Jack S. Elder, MD

• Clinical Professor of Urology, Case School of Medicine,
• Cleveland, Ohio
• Chief, Department of Urology, Henry Ford
• Health System, and Associate Director, Vattikuti Urology
• Institute, Department of Urology,
• Children? Hospital of Michigan,
• Detroit, Michigan

Use vancomycin plus gentamicin only for penicillin-allergic pts (preferable to desensitize to penicillin) and for isolates resistant to penicillin/ampicillin blood pressure 120 80 order plavix 75 mg on-line. Use gentamicin during initial 2 weeks; determine gentamicin susceptibility before initiating rifampin pulse pressure normal rate generic plavix 75 mg buy online. Some experts recommend that doxycycline be continued for 3­6 months unless all infection is resected surgically prehypertension medicine 75 mg plavix with mastercard. Doses of gentamicin pulse pressure meaning 75 mg plavix buy visa, streptomycin blood pressure medication used to treat anxiety purchase plavix with a visa, and vancomycin must be adjusted for reduced renal function. Ideal body weight is used to calculate doses of gentamicin and streptomycin per kilogram (men = 50 kg + 2. Adjust for trough level of 10­15 µg/mL for streptococcal and enterococcal infections and 15­20 µg/mL for staphylococcal infections. Source: Adapted from Olaison L, Pettersson G: Current best practices and guidelines indications for surgical intervention in infective endocarditis. Circulation 116:1736, 2007; Habib G et al: Guidelines on the prevention, diagnosis, and treatment of infective endocarditis. Organisms contained within the bowel or an intraabdominal organ enter the sterile peritoneal cavity, causing peritonitis and-if the infection goes untreated and the pt survives-abscesses. Primary peritonitis has no apparent source, whereas secondary peritonitis is caused by spillage from an intraabdominal viscus. The etiologic organisms and the clinical presentations of these two processes are different. The specific organisms depend on the flora present at the site of the initial process. Once infection has spread to the peritoneal cavity, pain increases; pts lie motionless, often with knees drawn up to avoid stretching the nerve fibers of the peritoneal cavity. There is marked voluntary and involuntary guarding of anterior abdominal musculature, tenderness (often with rebound), and fever. Vancomycin should be used instead of cefazolin if methicillin resistance is prevalent, if the pt has an overt exit-site infection, or if the pt appears toxic. Abscesses develop in untreated peritonitis as an extension of the disease process and represent host defense activity aimed at containing the infection. Serum levels of alkaline phosphatase are elevated in 70% of pts, and leukocytosis is common. Splenic Abscess · Epidemiology and pathogenesis: Splenic abscesses are much less common than liver abscesses and usually develop via hematogenous spread of infection. Gram-negative bacilli can cause splenic abscess in pts with urinary tract foci, with associated bacteremia, or with infection from another intraabdominal source; salmonellae are fairly commonly isolated, particularly from pts with sickle cell disease. Percutaneous drainage has been successful for single, small (<3-cm) abscesses and may also be useful for pts at high surgical risk. Perinephric and Renal Abscesses · Epidemiology and pathogenesis: Perinephric and renal abscesses are uncommon. More than 75% of these abscesses are due to ascending infection and are preceded by pyelonephritis. The most important risk factor is the presence of renal calculi that produce local obstruction to urinary flow. This diagnosis should be considered if pts with pyelonephritis have persistent fever after 4 or 5 days of treatment, if a urine culture yields a polymicrobial flora, if the pt has known renal stone disease, or if fever and pyuria occur in conjunction with a sterile urine culture. The wide range of clinical manifestations is matched by the wide variety of infectious agents involved (Table 85-1). Disease lasts <12 h and consists of diarrhea, nausea, vomiting, and abdominal cramping, usually without fever. The incubation period is 8­14 h, after which pts develop 24 h of diarrhea and abdominal cramps, without vomiting or fever. Infection requires ingestion of a relatively large inoculum (compared with that required for other pathogens) of 105­108 organisms. Clinical Manifestations After an incubation period of 24­48 h, pts develop painless watery diarrhea and vomiting that can cause profound, rapidly progressive dehydration and death within hours. After an incubation period of 4 h to 4 days, watery diarrhea, abdominal cramps, nausea, vomiting, and occasionally fever and chills develop. Diarrhea