Professor of Surgery, Pediatrics and Humanities in Medicine
Director of the
Division of Pediatric Surgery, Department of Surgery, Texas A&M Health Science
Center, Temple, Texas
Inactivation of tumor suppressor genes on arms 5q mens health gift guide purchase 0.2mg flomax with visa, 18q mens health dwayne johnson supplements flomax 0.4mg low cost, and 17p is thought to be essential in tumorigenesis prostate cancer 38 years old flomax 0.4mg generic. Clinical Presentations They may present with bleeding prostate pq 0.4 mg flomax amex, prolapse androgen hormone use in livestock discount 0.4 mg flomax with visa, and rarely intussusception prostate herbs discount 0.2 mg flomax with amex, but most commonly they are asymptomatic. They may, however, cause painless rectal bleeding or bleeding not apparent to the naked eye. Usually the colorectal polyps are the ones causing symptoms, such as bleeding, diarrhea, abdominal cramps, and anemia. In such cases surgery is performed, choosing between the same operations offered to patients with familial adenomatous polyposis: colectomy and ileorectal anastomosis, proctocolectomy and pouch, or proctocolectomy and ileostomy. Pictures are taken after rectal instillation of barium sulfate (a radiopaque contrast medium). The reason for this decrease in use as a diagnostic tool lies in the reduced sensitivity of this test in detecting polyps of lesser than 1 cm, in detecting polyps in areas where a single lumen is not detectable. If a polyp is greater than 1 cm, the diagnostic accuracy of this technique has been reported as up to 95%; for polyps smaller than 1 cm well-performed air-contrast barium enema has a sensitivity of 61%. Diverticulosis or redundant bowel can result in a false-negative rate of 10%, especially in the rectosigmoid. Figure 1 Polypoid lesion in a 56 year old female with familial history of adenomatous polyposis. Close-up view of an overhead image from a double-contrast enema examination shows a 1. Reported diagnostic accuracy for polyps >5 mm exceeds that of barium enema and approaches that of conventional colonoscopy. In contrast, colonoscopy is associated with appreciable morbidity and even mortality including significant cardiovascular effects related to sedation. Although it requires a full bowel cleansing similar to that required for conventional colonoscopy, the procedure requires no sedation or analgesia, and is faster to perform than conventional colonoscopy. Figure 2 (a) Polypoid lesion in a 65 year old frail and uncooperative patient with rectal bleeding. However, since it is only a screening procedure, patients with positive findings require conventional colonoscopy afterward. Diagnosis Diagnosis relies on good history and physical examination of patients at risk. Rectal examination can identify cancers up to 8 cm above the dentate line that represent 20% of colorectal cancer. Flexible sigmoidoscopy: Flexible sigmoidoscopy can reach as high as the descending colon and can be done by a trained primary care physician. Sigmoidoscopy has been proven to reduce the incidence and mortality of colon cancer through early detection, however, is not an adequate method of screening in hereditary colon cancer as 2/3 of the lesions develop proximal to the splenic flexure. Figure 3 Conventional colonoscopy of 53-year old female with familial history of adenomatous polyposis showing a 1 cm lesion of the ascending colon. Colonoscopy: Colonoscopy remains the gold standard for visualization, biopsy, and removal of colonic polyps. Colonoscopy is the "gold standard" for the detection of colonic neoplasms and the preferred colorectal cancer screening strategy. The incidence rate of colorectal cancer has been shown to be reduced up to 90% in subjects who had polypectomy versus patients in three reference groups, including two cohorts in which colonic polyps were not removed and one general-population registry. Colonoscopic screening in individuals with average risk has been found to be cost effective, and similar to cervical or breast cancer screening techniques in costeffectiveness per life-year saved. Medicare has approved the use of screening colonoscopy in average-risk beneficiaries. The evidence to support colonoscopy is derived from data showing a decreased incidence of colorectal cancer mortality in subjects who have undergone colonoscopic adenoma removal. Additionally, colonoscopic screening has been shown to have favorable cost effectiveness when compared to other screening strategies. The tumor consists typically of a huge amount of whitish fibrous tissue at cut section, especially in large lesions with central necroses. Metastases to regional lymph nodes and pulmonary and peritoneal spreading are common. The infiltrative type is the most common (over 70% of cases) and it appears as a sclerotic lesion with abundant fibrous tissue growing along the bile duct wall. It results in a diffuse, firm, gray-white annular thickening of the bile with complete or nearly complete obstruction of the lumen. The extent of the tumor may vary, ranging from few millimeters to several centimeters in length. A dense fibroblastic reaction may compress or encase the adjacent vascular structures. The tumor arises within the mucosa, invades the bile duct wall, and grows outward to form a nodular, exophytic mass. The tumors may arise at any part and from any component of the bile duct epithelium, ranging from the terminal ductules (canals of Hering) to the ampulla of Vater as well as at the peribiliary glands (intramural and extramural). According to the site of origin, cholangiocarcinoma can be differentiated into intrahepatic/peripheral, hilar (Klatskin tumor), and extrahepatic. Characteristically, the malignant cells are of cuboidal or low columnar type resembling biliary epithelium. In more poorly differentiated tumors, solid cords of cells without biliary ducts may be present. The dense fibrous stroma is characteristic and may dominate the histological architecture. Spread along the lumen of large bile ducts can be seen, especially in hilar tumors (2). It is associated with primary sclerosing cholangitis, intrahepatic stone disease, choledochal cyst, congenital hepatic fibrosis, clonorchiasis, and exposure to Thorotrast. Clinical signs and symptoms, including jaundice, itching, clay-colored stools, dark urine, weight loss, and abdominal pain, may vary according to the various sites of origin of the tumor (1, 3). Jaundice is usually the leading sign in tumors located in the common bile duct or common hepatic duct as a sign of biliary obstruction. Hyperechoic foci with acoustic shadowing, suggesting