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The Selenium and Vitamin E Cancer Prevention Trial (SELECT) assigned 35,533 men to receive 200 μg/d selenium, 400 IU/d α-tocopherol, selenium plus vitamin E, or placebo.Several favorable laboratory and observational studies led to the formal evaluation of selenium and α-tocopherol (vitamin E) as potential prostate cancer preventives.Overall, across years 1 through 4, there was no difference between the arms in the number of tumors with a Gleason score of 7 to 10; however, during years 3 and 4, there was a statistically significant difference in tumors with Gleason score of 8 to 10 in the dutasteride arm (12 tumors vs 1 tumor, respectively). The clinical importance of the apparent increased incidence of higher-grade tumors in the 5-α-reductase inhibitor arms of these trials is controversial. It may likely represent an increased sensitivity of PSA and digital rectal exam for high-grade tumors in men receiving these agents. The FDA has analyzed both trials, and it determined that the use of a 5-α-reductase inhibitor for prostate cancer chemoprevention would result in one additional high-grade (Gleason score 8 to 10) prostate cancer for every three to four lower-grade (Gleason score <6) tumors averted. Although it acknowledged that detection bias may have accounted for the finding, it stated that it could not conclusively dismiss a causative role for 5-α-reductase inhibitors. These agents are therefore not FDA-approved for prostate cancer prevention. Because all men in both the PCPT and REDUCE trials were being screened and because screening approximately doubles the rate of prostate cancer, it is not known if finasteride or dutasteride decreases the risk of prostate cancer in men who are not being screened. Several favorable laboratory and observational studies led to the formal evaluation of selenium and α-tocopherol (vitamin E) as potential prostate cancer preventives. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) assigned 35,533 men to receive 200 μg/d selenium, 400 IU/d α-tocopherol, selenium plus vitamin E, or placebo.A number of infectious agents cause cancer.Hepatitis B and C are linked to liver cancer; some HPV strains are linked to cervical, anal, and head and neck cancer; and Helicobacter pylori is associated with gastric adenocarcinoma and gastric lymphoma.Vaccines to protect against these agents may reduce the risk of their associated cancers. |
(E) As discussed in the text, a helix can be either right-handed or left-handed.Note that the helix in (D) has a wider path than that in (C), but the same number of subunits per turn.At the bottom, each of these helices is viewed from directly above the helix and seen to have two (A), three (B), and six (C and D) subunits per helical turn.These proteins generally have a relatively simple, elongated three-dimensional structure and are commonly referred to as fibrous proteins. One large family of intracellular fibrous proteins consists of α-keratin, introduced when we presented the α helix, and its relatives. Keratin filaments are extremely stable and are the main component in long-lived structures such as hair, horn, and nails. An α-keratin molecule is a dimer of two identical subunits, with the long α helices of each subunit forming a coiled-coil (see Figure 3–9). The coiled-coil regions are capped at each end by globular domains containing binding sites. This enables this class of protein to assemble into ropelike intermediate filaments—an important component of the cytoskeleton that creates the cell’s internal structural framework (see Figure 16–67). Fibrous proteins are especially abundant outside the cell, where they are a main component of the gel-like extracellular matrix that helps to bind collections of cells together to form tissues. Cells secrete extracellular matrix proteins into their surroundings, where they often assemble into sheets or long fibrils. Collagen is the most abundant of these proteins in animal tissues. A collagen molecule consists of three long polypeptide chains, each containing the nonpolar amino
Figure 3–21 actin filaments. (A) Transmission electron micrographs of negatively stained actin filaments. (B) The helical arrangement of actin molecules in an actin filament. (A, courtesy of Roger Craig.) Figure 3–22 Some properties of a helix. (A–D) A helix forms when a series of subunits bind to each other in a regular way. At the bottom, each of these helices is viewed from directly above the helix and seen to have two (A), three (B), and six (C and D) subunits per helical turn. Note that the helix in (D) has a wider path than that in (C), but the same number of subunits per turn. (E) As discussed in the text, a helix can be either right-handed or left-handed.Note that a helix retains the same handedness when it is turned upside down.(PDB code: 2DHB.)acid glycine at every third position.This regular structure allows the chains to wind around one another to generate a long regular triple helix (Figure 3–23A). |