lasting >2 weeks is generally defined as chronic; in such cases, many of the causes of acute diarrhea are much less likely, and a new spectrum of causes needs to be considered. Fever often implies invasive disease, although fever and diarrhea may also result from infection outside the gastrointestinal tract, as in malaria. Bloody stools without fecal leukocytes should alert the laboratory to the possibility of infection with Shiga toxin­producing enterohemorrhagic Escherichia coli. Frequent stools over a given period can provide the first warning of impending dehydration. Abdominal pain may be most severe in inflammatory processes like those due to Shigella, Campylobacter, and necrotizing toxins. Painful abdominal muscle cramps, caused by electrolyte loss, can develop in severe cases of cholera. An appendicitislike syndrome should prompt a culture for Yersinia enterocolitica with cold enrichment. Tenesmus (painful rectal spasms with a strong urge to defecate but little passage of stool) may be a feature of cases with proctitis, as in shigellosis or amebiasis. In the United States, 50% of outbreaks of nonbacterial gastroenteritis are caused by noroviruses. Thus, although the fecal­oral route is the primary mode of transmission, aerosolization, fomite contact, and person-to-person contact can also result in infection. Clinical Manifestations After a 24-h incubation period (range, 12­72 h), pts experience the sudden onset of nausea, vomiting, diarrhea, and/or abdominal cramps with constitutional symptoms. Asking pts whether anyone else they know is sick is a more efficient means of identifying a common source than is constructing a list of recently eaten foods. Current antibiotic therapy or a recent history of treatment suggests Clostridium difficile diarrhea. Antibiotic use may increase the risk of chronic intestinal carriage following salmonellosis. Vomiting often precedes diarrhea (loose, watery stools without blood or fecal leukocytes), and about one-third of pts have temperatures >39°C (>102. Prevention Rotavirus vaccines, two of which are available in the United States, are included in the routine vaccination schedule for U. Vaccination has led to a >70­ 80% decline in hospital visits due to rotavirus illness. Notably, the efficacy of rotavirus vaccines is lower (50­65%) in low-resource settings. Clinical Manifestations After an incubation period of 5 days to 3 weeks, the manifestations of infection range from asymptomatic carriage (most common) to fulminant diarrhea and malabsorption. Prolonged therapy with metronidazole (750 mg tid for 21 days) has been successful. Clinical Manifestations After an incubation period of 1 week, pts may remain asymptomatic or develop watery, nonbloody diarrhea, occasionally with abdominal pain, nausea, anorexia, fever, and/or weight loss lasting 1­2 weeks. Diagnosis On multiple days, fecal samples should be examined for oocysts (4­5 µm in diameter, smaller than most parasites). Detection of large oocysts (25 µm) in stool by modified acid-fast staining confirms the diagnosis. Clinical manifestations include diarrhea, flulike symptoms, flatulence, and burping. Diagnosis is made by detection of oocysts (spherical, 8­10 µm) in stool; targeted diagnostic studies must be specifically requested. Paratyphi survive within macrophages, then disseminate throughout the body via lymphatics, and ultimately colonize reticuloendothelial tissues. Epidemiology and Clinical Manifestations Depending on the specific species, salmonellosis results in typhoid fever or gastroenteritis. Other signs and symptoms may include sweating, cough, malaise, arthralgias, nausea, vomiting, and diarrhea-or, less often, constipation. Enteritidis), poultry, undercooked meat, dairy products, manufactured or processed foods, and fresh produce. Dublin, develops in 8% of pts; of these pts, 5­10% develop localized infections. Diagnosis Positive cultures of blood, stool, or other specimens are required for diagnosis. In developed countries, ingestion of contaminated poultry accounts for 30­70% of cases. Transmission to humans occurs via contact with or ingestion of raw or undercooked food products or direct contact with infected animals. Clinical Manifestations An incubation period of 2­4 days (range, 1­7 days) is followed by a prodrome of fever, headache, myalgia, and/or malaise. Within the next 12­48 h, diarrhea (with stools containing blood in 10% of cases in adults), cramping abdominal pain, and fever develop. Diagnosis the diagnosis is confirmed by cultures of stool, blood, or other specimens on special media and/or with selective techniques. Fluoroquinolones are an alternative choice, although resistance to fluoroquinolones is increasing. Humans are the major