calcifications, and segmental bile duct dilation in the presence of normal extrahepatic ducts may be observed. The mass is round or oval, more or less well demarcated, and may demonstrate segmental biliary ductal dilatation peripheral to the tumor. The central part of the tumor usually does not enhance during these phases, whereas there may be delayed enhancement based on the interstitial transition of extracellular iodinated contrast agents. Extrahepatic spread is common and lymph node metastasis with involvement of the celiac and left gastric areas or direct invasion of the omentum is frequently detected (1, 4). However, the signal intensity of the tumor is variable according to the amount of fibrosis, necrosis, and mucinous components within the tumor. After contrast medium administration the lesion shows minimal peripheral enhancement during the arterial (b) and portal venous (c) phases. Neoplasms, Bile Ducts 1207 A central hypointensity, corresponding to fibrosis, is usually best appreciated on T2-weighted images. Typically, Klatskin tumors manifest as segmental dilatation and nonunion of the right and left ducts at the porta hepatis. The dilated ducts will often almost reach the liver surface, which is pathognomonic. The associated cholangiocarcinoma is often at a hilar localization with a predominant involvement of the duct which drains the dependent segment (3, 4). Following intravenous contrast medium administration, enhancement of the lesion is poor to moderate. The degree of contrast enhancement probably depends on the presence of the fibroid components of the lesion. In a minority of cases there is early marked contrast uptake in the tumor, but often contrast enhancement is only noted on delayed scans (1, 4). Lymphatic metastases usually involve the portacaval, superior and posterior pancreatoduodenal lymph nodes. Retroperitoneal lymphadenopathy, peritoneal spread, and proximal intestinal obstruction occur in advanced stages. N 1208 Neoplasms, Bile Ducts Percutaneous transhepatic cholangiography is indicated in any patient who is cholestatic with nondilated bile ducts when there is doubt about the diagnosis and in whom an endoscopic intervention is not possible. Especially in the latter cases, even biopsy may be unable to resolve the diagnostic dilemma. After injection, the common bile duct and cystic duct are usually visualized within 15 min. However, additional findings of hepatoduodenal ligament adenopathy and tumor extension into adjacent structures are helpful diagnostic features supporting a malignant differential diagnosis (4). The differential diagnosis includes some bulky hepatic tumors of either primary or secondary origin. Due to a histologically similar appearance in metastatic adenocarcinomas, the differential diagnosis can be difficult for the pathologist. Springer, Berlin, Heidelberg Lencioni R, Cioni D, Bartolozzi C (2005) Focal Liver Lesions: Detection, Characterization, Ablation. It is indicated as a preoperative or preinterventional decompression procedure, particularly when endoscopic treatment has failed or is not indicated. Several studies show that the use of metallic stents is able to shorten hospitalization and to improve the quality of survival by lowering significantly the obstruction-related serum bilirubin levels. However, several early (fever, sepsis, bilioma, hemobilia, bile peritonitis, pancreatitis, cholecystitis) or late complications may occur. Late complications such as recurrent symptoms of cholangitis, cholangiohepatic abscess, or jaundice are usually related to stent occlusion by tumor ingrowth, overgrowth, and stent migration. In an attempt to prevent or to delay stent occlusion by tumor ingrowth, covered stents have been used. However, although covered devices impair tumor ingrowth, they cannot prevent neoplastic outgrowth. Bladder cancer is three times more common in men than women and it affects twice as many Whites as Blacks (1). The most well documented risk factor of bladder cancer is cigarette smoking, to which has been attributed up to 45% of urothelial cancers (1). Other risk factors include chronic bladder infection or inflammation, pelvic irradiation, and treatment with cyclophosphamide (1). Secondary involvement of the bladder by lymphoma may occur, representing direct spread from grossly involved pelvic lymph nodes. Metastases may also develop within the bladder wall, the extraluminal component being more obvious than the intraluminal mass, providing a clue to the diagnosis in patients with known disseminated disease due to cancers such as malignant melanoma and breast cancer. Transitional cell tumors account for 95% of all primary malignant bladder lesions (2). The rest are squamous cell carcinomas, mixed transitional and squamous cell tumors, adenocarcinomas, and undifferentiated lesions 4. Most bladder cancers arise on the lateral walls (47%) or in the region of the trigone (21%). Adenocarcinomas, which account for 3% of all bladder tumors, usually arise in the region of the trigone, but are occasionally seen as exophytic growths arising at the bladder dome and originating from a persistent urachus. About one-third of cancers are multifocal at the time of diagnosis, and the whole bladder epithelium may undergo malignant change. Bladder tumors show a variable pattern of growth and are classified as papillary, infiltrative, papillary and infiltrative, or nonpapillary and noninfiltrative (carcinoma in situ). Approximately one-third of patients present with muscle invasive disease at the time of initial diagnosis (1). Historically, tumors confined to the mucosa (Ta) and lamina propria (T1) have been classified as superficial; muscle invasive tumors are classified as T2-T3. In general, there is a correlation between T-stage and the risk of recurrence, progression, and metastasis. Once the tumor has penetrated the basement membrane (T1) or muscle (T2-T4), there is an increased likelihood of distant metastases, depending on the depth of penetration. The tumor may involve adjacent organs (prostate, uterus, vagina, rectum, small intestine) and extend to the pelvic side wall. The regional lymphatics include the paravesical, obturator, and external iliac lymph nodes. Clinical Presentation Patients most commonly present with painless hematuria, either gross or microscopic. The bleeding may be intermittent, so one should not be lured into a sense of false security by the spontaneous disappearance of bleeding. This constellation of symptoms, however, may also occur with benign entities, such as urinary tract infection, prostatism, and prostatits.