FIGURE 405-4 Mechanism of thyroid hormone receptor action.This concept has been corroborated by the finding that targeted deletion of the TR genes in mice has a less pronounced phenotypic effect than hormone deficiency.Consequently, hormone deficiency has a profound effect on gene expression because it causes gene repression as well as loss of hormone-induced stimulation.The receptors bind as homodimers or, more commonly, as heterodimers with retinoic acid X receptors (RXRs) (Chap. 400e). The activated receptor can either stimulate gene transcription (e.g., myosin heavy chain α) or inhibit transcription (e.g., TSH β-subunit gene), depending on the nature of the regulatory elements in the target gene. Thyroid hormones (T3 and T4) bind with similar affinities to TRα and TRβ. However, structural differences in the ligand binding domains provide the potential for developing receptor-selective agonists or antagonists, and these are under investigation. T3 is bound with 10–15 times greater affinity than T4, which explains its increased hormonal potency. Although T4 is produced in excess of T3, receptors are occupied mainly by T3, reflecting T4 → T3 conversion by peripheral tissues, greater T3 bioavailability in the plasma, and the greater affinity of receptors for T3. After binding to TRs, thyroid hormone induces conformational changes in the receptors that modify its interactions with accessory transcription factors. Importantly, in the absence of thyroid hormone binding, the aporeceptors bind to co-repressor proteins that inhibit gene transcription. Hormone binding dissociates the co-repressors and allows the recruitment of co-activators that enhance transcription. The discovery of TR interactions with co-repressors explains the fact that TR silences gene expression in the absence of hormone binding. Consequently, hormone deficiency has a profound effect on gene expression because it causes gene repression as well as loss of hormone-induced stimulation. This concept has been corroborated by the finding that targeted deletion of the TR genes in mice has a less pronounced phenotypic effect than hormone deficiency. FIGURE 405-4 Mechanism of thyroid hormone receptor action.In the absence of hormone, TR binds co-repressor (CoR) proteins that silence gene expression.The numbers refer to a series of ordered reactions that occur in response to thyroid hormone: (1) T4 or T3 enters the nucleus; (2) T3 binding dissociates CoR from TR; (3) co-activators (CoA) are recruited to the T3-bound receptor; and (4) gene expression is altered. |
Optimal therapy consists of radiation, or surgery alone, to limit the increased morbidity that occurs when the two treatment modalities are combined.A study using the National Cancer Institute’s Surveillance Epidemiology and End Results data by an intent-to-treat analysis showed that patients in the surgery arm had an improved survival when compared with patients in the radiation arm (58).This lesion should not be diagnosed as metastasis but rather as multifocal disease. Malignancies involving the peritoneal cavity (e.g., ovarian cancer) may be found in the cul-de-sac and extend directly into the vagina and cervix. Carcinomas of the urinary bladder and colon occasionally extend into the cervix. Cervical involvement by lymphoma, leukemia, and carcinoma of the breast, stomach, and kidney is usually part of the systemic pattern of spread for these malignancies. Isolated metastasis to the cervix in such cases may be the first sign of a primary tumor elsewhere in the body. Treatment Options The treatment of cervical cancer is similar to the treatment of any other type of malignancy in that both the primary lesion and potential sites of spread should be evaluated and treated. The therapeutic modalities for achieving this goal include primary treatment with surgery, radiotherapy, chemotherapy, or chemoradiation. Whereas radiation therapy can be used in all stages of disease, surgery is limited to patients with stage I to IIa disease. The 5-year survival rate for stage I cancer of the cervix is approximately 85% with either radiation therapy or radical hysterectomy. A study using the National Cancer Institute’s Surveillance Epidemiology and End Results data by an intent-to-treat analysis showed that patients in the surgery arm had an improved survival when compared with patients in the radiation arm (58). Optimal therapy consists of radiation, or surgery alone, to limit the increased morbidity that occurs when the two treatment modalities are combined.Table 36.4 Management of Invasive Cancer of the Cervix
