast delivery. This photomicrograph allergy medicine liver order fml forte 5 ml fast delivery, obtained at a higher magnification allergy testing nuts order 5 ml fml forte with visa, shows the brown adipose cells with round and often centrally located nuclei allergy medicine 7253 cheap fml forte generic. As with epithelial tumors and tumors of fibroblast origin allergy forecast eugene buy cheapest fml forte and fml forte, the variety of adipose tissue tumors reflects the normal pattern of adipose tissue differentiation; that is, discrete tumor types can be described that consist primarily of cells resembling a given stage in normal adipose tissue differentiation. For instance, the conventional lipoma consists of mature white adipocytes, whereas a fibrolipoma has adipocytes surrounded by an excess of fibrous tissue and an angiolipoma contains adipocytes separated by an unusually large number of vascular channels. The majority of lipomas show structural chromosome aberrations that include balanced rearrangements, often involving chromosome 12. Lipomas are usually found in subcutaneous tissues in middle-aged and elderly individuals. They are characterized as well-defined, soft, and painless masses of mature adipocytes usually found in the subcutaneous fascia of the back, thorax, and proximal parts of the upper and lower limbs. They are typically detected in older individuals and are mainly found in the deep adipose tissues of the lower limbs, abdomen, and the shoulder area. Tumors containing more cells in earlier stages of differentiation are more aggressive and more frequently metastasize. This photomicrograph was obtained from a tumor surgically removed from the retroperitoneal space of the abdomen. Well-differentiated liposarcoma is characterized by a predominance of mature adipocytes that vary in size and shape. They are interspersed between broad fibrous septa of connective tissue containing cells (the majority of them are fibroblasts) with atypical hyperchromatic nuclei. A relatively few scattered spindle cells with hyperchromatic and pleomorphic nuclei are found within connective tissue. Although the term lipoma relates primarily to white adipose tissue tumors, tumors of brown adipose tissue are also found. They are rare, benign, and slow-growing soft tissue tumors of brown fat most commonly arising in the periscapular region, axillary fossa, neck, or mediastinum. Most hibernomas contain a mixture of white and brown adipose tissue; pure hibernomas are very rare. In contrast to white adipocytes, differentiation of brown adipocytes is under the influence of a different pair of transcription factors. Clinical observations confirm that under normal conditions, brown adipose tissue can expand in response to increased blood levels of norepinephrine. This becomes evident in patients with pheochromocytoma, an endocrine tumor of adrenal medulla secreting excessive amounts of epinephrine and norepinephrine. In the past, it was thought that uncoupling proteins were expressed only in brown adipose tissue. Recently, several similar uncoupling proteins have been discovered in other tissues. Note that moderate increase of radioactive tracer uptake is also detectable in the myocardium (yellow color). Regions of extensive metabolic activity correlate with the distribution pattern of low-density brown adipose tissue. When oxidized, it produces heat to warm the blood flowing through the brown fat on arousal from hibernation and in the maintenance of body temperature in the cold. Brown adipose tissue is also present in nonhibernating animals and humans and again serves as a source of heat. As in the mobilization of lipid in white adipose tissue, lipid is mobilized, and heat is generated by brown adipocytes when they are stimulated by the sympathetic nervous system. Therefore, normally present brown adipose tissue can most likely be induced and function in the context of human adaptive thermogenesis. Future research is being directed toward finding mechanisms for increased brown fat differentiation, which may potentially be an the mitochondria in eukaryotic cells produce and store energy as an electrochemical proton gradient across the inner mitochondrial membrane. The energy produced by the mitochondria is then dissipated as heat in a process known as thermogenesis. The metabolic activity of brown adipose tissue is regulated by the sympathetic nerve system and is related to ambient outdoor temperature. In addition, cold stimulates glucose utilization in brown adipocytes by overexpression of glucose transporters (Glut-4). An increase in the amount of brown adipose tissue has been reported on the neck and supraclavicular regions during the winter months, especially in lean individuals. This is supported by autopsy