In addition prostate cancer 5k proven flomax 0.4 mg, as discussed in Section 7-14 prostate cancer keller williams buy flomax 0.2mg without prescription, during fetal development prostate 84 flomax 0.4mg otc, waves of: T cells with specific - and -gene rearrangements leave the thymus and migrate to these epithelial barriers androgen hormone quantitation buy flomax 0.2mg with amex. The development and organization of peripheral lymphoid tissues is controlled by cytokines and chemokines prostate zero cheap flomax 0.2mg amex. This has been best demonstrated by a series of knockout mice in which either the ligand or receptor has been inactivated mens health 082012 flomax 0.4 mg visa. In addition, it seems clear that there is some overlapping function or cooperation between ligands. Interestingly, not all lymph nodes are dependent on the same signals from these family members. Since some receptors bind more than one ligand, and some ligands bind more than one receptor, the roles are complex, and have been determined by analyzing a variety of mutant mice. Note that the receptors were named for the first known ligand that binds them, even though we now know that additional ligands can also bind. In some cases, the loss of one ligand leads to a different phenotype than the loss of another; this is due to the ability of the ligand to bind another receptor, and is indicated in the figure. The precise location of B cells, T cells, macrophages, and dendritic cells in peripheral lymphoid tissue is controlled by chemoattractant cytokines, or chemokines, which are produced by both stromal cells and bone marrow-derived cells. This may account for their characteristic migration pattern, which is first through the T zone (where they may linger if activated) and then to the follicle. The same combination of chemokines also attracts B cells into the developing lymph node (fourth panel). The B cells are able to either induce the differentiation of follicular dendritic cells or direct their recruitment into the lymph node. Only a small fraction of immature B cells mature and survive in peripheral lymphoid tissues. Our knowledge of the dynamics of B-cell populations comes from labeling immature B cells in the bone marrow of normal young adult mice with the thymidine analogue bromodeoxyuridine. The loss of more than half the initial pre-B cells may be due to failure to make a productive light-chain gene rearrangement and by the clonal deletion of self-reactive immature B cells within the bone marrow (see Section 7-17). When B cells emerge from bone marrow into the periphery, they are still functionally immature, expressing high levels of sIgM but little sIgD. Most of these immature cells will not survive to become fully mature B cells bearing low levels of sIgM and high levels of sIgD. B cells then migrate to the periphery where they enter the secondary lymphoid tissues. There seem to be two classes of peripheral B cell: long-lived B cells and short-lived B cells. Most of the turnover of short-lived B cells might result from B cells that fail to enter lymphoid follicles. In some cases this is a consequence of being rendered anergic by binding to soluble self antigen; for the remaining immature B cells, entry into lymphoid follicles is thought to entail some form of positive selection. Thus the remainder of the short-lived B cells fail to join the long-lived pool because they are not positively selected. About 90% of all peripheral B cells are relatively long-lived mature B cells that appear to have undergone positive selection in the periphery. These mature naive B cells recirculate through peripheral lymphoid tissues and have a half-life of 6 8 weeks in mice. Memory B cells, which have been activated previously by antigen and T cells, are thought to have a longer life. The daily output of new B cells is roughly 5 10% of the total B-lymphocyte population in the steady-state peripheral pool. Although the size of this pool is not easy to measure, it seems to remain constant in unimmunized animals, and the stream of new B cells must be balanced by the death of an equal number of peripheral B cells. The great majority of peripheral B cells (about 90%) are long-lived, however, and only 1 2% of these die each day. Most of the B cells that die are in the short-lived immature peripheral B-cell population, of which more than 50% dies every 3 days. Thus most B cells have a life-span of only a few days once they leave the bone marrow and enter the periphery; only a small number of newly made B cells survive to become part of the pool of relatively long-lived peripheral B cells. The failure of most B cells to survive for more than a few days in the periphery appears to be mainly due to competition between peripheral B cells for access to the follicles in the peripheral lymphoid tissues. The follicles appear to provide essential survival and possibly maturation signals for naive B cells. If newly made immature B cells do not enter a follicle, therefore, their passage through the periphery is halted and they die. The limited number of lymphoid follicles cannot accommodate the very large numbers of naive B cells poured out into the periphery each day and so there is continual competition for entry. The population dynamics indicate that competition for follicle entry favors mature B cells that are already established in the relatively long-lived and stable peripheral B-cell pool. Is its survival simply a matter of chance, or are survival and further development determined by positive selection involving the specificity of its antigen receptor, as in the positive selection of T cells in the thymus? Several experiments indicate that signaling through the B-cell receptor has a positive role in the maturation and continued recirculation of peripheral B cells. A clever method of inactivating the B-cell receptor in mature B cells by conditional gene deletion has demonstrated that continuous expression of the Bcell receptor is required for B-cell survival. Mice that lack the tyrosine kinase Syk, which is involved in signaling from the B-cell receptor (see Section 6-10), fail to develop mature B cells although they do have immature B cells. Thus, a Syk-transduced signal may be required for final B-cell maturation or for the survival of mature B cells. Nonetheless, receptor specificity might also have a part in selecting a peripheral B-cell pool that continues to do well in the ongoing competition to survive. We know that some of the short-lived peripheral B cells fail to survive because they have bound soluble self antigen and become anergic (see Section 7-17), and are excluded from the lymphoid follicles for this reason. In addition, recent evidence shows that the B-cell receptor repertoire of surviving mature B cells is enriched for certain antigen specificities compared with the immature population, strongly favoring the idea that there is positive selection of B cells for maturation. However, the extent to which recruitment of immature B cells into the long-lived pool of recirculating mature B cells is ligand-mediated and governed by receptor specificity is not known. Even among long-lived peripheral B cells the labeling studies in mice reveal a broad distribution of life-spans. One part of this population is composed of relatively long-lived mature naive B cells with a half-life of 1 2 months. As discussed above, these cells require a B-cell receptor for survival; the nature of other