reservoir, but Shigella can be found in other higher primates. The toxins target endothelial cells and play a significant role in the microangiopathic complications of Shigella and E. Clinical Manifestations After an incubation period of 1­4 days, shigellosis evolves through three phases: watery diarrhea, dysentery (bloody mucopurulent stools), and the postinfectious phase. If required, rehydration should be oral, and nutrition should be started as soon as possible. Septicemia can occur in pts with chronic liver disease, malignancy, diabetes mellitus, and other underlying illnesses. Diagnosis Stool culture studies for Yersinia must be specifically requested and require the use of special media. Infection follows ingestion of cysts from fecally contaminated water, food, or hands. Clinical Manifestations Most pts harboring Entamoeba species are asymptomatic, but some pts develop inflammatory colitis 2­6 weeks after ingestion of amebic cysts. Diagnosis Microscopic examination of three stool samples, often combined with serologic testing, remains the standard diagnostic approach. Indications for aspiration include the need to rule out pyogenic abscess, a lack of response to treatment in 3­5 days, an imminent threat of liver-abscess rupture, or the need to prevent left-lobe abscess rupture into the pericardium. The rate of fecal colonization is often 20% among adult pts hospitalized for >2 weeks; in contrast, the rate is 1­3% among community residents. Clinical Manifestations Most commonly, pts develop diarrhea, with stools that are not grossly bloody and are soft to watery, with a characteristic odor. Metronidazole is recommended only for mild to moderately severe disease when these other agents are not readily accessible. Options include an extended tapered vancomycin regimen (125 mg bid for 1 week, then daily for 1 week, then q2­3d for 2­8 weeks), administration of sequential therapy with vancomycin (125 mg qid for 10 days) followed by rifaximin (400 mg bid for 2 weeks), treatment with fidaxomicin, and fecal microbiota transplantation. Clinical Manifestations Urethritis in men produces urethral discharge, dysuria, or both, usually without frequency of urination. Moxifloxacin can be considered for treatment of refractory nongonococcal, nonchlamydial urethritis. Clinical Manifestations Acute epididymitis-almost always unilateral-produces pain, swelling, and tenderness of the epididymis, with or without symptoms or signs of urethritis. If symptoms persist after treatment, a testicular tumor or a chronic granulomatous disease. Clinical Manifestations Vulvovaginal infections encompass a wide array of specific conditions, each of which has different presenting symptoms. Diagnosis Evaluation of vulvovaginal symptoms includes a pelvic examination (with a speculum examination) and diagnostic testing. Treatment of sexual partners with the same regimen reduces the risk of reinfection and is the standard of care. Clinical Manifestations the presenting symptoms depend on the extent to which the infection has spread. Lower-quadrant, adnexal, or cervical motion or abdominal rebound tenderness is less severe in women with endometritis alone than in women who also have salpingitis. Nausea, vomiting, and increased abdominal tenderness may occur if peritonitis develops. Immediate treatment (before all test results are available) is often appropriate to improve response, reduce transmission, and cover pts who might not return for follow-up visits. Sexually acquired proctocolitis is most often due to Campylobacter or Shigella spp. Clinical Manifestations Anorectal pain and mucopurulent, bloody rectal discharge suggest proctitis or proctocolitis. Proctitis is more likely to cause tenesmus and constipation, whereas proctocolitis and enteritis more often cause diarrhea. Diagnosis Pts should undergo anoscopy to examine the rectal mucosa and exudates and to obtain specimens for testing for rectal gonorrhea, chlamydial infection, herpes, and syphilis. Epidemiology the 450,000 cases reported in the United States in 2016 probably represent only half the true number of cases because of underreporting, self-treatment, and nonspecific treatment without a laboratory diagnosis. Penicillin, ampicillin, and tetracycline are no longer reliable therapeutic agents, and oral cephalosporins and fluoroquinolones are no longer routinely recommended. In addition, strains highly resistant to ceftriaxone and azithromycin have been isolated in several countries, and combined resistance may contribute to the failure of the currently recommended dual therapy (see below). Pharyngeal infection almost always coexists with genital infection, resolves spontaneously, and is rarely transmitted to sexual contacts.