findings of larger amounts of brown fat in outdoor workers exposed to cold. Modern molecular imaging techniques now allow clinicians to precisely locate where brown fat is distributed in the body, which is essential for proper differential diagnosis of cancerous lesions (see Folder 9. Exposure to chronic cold temperatures increases the thermogenic needs of an organism. Studies have shown that in such a condition, mature white adipocytes can transform into brown adipocytes to generate body heat. Conversely, brown adipocytes are able to transform into white adipocytes when the energy balance is positive and the body requires an increase of triglyceride storage capacity. This phenomenon, known as transdifferentiation, was observed in experimental animals. These findings are also supported by observations of differential gene expressions. Worth mentioning is the fact that mice with abundant natural or induced brown adipose tissue are resistant to obesity, whereas genetically modified mice without functional brown adipocytes are prone to obesity and type 2 diabetes. If the browning phenomenon is achieved by a physiologic genome-reprogramming mechanism, this mechanism could be used for future therapeutic strategies aimed at controlling the amount of brown adipose tissue in the body. White-to-brown transdifferentiation of adipose tissue is induced by cold exposure and physical activity. Cold exposure and physical activity induce conversion of white-to-brown adipocytes via several molecular pathways. Cold temperatures are sensed by the central nervous system, causing increased stimulation of the noradrenergic sympathetic nerve system. Physical exercise stimulation is more complicated and involves the secretion of atrial and ventricular natriuretic peptides in the heart that act on the kidney, which in turn activate transcription factors essential for brown adipocyte differentiation. In the future, these signaling pathways and molecules involved in adipocyte transdifferentiation may open new avenues in pharmacologic treatment of obesity, diabetes, and other metabolic diseases. White adipose tissue with supporting collagen and reticular fibers forms the subcutaneous fascia, is concentrated in the mammary fat pads, and surrounds several internal organs. White adipocytes are very large cells (100 m or more in diameter) with a single, large lipid droplet (unilocular), a thin rim of cytoplasm, and a flattened, peripherally displaced nucleus. A single large lipid droplet within the white adipocyte represents cytoplasmic inclusion and is not membrane bound. Triglycerides stored in adipocytes are released by lipases that are activated during neural mobilization (involves norepinephrine released from sympathetic nerves) and/or hormonal mobilization (involves glucagon and growth hormone). Brown adipocytes are smaller than white adipocytes, contain many lipid droplets (multilocular) and cytoplasm with a round nucleus. The metabolic activity of brown adipose tissue is regulated by norepinephrine released from sympathetic nerves and is related to ambient outdoor temperature (cold weather increases the amount of brown adipose tissue). It is a specialized connective tissue consisting of triglyceride-storing cells, adipocytes. Adipocytes catabolize triglycerides, and when energy expenditure exceeds energy intake, fatty acids are released into circulation. In addition, glycerol and fatty acids released from the adipocytes participate in glucose metabolism. Adipose tissue has a rich blood supply, which complements its metabolic and endocrine functions. Its adipocytes are very large cells whose cytoplasm contains a single large vacuole in which the fat is stored in the form of triglycerides. When observed in a typical H&E section, white adipose tissue appears as a mesh-like structure (see orientation micrograph). Brown adipose tissue is found in human newborns where it assists in maintaining body temperature. The loss of the fat within the cell during routine H&E slide preparation gives the adipose tissue a mesh-like appearance. This is a higher magnification micrograph of white adipose tissue from the specimen shown in the orientation micrograph. In well-preserved specimens, the adipocytes (A) have a spherical profile in which they exhibit a very thin rim of cytoplasm surrounding a single, large fat-containing vacuole. Because the fat is lost during tissue preparation, one only sees the rim of cytoplasm and an almost clear space. The majority of nuclei that are observed within the adipose tissue belong to fibroblasts, adipocytes, or cells of small blood vessels. However, distinguishing between fibroblast nuclei and adipocyte nuclei is often difficult. It appears to reside within the rim of cytoplasm (Cy), giving the adipocyte