signals required for their maintenance is not clear. They might obtain a variety of survival signals from their normal environment, the B-cell follicle, through which they recirculate every few days. These include the memory B cells that differentiate from mature B cells after their first encounter with antigen (see Section 1-12). Memory B cells persist for extended periods after antigenic stimulation and may require intermittent follicular signals for their survival; we will return to B-cell memory in Chapter 10. The continual production and loss of new B cells ensures that the receptor repertoire is continually changing in order to meet new antigenic challenges. On the other hand, the persistence of memory cells the progeny of cells that have been activated ensures that those cells proven to recognize pathogens are retained to combat reinfection. When T cells have expressed their receptors and co-receptors, and matured within the thymus for a further week or so, they emigrate to the periphery. Current evidence favors the idea that these ligands are encountered on lymphoid dendritic cells in T-cell zones (see Section 7-29). These cells are similar to the dendritic cells that migrate to the lymph nodes from peripheral sites (see Section 1-6), but lack sufficient co-stimulatory potential to induce full T-cell activation. However, the study of peripheral positive selection is still in its infancy, and a clear picture has yet to emerge. Paradoxically, their turnover is faster than that of the naive T cells although expanded clones of memory cells are maintained at a relatively constant size by balanced proliferation and cell death. Tumors retain many of the characteristics of the cell type from which they arose, especially when the tumor is relatively differentiated and slow growing. Tumors corresponding to essentially all stages of B-cell development have been found in humans, from the earliest stages to the myelomas that represent malignant outgrowths of plasma cells. B-cell tumors represent clonal outgrowths of B cells at various stages of development. Each type of tumor cell has a normal B-cell equivalent, homes to similar sites, and has behavior similar to that cell. Thus, myeloma cells look much like the plasma cells from which they derive, they secrete immunoglobulin, and they are found predominantly in the bone marrow. Many lymphomas and myelomas can go through a preliminary, less aggressive, lymphoproliferative phase, and some mild lympho-proliferations seem to be benign. Thus, a tumor that resembles mature, germinal center or memory cells homes to follicles in lymph nodes and spleen, giving rise to a follicular center cell lymphoma, whereas a tumor of plasma cells usually disperses to many different sites in the bone marrow much as normal plasma cells do, from which comes the clinical name of multiple myeloma (tumor of bone marrow). These similarities mean that it is possible to use tumor cells, which are available in large quantities, to study the cell-surface molecules and signaling pathways responsible for homing behavior. The status of the immunoglobulin genes in a B-cell tumor provides important information on its origin (see. Later-stage B-cell tumors such as multiple myelomas contain mutated genes but do not display intraclonal variation; this is because by this stage in B-cell development somatic hypermutation has ceased. In nearly all cases, Reed-Sternberg cells lack expression of surface immunoglobulin, which had prevented their earlier recognition as of B-cell origin. In many cases, the reason for loss of surface immunoglobulin is a somatic mutation that inactivates one of the Ig V-region genes. Recently, techniques that allow the comprehensive description of genes expressed in tumor cells and in normal cells have provided further insights into how tumors relate to normal tissues (see Appendix I, Section A-35). These molecularly based subdivisions have prognostic significance in that tumors that resemble germinal center cells respond much better to therapy. Expansions and variations on this molecular approach to classifying tumors of the immune system will no doubt lead to further understanding of tumors as well as better prognosis and therapy. The general conclusion that a tumor represents the clonal outgrowth of a single transformed cell is very clearly illustrated by tumors of B-lineage cells. All the cells in a B-cell tumor have identical immunoglobulin gene rearrangements, decisively documenting their origin from one cell. This is useful for clinical diagnosis, as tumor cells can be detected by sensitive assays for these homogeneous rearrangements. The intensity of the bands compared with that of the germline band gives an indication of the abundance of tumor cells in the sample. After antitumor treatment (see patient 1), the intensity of the tumor-specific bands can be seen to diminish. Right panel: the unique rearrangement events in each T cell can be similarly used to identify tumors of T cells by Southern blotting. The probe used in this case was for the T-cell receptor -chain constant regions (C1 and C2). A range of tumors of immune system cells throws light on different stages of T-cell development. We saw in the preceding section that tumors of lymphoid cells corresponding in phenotype to intermediate stages in the development of the B cell provide invaluable tools in the analysis of B-cell differentiation. Tumors of T cells and other cells involved in T-cell development have been identified but, unlike the malignancies of B cells, few that correspond to intermediate stages in T-cell development have been identified in humans. Instead, the tumors resemble either mature T cells or, in acute lymphoblastic leukemia, the earliest type of lymphoid progenitor. One possible reason for the rarity of tumors corresponding to intermediate stages is that immature T cells are programmed to die unless rescued within a very narrow time window by positive selection (see Section 7-21). Thymocytes might simply not linger long enough at the intermediate stages of their development to provide an opportunity for malignant transformation. Thus, only cells that are already transformed at earlier stages, or that do not become transformed until the T cell has matured, are ever seen as tumors. Each distinct T-cell tumor has a normal equivalent, as also seen with B-cell tumors, and retains many of the properties of the cell from which it develops. However, unlike B-cell tumors, tumors of T cells lack the intermediates in the T-cell developmental pathway. For example, acute lymphoblastic leukemia is derived from the lymphoid progenitor cell. The behavior of T-cell and other lymphoid tumors has provided insight into different aspects of T-cell biology, and vice versa. T-cell tumors provide valuable information about the phenotype, homing properties, and receptor gene rearrangements of normal T-cell types. Finally, a tumor of thymic stroma, called a thymoma, is frequently present in certain types of autoimmune disease, and removal of these tumors often ameliorates the disease. Malignant lymphocyte tumors frequently carry chromosomal translocations that join immunoglobulin loci to genes regulating cell growth. The unregulated accumulation of cells of a single clone, which is the most striking characteristic of tumors, is caused by mutations that release the founder cell from the normal restraints on its growth or prevent its normal programmed death.