LVSI, lymphovascular space invasion.than radiation, because of vaginal shortening, fibrosis, and atrophy of the epithelium associated with radiation.Surgical therapy shortens the vagina, but gradual lengthening can be brought about by sexual activity. |
There is no seasonal pattern.Infections tend to be endemic, with sporadic epidemics every 4–7 years.Outbreaks of M. pneumoniae illness often occur in institutional settings such as military bases, boarding schools, and summer camps.Intrafamilial attack rates are as high as 84% among children and 41% among adults.Lung biopsy specimens from patients with
M. pneumoniae respiratory tract infection reveal an inflammatory process involving the trachea, bronchioles, and peribronchial tissue, with a monocytic infiltrate coinciding with a luminal exudate of polymorphonuclear leukocytes. Experimental evidence indicates that innate immunity provides most of the host’s defense against mycoplasmal infection in the lungs, whereas cellular immunity may actually play an immunopathogenic role, exacerbating mycoplasmal lung disease. Humoral immunity appears to provide protection against dissemination of M. pneumoniae infection; patients with humoral immunodeficiencies do not have more severe lung disease than do immunocompetent patients in the early stages of infection but more often develop disseminated infection resulting in syndromes such as arthritis, meningitis, and osteomyelitis. The immunity that follows severe M. pneumoniae infections is more protective and longer-lasting than that following mild infections. M. pneumoniae infection occurs worldwide. It is likely that the incidence of upper respiratory illness due to M. pneumoniae is up to 20 times that of pneumonia caused by this organism. Infection is spread from one person to another by respiratory droplets expectorated during coughing and results in clinically apparent disease in an estimated 80% of cases. The incubation period for M. pneumoniae is 2–4 weeks; therefore, the time-course of infection in a specific population may be several weeks long. Intrafamilial attack rates are as high as 84% among children and 41% among adults. Outbreaks of M. pneumoniae illness often occur in institutional settings such as military bases, boarding schools, and summer camps. Infections tend to be endemic, with sporadic epidemics every 4–7 years. There is no seasonal pattern.For community-acquired pneumonia in adults,
M. pneumoniae is the most frequently detected “atypical” organism. |
From the outside to the inside, they are as follow.The wall of the heart is composed of three layers.The structural organization of the wall of the heart is continuous within the atria and ventricles.The wall of the heart is composed of three layers: epicardium, myocardium, and endocardium.The coronary sinus drains into right atrium.The heart has been cut open in the coronal plane to expose its interior and the main parts of its impulse-conducting system (indicated in yellow). Impulses are generated in the sinuatrial (SA) node, transmitted through the atrial wall to the atrioventricular (AV) node and then sent along the AV bundle to the Purkinje fibers. impulses that cause the heart to contract and supply blood to the body. Sudden cardiac arrest is a medical emergency; first-aid treatment such as cardiopulmonary resuscitation (CPR) and defibrillation (delivering a therapeutic dose of electrical energy to the heart) can improve the chances of survival. If not treated, cardiac arrest leads to sudden cardiac death. Heart rhythm pathologies associated with cardiac arrest include tachycardia (accelerated heart rhythm), fibrillation (rapid, irregular, and ineffective contractions), bradycardia (decelerated heart rhythm), and asystole (total absence of heart rhythm). A coronary vasculature that consists of two coronary arteries and cardiac veins. The right and left coronary arteries provide the arterial blood supply to the heart. They originate from the initial part of the ascending aorta near the aortic valves and circle the base of the heart, with branches converging toward the apex of the heart. Venous drainage of the heart occurs via several cardiac veins, most of which drain into the coronary sinus located on the posterior surface of the heart. The coronary sinus drains into right atrium. The wall of the heart is composed of three layers: epicardium, myocardium, and endocardium. The structural organization of the wall of the heart is continuous within the atria and ventricles. The wall of the heart is composed of three layers. From the outside to the inside, they are as follow.It consists of a single layer of mesothelial cells and underlying connective and adipose tissue.The blood vessels and nerves that supply the heart lie in the epicardium and are surrounded by adipose tissue that cushions the heart in the pericardial cavity. |