Dobutamine pharmacologic stress echo can be substituted for pts who cannot exercise arrhythmia or panic attack purchase 75 mg plavix with mastercard. Nuclear imaging is more sensitive blood pressure over 60 order plavix 75 mg online, but less specific blood pressure medication compliance buy cheap plavix 75 mg line, than stress echocardiography for detection of ischemia heart attack survival rate generic 75 mg plavix. For pts who cannot exercise blood pressure home monitors buy cheapest plavix, pharmacologic perfusion imaging with adenosine, regadenoson, dipyridamole, or dobutamine is used instead (Chap. It is most useful in evaluation of suspected coronary anatomic anomalies and to exclude high-grade coronary stenoses in pts with chest pain and intermediate pretest probability of coronary artery disease. Table 114-2 summarizes key diagnostic features of the noninvasive imaging modalities. Physical Examination Wide, fixed splitting of S2, systolic murmur from flow across pulmonic valve, possible diastolic flow rumble across tricuspid valve, prominent jugular venous v wave. Echo contrast (agitated saline injection into peripheral systemic vein) may visualize transatrial shunt. Physical Examination Holosystolic murmur at lower left sternal border, which may be accompanied by a palpable thrill, loud P2; diastolic flow murmur across mitral valve. Therapeutic options are limited and include pulmonary artery vasodilators (see Chap. May go undetected in early life or suspected by the presence of a systolic ejection click; often identified during echocardiography that was obtained for another reason. Usually asymptomatic, but may cause headache, fatigue, or claudication of lower extremities. Physical Examination Hypertension in upper extremities; delayed femoral pulses with decreased pressure in lower extremities. Systolic murmur is best heard over the upper back at the left interscapular space. Continuous murmur over the scapula may also be present due to collateral blood flow. Echocardiography Can delineate site and length of coarctation, and Doppler determines the pressure gradient across it. Recurrent coarctation after surgical repair may be amenable to percutaneous balloon dilatation. Repaired congenital heart disease with residual defects adjacent to site of a prosthetic patch or transcatheter device 3. Principal symptoms are dyspnea and cough precipitated by exertion, excitement, fever, anemia, tachycardia, pregnancy, sexual intercourse, and thyrotoxicosis. Diastolic rumbling murmur, best heard at apex in left lateral decubitus position, with presystolic accentuation when in sinus rhythm. Doppler assessment provides estimation of transvalvular peak and mean gradients, mitral valve area, and degree of pulmonary hypertension (Chap. For dyspnea, prescribe sodium restriction and oral diuretic therapy; beta blockers, ratelimiting calcium channel antagonists. Murmur typically radiates to axilla, but may radiate to base instead when due to prolapsing or flail posterior leaflet. Operation should be carried out before development of chronic heart failure symptoms. Transcatheter mitral valve repair, using a clip to tether the mid-portion of the leaflet edges together, is commercially available for symptomatic pts with severe, primary. Potential symptoms include vague chest discomforts and supraventricular and ventricular arrhythmias. Rarely, systemic emboli from platelet-fibrin deposits on valve lead to transient ischemic attacks. Click and murmur move earlier and are exaggerated by Valsalva maneuver; they are delayed and softened by squatting and isometric exercise (Chap. Prophylaxis for infective endocarditis is indicated only if prior history of endocarditis. Murmur is typically loudest at second right intercostal space, with radiation to carotids and sometimes to the apex (Gallavardin effect). Dilated aortic root: dilatation due to cystic medial necrosis, aortic dissection, ankylosing spondylitis, syphilis. Diastolic rumbling murmur along left sternal border increased by inspiration with loud presystolic component. Doppler echocardiography demonstrates thickened valve and impaired separation of leaflets and provides estimate of transvalvular gradient. Other causes include rheumatic disease, endocarditis, myxomatous valve disease, and carcinoid valvular disease. In severe cases surgical