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Innate immunity provides a front line of host defense through effector mechanisms that engage the pathogen directly prostate knotweed control buy 0.4 mg flomax overnight delivery, act immediately on contact with it mens health 50 plus order 0.2mg flomax free shipping, and are unaltered in their ability to resist a subsequent challenge with either the same or a different pathogen prostate cancer stage 7 buy flomax 0.2mg free shipping. These mechanisms often succeed in preventing an infection from becoming established prostate cancer 6 gleason discount flomax 0.4 mg with amex. If not androgen hormone x organic discount flomax 0.2mg with mastercard, they are reinforced through the recruitment and increased production of further effector molecules and cells in a series of induced responses that we will consider later in this chapter mens health issues order 0.2mg flomax with amex. In that case, macrophages and other cells activated in the early innate response help to initiate the development of an adaptive immune response. Complement was discovered many years ago as a heat-labile component of normal plasma that augments the opsonization of bacteria by antibodies and allows antibodies to kill some bacteria. Although first discovered as an effector arm of the antibody response, complement can also be activated early in infection in the absence of antibodies. Indeed, it now seems clear that complement first evolved as part of the innate immune system, where it still plays an important role. The complement system is made up of a large number of distinct plasma proteins that react with one another to opsonize pathogens and induce a series of inflammatory responses that help to fight infection. A number of complement proteins are proteases that are themselves activated by proteolytic cleavage. The digestive enzyme pepsin, for example, is stored inside cells and secreted as an inactive precursor enzyme, pepsinogen, which is only cleaved to pepsin in the acid environment of the stomach. In the case of the complement system, the precursor zymogens are widely distributed throughout body fluids and tissues without adverse effect. At sites of infection, however, they are activated locally and trigger a series of potent inflammatory events. In such a cascade, an active complement enzyme generated by cleavage of its zymogen precursor then cleaves its substrate, another complement zymogen, to its active enzymatic form. In this way, the activation of a small number of complement proteins at the start of the pathway is hugely amplified by each successive enzymatic reaction, resulting in the rapid generation of a disproportionately large complement response. As might be expected, there are many regulatory mechanisms to prevent uncontrolled complement activation. In this case, a small injury to a blood vessel wall can lead to the development of a large thrombus. There are three distinct pathways through which complement can be activated on pathogen surfaces. These pathways depend on different molecules for their initiation, but they converge to generate the same set of effector molecules. First, it generates large numbers of activated complement proteins that bind covalently to pathogens, opsonizing them for engulfment by phagocytes bearing receptors for complement. Second, the small fragments of some complement proteins act as chemoattractants to recruit more phagocytes to the site of complement activation, and also to activate these phagocytes. Third, the terminal complement components damage certain bacteria by creating pores in the bacterial membrane. All of these pathways generate a crucial enzymatic activity that, in turn, generates the effector molecules of complement. The three main consequences of complement activation are opsonization of pathogens, the recruitment of inflammatory cells, and direct killing of pathogens. Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes. In the early phases of an infection, the complement cascade can be activated on the surface of a pathogen through any one, or more, of the three pathways shown in. The classical pathway can be initiated by the binding of C1q, the first protein in the complement cascade, directly to the pathogen surface. It can also be activated during an adaptive immune response by the binding of C1q to antibody:antigen complexes, and is thus a key link between the effector mechanisms of innate and adaptive immunity. Finally, the alternative pathway can be initiated when a spontaneously activated complement component binds to the surface of a pathogen. Each pathway follows a sequence of reactions to generate a protease called a C3 convertase. The active protease is retained at the pathogen surface, and this ensures that the next complement zymogen in the pathway is also cleaved and activated at the pathogen surface. By contrast, the small peptide fragment is released from the site of the reaction and can act as a soluble mediator. The early events of all three pathways of complement activation involve a series of cleavage reactions that culminate in the formation of an enzymatic activity called a C3 convertase, which cleaves complement component C3 into C3b and C3a. The production of the C3 convertase is the point at which the three pathways converge and the main effector functions of complement are generated. C3b binds covalently to the bacterial cell membrane and opsonizes the bacteria, enabling phagocytes to internalize them. C5a and C5b are generated by cleavage of C5b by a C5 convertase formed by C3b bound to the C3 convertase (not shown in this simplified diagram). C5b triggers the late events in which the terminal components of complement assemble into a membrane-attack complex that can damage the membrane of certain pathogens. C4a is generated by the cleavage of C4 during the early events of the classical pathway, and not by the action of C3 convertase, hence the *; it is also a peptide mediator of inflam-mation but its effects are relatively weak. The C3 convertases formed by these early events of complement activation are bound covalently to the pathogen surface. Here they cleave C3 to generate large amounts of C3b, the main effector molecule of the complement system, and C3a, a peptide mediator of inflammation. The C3b molecules act as opsonins; they bind covalently to the pathogen and thereby target it for destruction by phagocytes equipped with receptors for C3b. These comprise a sequence of polymerization reactions in which the terminal complement components interact to form a membraneattack complex, which creates a pore in the cell membranes of some pathogens that can lead to their death. The nomenclature of complement proteins is often a significant obstacle to understanding this system, and before discussing the complement cascade in more detail, we will explain the conventions, and the nomenclature used in this book. All components of the classical complement pathway and the membrane-attack complex are designated by the letter C followed by a number. The native components have a simple number designation, for example, C1 and C2, but unfortunately, the components were numbered in the order of their discovery rather than the sequence of reactions, which is C1, C4, C2, C3, C5, C6, C7, C8, and C9. The products of the cleavage reactions are designated by added lower-case letters, the larger fragment being designated b and the smaller a; thus, for example, C4 is cleaved to C4b, the large fragment of C4 that binds covalently to the surface of the pathogen, and C4a, a small fragment with weak pro-inflammatory properties. The components of the alternative pathway, instead of being numbered, are designated by different capital letters, for example factor B and factor D. As with the classical pathway, their cleavage products are designated by the addition of lower-case a and b: thus, the large fragment of B is called Bb and the small fragment Ba. Activated complement components are often designated by a horizontal line, for example,; however, we will not use this convention. It is also useful to be aware that the large active fragment of C2 was originally designated