the classic "signet ring" appearance. Because of the relatively large size of the adipocyte, it is very infrequent that the nucleus of the cell is included in the plane of section of a given cell. The brown adipose tissue shown here consists of small fat cells that are very closely packed with minimal intercellular space. Because of this arrangement, it is hard to define individual cells at this magnification. At higher magnification (not shown), it is possible to identify some individual cells. One cell, whose boundaries could be identified at higher magnification, is circumscribed by a dotted line. It is even more difficult to distinguish fibroblasts within the lobule from nuclei of the fat cells. Even at higher magnification (inset), it is difficult to determine which nuclei belong to which cells. Where the lobules are slightly separated from one another (arrows), small elongate nuclei of fibroblasts in the connective tissue septa can be recognized. Blood consists of cells and their derivatives and a proteinrich fluid called plasma. Blood cells and their derivatives include: Like the other connective tissues, blood consists of cells and an extracellular component. Total blood volume in the average adult is about 6 L or 7% to 8% of total body weight. Plasma is the liquid extracellular material that imparts fluid properties to blood. The relative volume of cells and plasma in whole blood is approximately 45% and 55%, respectively. A normal hematocrit reading is about 39% to 50% in men and 35% to 45% in women; thus, 39% to 50% and 35% to 45% of the blood volume for men and women, respectively, consists of erythrocytes. Low hematocrit 270 microhematocrit tube 100 1,000 times more erythrocytes (5 1012 cells/L of blood) than leukocytes (7 109/L of blood). More than 90% of plasma by weight is water, which serves as the solvent for a variety of solutes, including proteins, dissolved gases, electrolytes, nutrients, regulatory substances, and waste materials. The solutes in the plasma help maintain homeostasis, a steady state that provides optimal pH and osmolarity for cellular metabolism. Blood composition is clearly apparent after centrifuging a small volume of blood in the microhematocrit tube. The volume of packed erythrocytes occupies about 45% of whole blood (this fraction is called hematocrit). The thin layer between erythrocytes and plasma contains leukocytes and platelets; it is often referred to as a buffy coat. The remaining volume (about 55%) consists of a pale yellow, opaque fluid and represents protein-rich blood plasma. In a blood sample that has been centrifuged, the cell fraction (the part of the sample that contains the cells) consists mainly of packed erythrocytes (99%). Albumin is the main protein constituent of the plasma, accounting for approximately half of the total plasma proteins. Albumin is responsible for exerting the concentration gradient between blood and extracellular tissue fluid. This major osmotic pressure on the blood vessel wall, called the colloid osmotic pressure, maintains the correct proportion of blood to tissue fluid volume. If a significant amount of albumin leaks out of the blood vessels into the loose connective tissue or is lost from the blood to urine in the kidneys, then the colloid osmotic pressure of the blood decreases, and fluid accumulates in the tissues. Globulins include the immunoglobulins (-globulins), the largest component of the globulin fraction, and nonimmune globulins (-globulin and -globulin). The immunoglobulins are antibodies, a class of functional immunesystem molecules secreted by plasma cells. They help maintain the osmotic pressure within the vascular system and also serve as carrier proteins for various substances such as copper (by ceruloplasmin), iron (by transferrin), and the protein hemoglobin (by haptoglobin). Nonimmune globulins also include fibronectin, lipoproteins, coagulation factors, and other molecules that may exchange between the blood and the extravascular connective tissue. In a series of cascade reactions with other coagulation factors, soluble fibrinogen is transformed into the insoluble protein fibrin (323 kDa). During conversion of fibrinogen to fibrin, fibrinogen chains are broken to produce fibrin monomers that rapidly polymerize to form long fibers. These fibers become cross-linked to form an impermeable net at the site of damaged blood vessels, thereby preventing further blood loss.