treatment consists of tricuspid annuloplasty or valve replacement. The chest x-ray shows right atrial and right ventricular enlargement; post-stenotic enlargement of the pulmonary artery may be present. Doppler echocardiography demonstrates the stenotic valve and quantitates the transvalvular gradient. Table 117-2 details the comprehensive initial evaluation of suspected cardiomyopathies. Atrial fibrillation Normal or increased Increased; may be massive Related to endocardial involvement; frequent mitral and tricuspid regurgitation, rarely severe Exertional intolerance, fluid retention early Right often dominates Ventricular uncommon except in sarcoidosis, conduction block in sarcoidosis and amyloidosis. Atrial fibrillation Markedly increased Increased Related to valve-septum interaction: mitral regurgitation Exertional intolerance; may have chest pain Left-sided congestion may develop late Ventricular tachyarrhythmias; atrial fibrillation Left-sided symptoms of pulmonary congestion: dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea. Right-sided symptoms of systemic venous congestion: hepatic and abdominal distention, discomfort on bending, peripheral edema. Technetium pyrophosphate nuclear imaging is sensitive for detection of transthyretin amyloidosis. Anticoagulation often indicated, particularly in pts with eosinophilic endomyocarditis. Typically results from mutations in sarcomeric proteins (autosomal dominant transmission). Digoxin, other inotropes, diuretics, and vasodilators should generally be avoided. Antiarrhythmic agents, especially amiodarone, may suppress atrial and ventricular arrhythmias. Rare etiologies include eosinophil myocarditis, hypersensitivity myocarditis, and systemic inflammatory diseases. Pain is usually retrosternal or left precordial, radiating to neck, left shoulder, trapezius ridge, and/or arms; fever and palpitations are common. Intractable, prolonged pain or frequently recurrent episodes may require pericardiectomy. Anticoagulants are relatively contraindicated in acute pericarditis because of risk of pericardial hemorrhage. If tamponade develops subacutely, peripheral edema, hepatomegaly, and ascites may be present. Viral, tuberculosis (mostly in developing nations), previous cardiac surgery, collagen vascular disorders, uremia, neoplastic, and radiation-associated pericarditis are potential causes. Dramatic effects of respiration: During inspiration the ventricular septum shifts to the left with prominent reduction of blood flow velocity across mitral valve; pattern reverses during expiration (opposite pattern across the tricuspid valve with respiration). Hypertension is major contributor to cardiovascular diseases and complications; etiology is unknown in 80­95% of pts ("essential hypertension"). Always consider a secondary correctable form of hypertension, especially in pts aged 30 or those who become hypertensive after 55. Isolated systolic hypertension (systolic 140, diastolic <90) most common in elderly pts, due to reduced vascular compliance. Presents with recent onset of hypertension, refractory to usual antihypertensive therapy. Abdominal bruit is present in 50% of cases; hypokalemia due to activation of the renin-angiotensin-aldosterone system may be present. Renal Parenchymal Disease Elevated serum creatinine and/or abnormal urinalysis, containing protein, cells, or casts. Coarctation of Aorta Presents in children or young adults (including 35% of pts with Turner syndrome); constriction is usually present in aorta at origin of left subclavian artery. Examination shows diminished, delayed femoral pulsations; systolic murmur loudest at left infrascapular region. Doppler echocardiography identifies region of constriction and measures associated pressure gradient. Pheochromocytoma A catecholamine-secreting tumor, typically of the adrenal medulla or extraadrenal paraganglion tissue. Associated findings include chronic weight loss, orthostatic hypotension, and impaired glucose tolerance. Pheochromocytomas may be localized to the bladder wall and may present with micturition-associated symptoms of catecholamine excess. In pts with systolic hypertension and wide pulse pressure, consider thyrotoxicosis, aortic regurgitation (Chap. Physical examination: Measure bp with appropriate-sized cuff (large cuff for large arm). Signs of hypertension