C2a, and is still called that in some texts and research papers. Here, for consistency, we will call all large fragments of complement b, so the large active fragment of C2 will be designated C2b. The formation of C3 convertase activity is pivotal in complement activation, leading to the production of the principal effector molecules, and initiating the late events. In the alternative pathway, a homologous C3 convertase is formed from membrane-bound C3b complexed with Bb. The alternative pathway can act as an amplification loop for all three pathways, as it is initiated by the binding of C3b. It is clear that a pathway leading to such potent inflammatory and destructive effects, and which, moreover, has a series of built-in amplification steps, is potentially dangerous and must be subject to tight regulation. One important safeguard is that key activated complement components are rapidly inactivated unless they bind to the pathogen surface on which their activation was initiated. There are also several points in the pathway at which regulatory proteins act on complement components to prevent the inadvertent activation of complement on host cell surfaces, hence protecting them from accidental damage. We have now introduced all the relevant components of complement and are ready for a more detailed account of their functions. To help distinguish the different components according to their functions, we will use a color code in the figures in this part of the chapter. As we will see in Chapter 9, the first component of this pathway, C1q, links the adaptive humoral immune response to the complement system by binding to antibodies complexed with antigens. C1q can, however, also bind directly to the surface of certain pathogens and thus trigger complement activation in the absence of antibody. C1q is part of the C1 complex, which comprises a single C1q molecule bound to two molecules each of the zymogens C1r and C1s. C1q is a calcium-dependent sugarbinding protein, a lectin, belonging to the collectin family of proteins, which contains both collagen-like and lectin domains hence the name collectin. It has six globular heads, linked together by a collagen-like tail, which surround the (C1r:C1s)2 complex. Binding of more than one of the C1q heads to a pathogen surface causes a conformational change in the (C1r:C1s)2 complex, which leads to activation of an autocatalytic enzymatic activity in C1r; the active form of C1r then cleaves its associated C1s to generate an active serine protease. The heads can bind to the constant regions of immunoglobulin molecules or directly to the pathogen surface, causing a conformational change in C1r, which then cleaves and activates the C1s zymogen. Once activated, the C1s enzyme acts on the next two components of the classical pathway, cleaving C4 and then C2 to generate two large fragments, C4b and C2b, which together form the C3 convertase of the classical pathway. In the first step, C1s cleaves C4 to produce C4b, which binds covalently to the surface of the pathogen. The covalently attached C4b then binds one molecule of C2, making it susceptible, in turn, to cleavage by C1s. C1s cleaves C2 to produce the large fragment C2b, which is itself a serine protease. The complex of C4b with the active serine protease C2b remains on the surface of the pathogen as the C3 convertase of the classical pathway. Its most important activity is to cleave large numbers of C3 molecules to produce C3b molecules that coat the pathogen surface. At the same time, the other cleavage product, C3a, initiates a local inflammatory response. These reactions, which comprise the classical pathway of complement activation, are shown in schematic form in. The classical pathway of complement activation generates a C3 convertase that deposits large numbers of C3b molecules on the pathogen surface. The cleavage of C4 by C1s exposes a reactive group on C4b that allows it to bind covalently to the pathogen surface. The larger C2b fragment is the active protease component of the C3 convertase, which cleaves many molecules of C3 to produce C3b, which binds to the pathogen surface, and C3a, an inflammatory mediator. Mannan-binding lectin binds specifically to mannose residues, and to certain other sugars, which are accessible and arranged in a pattern that allows binding on many pathogens. On vertebrate cells, however, these are covered by other sugar groups, especially sialic acid. Thus, mannan-binding lectin is able to initiate complement activation by binding to pathogen surfaces. It is present at low concentrations in normal plasma of most individuals, and, as we will see in the last part of this chapter, its production by the liver is increased during the acute-phase reaction of the innate immune response. Mannan-binding lectin forms a complex with serine proteases that resembles the complement C1 complex. Complement activation is largely confined to the surface on which it is initiated. During the triggered-enzyme cascade that follows, it is important that activating events are confined to this same site, so that C3 activation also occurs on the surface of the pathogen, and not in the plasma or on host cell surfaces. This is achieved principally by the covalent binding of C4b to the pathogen surface. Cleavage of C4 exposes a highly reactive thioester bond on the C4b molecule that allows it to bind covalently to molecules in the immediate vicinity of its site of activation. If C4b does not rapidly form this bond, the thioester bond is cleaved by reaction with water and this hydrolysis reaction irreversibly inactivates C4b. This helps to prevent C4b from diffusing from its site of activation on the microbial surface and becoming coupled to host cells. Cleavage of C4 exposes an active thioester bond that causes the large fragment, C4b, to bind covalently to nearby molecules on the bacterial cell surface. Intact C4 consists of an, a, and a chain with a shielded thioester bond on the chain. The thioester bond (marked by an arrow in the third panel) is rapidly hydrolyzed (that is, cleaved by water), inactivating C4b unless it reacts with hydroxyl or amino groups to form a covalent linkage with molecules on the pathogen surface. The homologous protein C3 has an identical reactive thioester bond that is also exposed on the C3b fragment when C3 is cleaved by C2b. The covalent attachment of C3b and C4b enables these molecules to act as opsonins and is important in confining complement activation to the pathogen surface. C2 becomes susceptible to cleavage by C1s only when it is bound by C4b, and the C2b serine protease is thereby also confined to the pathogen surface, where it remains associated with C4b, forming a C3 convertase. Furthermore, the C3b cleavage product is also rapidly inactivated unless it binds covalently by the same mechanism as C4b, and it therefore opsonizes only the surface on which complement activation has taken place. This pathway can proceed on many microbial surfaces in the absence of specific antibody, and it leads to the generation of a distinct C3 convertase designated C3b,Bb. A number of mechanisms ensure that the activation pathway will only proceed on the surface of a pathogen. Complement activated by the alternative pathway attacks pathogens while sparing host cells, which are protected by complement regulatory proteins. The complement component C3 is cleaved spontaneously in plasma to give C3(H2O), which binds factor B and enables the bound factor B to be cleaved by factor D (top panel). The resulting soluble C3 convertase cleaves C3 to give C3a and C3b, which can attach to host cells or pathogen surfaces (second panel). Covalently bound C3b binds factor B, which in turn is rapidly cleaved by factor D to Bb, which remains bound to C3b to form a C3 convertase, and Ba, which is released (third panel). Bacterial surfaces (bottom right panels) do not express complement-regulatory proteins and favor binding of factor P (properdin), which stabilizes the C3b,Bb convertase activity. This occurs through the spontaneous hydrolysis of the thioester bond in C3 to form C3(H2O) which has an altered conformation, allowing binding of the plasma protein factor B.