The drawing allergy testing colorado springs generic fml forte 5 ml without prescription, at the electron microscopic level allergy medicine nightmares purchase fml forte now, shows the sectioned face on the right and a three-dimensional view of the basolateral surface of a cell with a partial cut face on the left allergy symptoms medications cheap fml forte 5 ml buy on-line. Here the interdigitating parts of the adjoining cell have been removed to show the basolateral interdigitations allergy treatment products generic 5 ml fml forte visa. The processes are long in the basal region and create an elaborate extracellular compartment adjacent to the basal lamina allergy medication for dogs 5 ml fml forte order overnight delivery. In some locations, the microvilli have been omitted, thereby revealing the convoluted character of the apical cell boundary. Of the 180 L/day of ultrafiltrate entering the nephrons, approximately 120 L/day, or 65% of the ultrafiltrate, is reabsorbed by the proximal convoluted tubule. They are responsible for the reabsorption of Na, which is the major driving force for reabsorption of water in the proximal convoluted tubule. As in the intestinal and gallbladder epithelia, this process is driven by active transport of Na into the lateral intercellular space. Here, the fluid is reabsorbed into the vessels of the peritubular capillary network. The proximal convoluted tubule also reabsorbs nearly all glucose, amino acids, and small polypeptides. The proximal convoluted tubule also recovers approximately 98% of the filtered amino acids. These amino acids are absorbed by several amino acid transporters that either exchange Na, H, and K ions (acidic amino acid transporters) or Na and H ions (basic and neutral amino acid transporters). The brush border in the proximal convoluted tubule resembles that of a striated border in the small intestine in that it possesses many peptidases that degrade large proteins into smaller proteins and polypeptides. Small polypeptides are recovered in a process similar to that of glucose that employs apical surface H peptide cotransporters (PepT1 and PepT2). Once inside the cell, polypeptides are rapidly degraded and transported across the basolateral membrane as free amino acids. This section is almost tangential and slightly oblique to the base of a proximal convoluted tubule cell and the subjacent basal lamina and capillary. Characteristically, the endothelium possesses numerous fenestrations (EnF), and in this plane of section, the fenestrations are seen en face, displaying circular profiles. To the right of the basal lamina are the interdigitating basal processes of the proximal tubule cells. The long, straight processes contain longitudinally oriented actin filaments (arrows). In this plane of section, the basal extracellular space appears as a maze between the cellular processes. The accumulation of NaCl in the lateral intercellular spaces creates an osmotic gradient that draws water from the lumen into the intercellular compartment. This compartment distends as the amount of fluid in it increases; the lateral folds separate to allow this distension. Immunocytochemical methods can be used to demonstrate the presence of these proteins. Deep tubular invaginations are present between the microvilli of the proximal convoluted tubule cells. Proteins in the ultrafiltrate, on reaching the tubule lumen, bind to endocytotic receptors expressed on the plasma membrane. These early endosomes are destined to become lysosomes, and the endocytosed proteins are degraded by acid hydrolases. The amino acids produced in the lysosomal degradation are recycled into the circulation via the intercellular compartment and the interstitial connective tissue. Also, the pH of the ultrafiltrate is modified in the proximal convoluted tubule by the reabsorption of bicarbonate and by the specific secretion into the lumen of exogenous organic acids and organic bases derived from the peritubular capillary circulation. They are shorter, with a less well-developed brush border and with fewer and less complex lateral and basolateral processes. The mitochondria are smaller than those of the cells of the convoluted segment and are randomly distributed in the cytoplasm. There are fewer apical invaginations and endocytotic vesicles as the hydrostatic pressure that builds up in the distended intercellular compartment, presumably aided by contractile well as fewer lysosomes. Cells in the proximal straight tubule are designed to recover the remaining glucose that escaped recovery in the proximal convoluted tubules before it enters the thin segment of the loop of Henle. Juxtamedullary nephrons have the longest limbs; cortical nephrons have the shortest. In the light microscope, it is possible to detect at least two kinds of thin segment tubules, one with a more squamous epithelium than the other. Morphologic differences, such as microvilli, mitochondria, and degree of cellular interdigitation, probably reflect specific active or passive roles in this process. The thin descending and ascending limbs of the loop of