include retinal arteriolar changes (narrowing/nicking); left ventricular lift, loud A2, S4. Clues to secondary forms of hypertension include cushingoid appearance, thyromegaly, abdominal bruit (renal artery stenosis), delayed femoral pulses (coarctation of aorta). Diuretics Thiazides preferred over loop diuretics because of longer duration of action; however, the latter are more potent when serum creatinine >2. Major side effects include hypokalemia, hyperglycemia, and hyperuricemia, which can be minimized by using low dosage. May be used as monotherapy or in combination with a diuretic, calcium antagonist, or beta blocker. Note that renal function may deteriorate rapidly as a result of inhibition of the renin-angiotensin system in pts with bilateral renal artery stenosis. Use sustained-release formulations, as short-acting dihydropyridine calcium channel blockers may increase incidence of coronary events. If bp proves refractory to drug therapy, evaluate for secondary forms of hypertension, especially renal artery stenosis and pheochromocytoma. Beta blockers should be used cautiously; fetal hypoglycemia and low birth weights have been reported. Subsequent doses and intervals of administration should be adjusted according to the blood pressure response and duration of action of the specific agent. Malignant Hypertension Defined as an abrupt increase in bp in pt with chronic hypertension or sudden onset of severe hypertension; a medical emergency. In absence of hypertensive encephalopathy, goal is to lower mean arterial pressure gradually over several hours to prevent precipitous reduction in cerebral, coronary, and renal blood flow. Increased intracellular fatty acid metabolites contribute to insulin resistance by impairing insulin-signaling pathways and accumulating as triglycerides in skeletal and cardiac muscle, while stimulating hepatic glucose and triglyceride production. In this analysis, the following thresholds for waist circumference were used: white men, 94 cm; African-American men, 94 cm; Mexican-American men, 90 cm; white women, 80 cm; African-American women, 80 cm; Mexican-American women, 80 cm. For participants whose designation was "other race-including multiracial," thresholds that were once based on Europid cutoffs (94 cm for men and 80 cm for women) and on South Asian cutoffs (90 cm for men and 80 cm for women) were used. For participants who were considered "other Hispanic," the International Diabetes Federation thresholds for ethnic South and Central Americans were used. In general, recommendations for weight loss include a combination of caloric restriction, increased physical activity, and behavior modification. Weight loss drugs or bariatric surgery are adjuncts that may be considered for obesity management (Chap. Other in-hospital antiarrhythmic therapy should be reserved for pts with sustained ventricular arrhythmias. Ventricular Tachycardia If hemodynamically unstable, perform immediate electrical countershock (unsynchronized discharge of 200­300 J or 50% less if using biphasic device). Supraventricular Arrhythmias Sinus tachycardia may result from heart failure, hypoxemia, pain, fever, pericarditis, hypovolemia, administered drugs. If no cause is identified, suppressive beta blocker therapy may be beneficial to reduce myocardial oxygen demand. Other supraventricular arrhythmias (paroxysmal supraventricular tachycardia, atrial flutter, and fibrillation) are often secondary to heart failure. In absence of acute heart failure, suppressive alternatives include beta blockers, verapamil, or diltiazem (Chap. Part 7: the era of reperfusion: Section 1: Acute coronary syndromes [acute myocardial infarction]. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Noncardiac causes of hypotension should be considered: hypovolemia, acute arrhythmia, or sepsis. Echocardiography and Doppler interrogation can confirm presence of these complications. Pericarditis Characterized by pleuritic, positional pain, and pericardial rub (Chap. Anticoagulants should be avoided when pericarditis is suspected to avoid development of pericardial bleeding/ tamponade. Typically an aneurysm is confirmed by echocardiography or by left ventriculography. Small troponin elevations may also occur in pts with heart failure, myocarditis, pulmonary embolism, and other conditions in Table 122-1.