Multispectral imaging can be easily achieved using appropriate filters or monochromators although appropriate postprocessing spectral differentiation techniques may be required to reduce cross-talk between fluorochromes that have overlapping spectra prostate laser treatment flomax 0.4 mg otc. This latter application is more important for imaging application in the visible prostrate juniper 0.4 mg flomax visa, since weak autofluorescence is generally observed in the near-infrared prostate oncology kingston purchase flomax 0.2mg with amex. Each has distinct advantages and disadvantages and the selection of an appropriate technology largely depends on the specifics of the application man health 2014 report generic 0.4mg flomax with mastercard. Time-domain methods illuminate tissue with ultrafast photon pulses (femto-second to pico-second range) and 726 Fluorescence Imaging resolve the arrival of photons as a function of time at different locations around the tissue boundary prostate massages men on film in living color safe 0.4 mg flomax. Frequency domain technology uses light of modulated intensity at a frequency f androgen hormone during pregnancy order 0.2mg flomax fast delivery, which establishes a photon wave of the same frequency in the diffuse medium. They can be further used to improve resolution, for example using early-arriving photons. Nevertheless, significant progress has been achieved towards the validation of the technique in transgenic animal models that resemble human disease, for example in spontaneous or induced models of colon, lung, or breast cancer. At the clinical research level, autofluorescence colposcopy has also shown good performance in detecting cervical cancer (6). The following list summarizes areas where fluorescence imaging has strong potential to be used as a diagnostic method. Endoscopy Colposcopy Intraoperative imaging Laparoscopy Breast cancer Oral cancers Skin cancers Skin diseases (other) Arthritis Inflammation. In-vivo Applications Fluorescence imaging can be used in combination with many developed or upcoming fluorescent probes to visualize a multitude of processes in tissues. Examples of imaging protease expression associated with various cancers and inflammation using activatable probes have been demonstrated with epi-illumination or tomographic methods. Imaging of cellular receptors using peptidenear-infrared dye conjugates has been also shown feasible in animal studies. Several other examples have been also demonstrated in applications ranging from imaging apoptosis using annexin-V-fluorochrome conjugates to imaging angiogenesis using fluorescent nanoparticles. Overall, with the increasing technical ability of fluorescence imaging and the growing list of available fluorescent probes and nanoparticles for in-vivo use the list of applications is expected to significantly grow. Clinical Applicability Much of the in-vivo demonstration of fluorescence imaging methods has been so far achieved using small animals. However feasibility to detect fluorochromes from human tissues has been demonstrated in the past for several applications, for example using epi-illumination (endoscopy) in skin, esophageal, cervical, lung, and other accessible epithelial cancers or using tomography through the entire human breast for breast cancer detection (4, 5). As adept new fluorescent probes propagate into the clinic, a significant number of these technologies can be adapted for human imaging, that is intraoperative imaging for tumor margin and metastasis identification, in several endoscopic applications or in the detection of breast cancer. It is a cortical malformation that involves the whole cortex and, to a variable extent, the underlying white matter. Contrast Media, Ultrasound, Applications in Focal Splenic Lesions Focal Acute Pyelonephritis with Abscess Formation Abscess, renal Follicle Cysts Cysts, Follicular, Ovarium 728 Follicular Cysts Follicular Cysts Follicular cysts present as smooth and thin-walled unilocular cysts within the ovaries. They are most commonly asymptomatic and can only be differentiated from follicles when they exceed a size of 3 cm. Besides acute symptoms of respiratory distress, recurrent pneumonia is observed as late sequelae, especially in patients who aspirated organic material (2). Imaging Chest radiography is usually the first imaging technique performed in children with suspected foreign body aspiration. Because most aspirated foreign bodies are radiolucent, the diagnosis is commonly based on indirect signs, such as obstructive emphysema, shifting of the mediastinum and unequal movement of the hemidiaphragms. Assessment by inspiratory and expiratory chest X-rays, lateral decubitus radiographs or with the use of fluoroscopy is often necessary additionally to plain chest radiographs. The worst case is complete airway obstruction with total occlusion of the trachea above the carina. Partial obstruction occurs, when the trachea is partially occluded or when the foreign body obstructs bronchi distal the carina. The majority of foreign bodies lodge in the main bronchi with almost equal incidence on the right and left side. Nuclear Medicine There are only a few studies dealing with scintigraphy in foreign body aspiration in children. In a European multicentre study many children with foreign body aspiration showed scintigraphic abnormalities 6 months after removal of the foreign body with persistent matched defects of perfusion and ventilation although the chest radiographs were considered normal (4). Pathology/Histopathology Food particles or organic materials may absorb water from bronchial secretions and tend to increase in size. Oil, salt and vegetable proteins irritate the mucosa, leading to oedema and formation of granulation tissue with subsequent narrowing of the bronchial lumen (1). Nonorganic materials are usually inert to the bronchial mucosa, unless they remain in the tracheobronchial tree for a longer time and induce chronic inflammatory changes, such as ulcerations or epithelialisation (1). Diagnosis In children with partial airway obstruction, the plain chest X-ray during inspiration often reveals unremarkable findings. Expiratory films are more sensitive by demonstrating air-trapping with over distension of the affected lung distal to the obstruction (obstructive emphysema), deviation of the mediastinum to the contralateral side, a low ipsilateral hemidiaphragm and wide intercostal spaces. A valve-mechanism in foreign body aspiration is easily Clinical Presentation Children with foreign body aspiration usually present with the classical triad of choking, coughing and wheezing. Crackles, decreased breath sounds in the affected lung and unequal chest expansion may be found on physical examination, Foreign Bodies, Aspiration, Children (Chest View) 729 Foreign Bodies, Aspiration, Children (Chest View). Figure 1 Chest radiograph of a 3-year-old infant with aspiration of a peanut into the left main bronchus. Hyperinflation of the left lung with shifting of the mediastinum to the contralateral side is visible. The mediastinum shifts to the ipsilateral obstructed side during inspiration and to the contralateral side during expiration. A complete airway obstruction leads to a collapse of the lung distal to the obstruction or to segmental atelectasis. Occasionally a localised pneumothorax may develop peripheral to the collapsed lobe. Images during inspiration and expiration demonstrate the shifting of the mediastinum and a paradoxical movement of the hemidiaphragms. Although exact figures are