Henle differ in structural and functional properties. The cells have almost no interdigitations with neighboring cells and few organelles. The ultrafiltrate that enters the thin descending limb is isosmotic, whereas the ultrafiltrate leaving the thin ascending limb is hyposmotic to plasma. This limb is much less permeable to Na and urea; however, it does permit small amounts to enter the nephron at this site. Because the interstitial fluid in the medulla is hyperosmotic, water exits this nephron segment by osmosis, causing the luminal content of Na and Cl to become progressively more concentrated. The cells of this limb do not actively transport ions; thus, the increased tubular fluid osmolality that occurs in this nephron segment is caused in large part by the passive movement of water into the peritubular connective tissue. The thin ascending limb of the loop of Henle is highly permeable to Na and Cl due to the presence of Na /K /2Cl cotransporters in the apical plasma cell membranes. Counter ions, in this case, Na (the majority) and K, follow passively to maintain electrochemical neutrality. The hyperosmolarity of the interstitium is directly related to the transport activity of the cells in this nephron segment. This diagram shows the various types of epithelia and the region where they are found in the thin limb of the short and long loops of Henle. The diagrams of the epithelium do not include nuclear regions of the epithelial cells. For this reason, the thin ascending limb is sometimes referred to as the diluting segment of the nephron. In addition, epithelial cells lining the thick ascending limb produce an 85 kDa protein called uromodulin (Tamm-Horsfall protein) that influences NaCl reabsorption and urinary concentration ability. Uromodulin also modulates cell adhesion and signal transduction by interacting with various cytokines. It also inhibits the aggregation of calcium oxalate crystals (preventing kidney stone formation) and provides a defense against urinary tract infection. In individuals with inflammatory kidney diseases, a precipitated uromodulin is detected in urine in the form of urinary casts (see Folder 20. The distal straight tubule (thick ascending limb), as previously noted, is part of the ascending limb of the loop of Henle and includes both medullary and cortical portions, with the latter located in the medullary rays. The distal straight tubule, like the ascending thin limb, transports ions from the tubular lumen to the interstitium. The apical cell membrane in this segment has electroneutral transporters (synporters) that allow Cl, Na, and K to enter the cell from the lumen. Some K ions leak back into the tubular fluid through K channels, causing the tubular lumen to be positively charged with respect to the interstitium. This positive gradient provides the driving force for the reabsorption of many other ions such as Ca2 and Mg2. Note that this significant movement of ions occurs without the movement of water through the wall of the distal straight tubule, resulting in separation of water from its solutes. In routine histologic preparations, the large cuboidal cells of the distal straight tubule stain lightly with eosin, and the lateral margins of the cells are indistinct (Plate 77, page 736). The nucleus is located in the apical portion of the cell and sometimes, especially in the straight segment, causes the cell to bulge into the lumen. As in the proximal tubule cell, the mitochondria account for the appearance of basal striations in the light microscope. The cells of the distal convoluted tubule resemble those of the distal straight tubule (thick ascending limb) but are considerably taller and lack a well-developed brush border. Similar to the distal straight tubule, the epithelium in the distal convoluted tubule is also relatively impermeable to water. The early part of the distal convoluted tubule is the primary site for parathyroid hormone­regulated Ca2 reabsorption. This short tubule is responsible for: Distal Convoluted Tubule the structure and function of the distal convoluted tubule depends on the delivery and uptake of Na. It begins at a variable distance beyond the macula densa and extends to the connecting tubule, which connects the nephron with the cortical collecting duct. Connecting tubules of the subcapsular nephrons join directly to the cortical collecting duct, whereas the connecting tubules from the midcortical and juxtamedullary nephrons merge with other connecting tubules first to form an arched connecting tubule before uniting with the cortical collecting duct. The epithelium of this segment undergoes a gradual transition from the distal convoluted tubule to the collecting duct and consists of intermingling cells from both regions. Both morphologic