For patients with Child’s class A cirrhosis with preserved liver function and no portal hypertension, resection also is considered.For patients without cirrhosis who develop HCC, resection is the treatment of choice.31-20.A complete algorithm for the evaluation and management of HCC is shown in Fig.In a person with cirrhosis, the annual conversion rate to HCC is 2% to 6%.79 In patients with chronic HCV infection, cirrhosis usually is present before the HCC develops; however, in cases of hepatitis B virus infection, HCC tumors can occur before the onset of cirrhosis. HCCs are typically hypervascular with blood supplied predominantly from the hepatic artery. Thus, the lesion often appears hypervascular during the arterial phase of CT studies (Fig. 31-19) and relatively hypodense during the delayed phases due to early washout of the contrast medium by the arterial blood. MRI imaging also is effective in character-izing HCC. HCC is variable on T1-weighted images and usu-ally hyperintense on T2-weighted images. As with contrast CT, HCC enhances in the arterial phase after gadolinium injection because of its hypervascularity and becomes hypointense in the delayed phases due to contrast washout. HCC has a tendency to invade the portal vein, and the presence of an enhancing portal vein thrombus is highly suggestive of HCC.The treatment of HCC is complex and is best managed by a multidisciplinary liver transplant team. A complete algorithm for the evaluation and management of HCC is shown in Fig. 31-20. For patients without cirrhosis who develop HCC, resection is the treatment of choice. For patients with Child’s class A cirrhosis with preserved liver function and no portal hypertension, resection also is considered.Living donor liver trans-plantation also is an alternative for patients with HCC awaiting transplantation to avoid dropout as a candidate for cadaveric donor liver transplantation due to tumor progression.81 Specific treatment options are described in the next section.CholangiocarcinomaCholangiocarcinoma, or bile duct cancer, is the second most common primary malignancy of the liver. |
The most common identifiable lower urinary tract causes of hematuria include urinary tract infection (UTI), kidney stones, and hypercalciuria.Poststreptococcal glomerulonephritis (PSGN) is the most common form of acute GN, and IgA nephropathy is the most common chronic GN, but many other types of GN can occur.Immune-mediated inflammation is the mechanism of glomerulonephritis (GN).Transient (up to 3 days) proteinuria may occur with intercurrent infection in children with MCNS and is not considered a relapse. Steroid therapy is typically effective for true relapse. Steroid-responsive patients have little risk of chronic renal failure. Patients with FSGS may initially respond to steroids but later develop resistance. Many children with FSGS progress to end-stage kidney failure (see Chapter 165). Recurrence of FSGS occurs in 30% of children who undergo renal transplantation. A child with gross hematuria may have a serious disease and requires prompt evaluation. Microscopic hematuria, defined as more than 3 to 5 red blood cells (RBCs) per high-power field on freshly voided and centrifuged urine, is often benign. Isolated asymptomatic microscopic hematuria is found in up to 4% of healthy children. In most cases this is a transient finding. Hematuria may originate from glomerular disease, tubulointerstitial processes, and lower urinary tract disorders (Table 163-1). Immune-mediated inflammation is the mechanism of glomerulonephritis (GN). Poststreptococcal glomerulonephritis (PSGN) is the most common form of acute GN, and IgA nephropathy is the most common chronic GN, but many other types of GN can occur. The most common identifiable lower urinary tract causes of hematuria include urinary tract infection (UTI), kidney stones, and hypercalciuria.Children with acute GN commonly present with hematuria (gross or microscopic) along with other cardinal features of glomerular injury (proteinuria, hypertension, edema, oliguria, renal insufficiency).PSGN occurs most frequently in children 2 to 12 years of age and is more common in boys. |