unavailable, foreign body ingestion is very common among children. While children younger than 6 months are rarely able to get a foreign object into the oropharynx, infants can ingest foreign bodies with the assistance of a sibling. Any child can swallow a foreign body; most incidents result in minor annoyance, but a few can lead to major catastrophe. Pathology/Histopathology the oropharynx is well-innervated, and patients can typically localize oropharyngeal foreign bodies. Scratches or abrasions to the mucosal surface of the oropharynx can create a foreign body sensation. Chronic foreign bodies or perforations can cause infections in surrounding soft tissues of the throat and neck. Patients can usually localize foreign bodies in the upper esophagus but localize them poorly in the lower two-thirds of the structure. Structural abnormalities of the esophagus, including strictures, webs, diverticula, and malignancies, increase the risk of foreign body entrapment, as do motor disturbances such as scleroderma, diffuse esophageal spasm, or achalasia (3). Most foreign objects will pass through the pylorus, although on occasion, some objects may remain in the stomach for a long period. Once beyond the pyloric canal most objects, even sharply edged foreign bodies such as pieces of glass or nails, will pass without harm until the terminal ileum which is again a predilection site for obstruction. Ingested objects may occasionally remain fixed in the cecum, ascending colon, or sigmoid. Foreign bodies detected in the rectum have in most instances been introduced transanally. Foreign bodies may be ingested, inserted into a body cavity, or deposited into the body by a traumatic or iatrogenic injury. In general, foreign bodies in the air and food passages are the sixth most common cause of accidental death in the United States (1). Clinical Presentation Nearly one-third of pediatric patients with esophageal foreign bodies are asymptomatic. Symptoms related to esophageal foreign bodies are Foreign Bodies, Gastrointestinal 731 choking, gagging, coughing, wheezing, dysphagia, dyspnea, fever, hematochezia, or neck, chest, or abdominal pain. Children with chronic esophageal foreign bodies may also present with poor feeding, irritability, fever, or stridor. Children with a battery lodged in the esophagus typically present with the above mentioned symptoms. Rashes following disk battery ingestion have also been reported and may be a manifestation of nickel hypersensitivity. It is clear that thin, sharp objects carry a higher risk of perforation; and a safe policy is to treat the patient expectantly unless there are indications for a more aggressive approach. Large foreign bodies are not generally encountered in the small bowel in that rarely pass beyond the pylorus or the duodenojejunal flexure. A perforation of the peritoneal cavity can cause peritonitis whereas a retroperitoneal perforation, at the duodenojejunal flexure for example, can lead to the involvement of the psoas and the formation of an abscess. Nonetheless, the perforation of jejunal or ileal loop is a rare event (<1% of cases) and is usually caused by extremely pointed objects, such as fish bones, chicken bones, and toothpicks (3). Patients with a rectal foreign body may present with abdominal or rectal pain, pruritus, or bleeding. F Imaging the relative difficulty in identifying a foreign body varies according to the type of object ingested and its radioopacity. Metal objects with a relatively high atomic weight are readily visible with plain film radiography in that they are intensely radiopaque regardless of their volume. Nonradiopaque materials at times may not be identifiable as they are composed of material with a relatively low atomic weight and therefore have intrinsically low radiopacity. Nonradiopaque materials are most foods and medicines; most fish bones; most wood, splinters, thorns of all types; most plastics; most aluminum objects (3). In older children and adults, plain films of the neck, chest, and abdomen should be obtained. The progress in the bowel, if needed, can be checked periodically with radiographs. If the tip of a sharp-edged foreign body has perforated the wall, it may project outside the air-containing lumen. Indirect signs, visible on the plain radiograph are soft tissue swelling or air due to edema or hematoma. Barium or Gastrografin Studies Barium study may be indicated in cases of ingestion of nonopaque foreign bodies. A barium or gastrografin study, without cotton balls, can sometimes outline the foreign body, but, again, the yield is very low. Barium swallow can be used for food impactions; however, most authorities believe that it adds nothing to the evaluation and delays definitive treatment. Contrast studies are not useful in detecting foreign bodies in the stomach or small intestine. Esophagography should first be performed with hydrosoluble contrast medium to exclude perforation Foreign Bodies, Gastrointestinal 733 F Foreign Bodies, Gastrointestinal. The contrast medium may impregnate the surface of the foreign body and render it more conspicuous. It is now considered the imaging modality of choice to locate nonradiopaque foreign objects in the oropharynx, esophagus, stomach, small intestine, and large intestine. However, the application is probably unwarranted in every case of acute bone dysphagia, as only a minority of patients who sense foreign bodies after eating chicken or fish have a bone present. Perforation of intestinal structures by ingested foreign bodies is a challenging diagnosis that should always be invocated in cases of acute abdominal symptoms. It is also superior to other imaging modalities in demonstration of obstruction caused by a foreign body. Endoscopic procedures are also used for the purpose of treatment besides the diagnostic challenge. Early endoscopic removal from the stomach or 734 Foreign Body Foreign Body An object that is inappropriately ingested or inhaled. A fracture is an acute break in the customary continuity of a bone or its growth cartilage or an acute disturbance of trabeculae, which will result in the formation of callus on follow-up imaging. Avulsion is the discontinuity of a bony or cartilaginous element by traction from muscle, tendon, or ligament. In traumatic dislocations, a shift in relationship occurs between bones that usually articulate with each other so that the articulation is disturbed. Epiphyseal fractures extend solely through secondary growth centers or their enchondrally-derived equivalents (such as tarsal, carpal, or sesamoid bones or apophyses). In traumatic plastic bowing (1), bones bend but do not break, but do not return to their preinjury shape. Fractures, Bone, Childhood 735 Pathology/Histopathology Bone is structure that offers support to the body; the characteristics that make it strong also leave it liable to fracture from various forces. The callus of healing has a characteristic histologic pattern that changes through time and space. Typically at a break in a bone, the periosteal reaction begins to calcify at the greater distance from the fracture site and then proceeds inward toward the break under the lifted periosteum. Secondary growth centers, tarsal and carpal bones, and the sesamoids, including the patella, have no periosteum; their healing is by endosteal callus alone: without periosteum, one can have no periosteal reaction. Various epiphyses slip in scurvy in association with osteoporotic weakening of the bone adjacent to the physis.
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