and physiologic studies demonstrated that connecting tubules play an important role in K secretion (most likely attributed to the presence of the principal cells), which is in part regulated by mineralocorticoids secreted by the adrenal cortex. The cortical collecting ducts have flattened cells, somewhat squamous to cuboidal in shape. The medullary collecting ducts have cuboidal cells, with a transition to columnar cells as the ducts increase in size. The collecting ducts are readily distinguished from proximal and distal tubules by virtue of the cell boundaries that can be seen in the light microscope (Plate 77, page 736). Microplicae, cytoplasmic folds, are present on their apical surface, as well as microvilli. They do not show basal infoldings but have basally located interdigitations with neighboring cells. The intercalated cells are involved in the secretion of H (-intercalated cells) or bicarbonate (-intercalated cells), depending on the whether the kidneys need to excrete acid or alkali. The -intercalated cells have opposite polarity and secrete bicarbonate ions into the lumen of the collecting duct. Because of the nature of the diet and thus the need to excrete acid, the epithelium of collecting ducts contains more - than -intercalated cells. The number of dark cells gradually decreases until there are none in the ducts as they approach the papilla. Aldosterone does not function at the distal convoluted tubule but rather at the connecting tubules and collecting ducts. They are pale-staining cells with true basal infoldings rather than processes that interdigitate with those of adjacent cells. However, new molecular research methodologies show that aldosterone acts mainly on the principal (light) cells of the collecting ducts. As mentioned above, principal cells are not present in the distal convoluted tubule but do have a scattered presence in the connecting tubules. The reason for this confusion relates to the fact that the collected tubular fluid during micropuncture experiments often had contact with cells of the connecting tubules and cortical collecting ducts, providing an impression that the experimental treatment with aldosterone had an effect on the distal convoluted tubule. Molecular studies of gene expression provided clear evidence of mineralocorticoid (aldosterone) receptor presence in the principal cells. Aldosterone bound to mineralocorticoid receptors in the principal cells acts as a transcription factor for proteins involved in exchanges of Na for K. This micrograph shows dark cells (asterisks), with numerous short lamellipodia or microridges on their surface, and light (principal) cells, each with a primary cilium on its free surface along with small microvilli. The terms light and dark refer to the staining character of sectioned cells and not to the density differences reflecting charge characteristics of the coated surface of the specimen. Each protein consists of six transmembrane domains arranged to form a distinct pore. Synthesis of new channel proteins and enzymes takes approximately 6 hours to implement. The net result of aldosterone action is the increase of reabsorption of Na and secretion of K by the principal cells. This increases blood serum Na concentration, which in turn increases blood volume and blood pressure. This tissue increases considerably in amount from the cortex (where it constitutes approximately 7% of the volume) to the inner region of the medulla and papilla (where it may constitute more than 20% of the volume). In the cortex, two types of interstitial cells are recognized: cells that resemble fibroblasts, found between the basement membrane of the tubules and the adjacent peritubular capillaries, and occasional macrophages. In their intimate relationship with the base of the tubular epithelial cells, the fibroblasts resemble the subepithelial fibroblasts of the intestine. These cells synthesize and secrete the collagen and glycosaminoglycans of the extracellular matrix of the interstitium. They are oriented to the long axes of the tubular structures and may have a role in compressing these structures. Prominent lipid droplets in the cytoplasm appear to increase and decrease in relation to the diuretic state. Most fibroblasts originate within the interstitial tissue through a mechanism called epithelial­mesenchymal transition. The conversion of tubular epithelial cells into a mesenchymal phenotype is initiated by an alteration in the balance of local cytokine concentrations. During persistent injury and chronic inflammation of the kidney parenchyma, fibroblasts increase their numbers and, by secreting excess extracellular matrix, destroy normal interstitial architecture of the kidney.

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