The acroplaxome heart attack meme buy 75 mg plavix visa, a cytoskeletal plate arrhythmia institute plavix 75 mg buy online, links the acrosome to the nuclear envelope blood pressure kits for sale buy 75 mg plavix mastercard. The annulus hypertension 4011 buy cheap plavix on-line, containing the protein septin 4 heart attack while pregnant purchase plavix on line, represents a limiting ring-shaped region between the middle piece and the principal piece. This temperature is achieved in the scrotum by the pampiniform plexus and spermatid artery participating in countercurrent heat exchange. Varicocele (dilation of the veins of the pampiniform plexus) hampers heat exchange and may lead to a decrease in sperm production. Spermatic cord torsion is caused by a twisting of the spermatic cord that disrupts the testicular arterial blood supply and venous drainage. This condition is generally caused by physical trauma or abnormally mobile testes within the tunica vaginalis. Cryptorchidism (or undescended testes) is the developmental failure of one or both testes to reach the scrotal sac. These two hormones regulate the development of the gubernaculum, a ligament connecting the testisepididymis complex to the scrotal sac. Mumps is a systemic viral infection with a 20% to 30% incidence of unilateral or bilateral acute orchitis. It is characterized by sudden edema and infiltration of lymphocytes of the seminiferous intertubular space in postpubertal males. Clusters of Leydig cells are observed in the intertubular space, associated with blood vessels and lymphatic channels. Enzymes of the smooth endoplasmic reticulum convert pregnenolone to progesterone to testosterone. Review 20-14 to integrate the various aspects of the hormonal regulation of spermatogenesis. The maintenance and progression of spermatogenesis depends also on other factors, involving Sertoli cell function. Let us focus on the most relevant functions: (1) Sertoli cells assist in the translocation of interconnected members of the spermatogonia progeny across inter-Sertoli cell tight junctions, from the basal compartment to the adluminal compartment of the seminiferous epithelium. This mechanism allows Sertoli cells to ensure a steady sperm release by timing the start of a new spermatogonial cell progeny. It enhances androgen concentration in the epididymis, assisting in sperm maturation (remote action). As a result of synchrony and overlapping spermatogenic cell progenies, a series of cellular combinations, called a cellular associations visualized in cross sections of seminiferous tubules. A spermatogenic cycle is defined as the time it takes for the reappearance of the same stage, or cellular association, within a given segment of the seminiferous tubule. A spermatogenic wave is defined as the distance (space) between two identical stages, or cellular associations, along the length of the seminiferous tubule. The progression of spermatogenic cell progenies in human testes is helicoidal, instead of linear as in rodents. The basis of epigenetics is the methylation of cytosine-phospho-guanosine (CpG) islands seen predominantly in actively transcribing genes. During spermatogenesis and oogenesis, the genetic imprints of the gametes are erased, allowing the epigenetic reprogramming of the embryos. Reprogramming consists of the differential expression of a number of alleles in the paternal and maternal gametes. The pluripotent inner cell mass of the blastocyst erases the epigenetic memory before implantation. Histone deacetylation enables histone methyltransferases to methylate histone 3 and recruit heterochromatin protein-1 to trigger chromatin condensation. As you already know, heterochromatin (condensed chromatin) is transcriptionally inactive. An increase in X-chromosome number is a common feature of testicular germ cell tumors. The tumor cells show large nuclei with an irregular outline and noticeable nucleoli. Teratoma is a benign germ cell tumor derived from a combination of tissues from all three embryonic layers (ectoderm, mesoderm and endoderm). The tumor consists of blood vessels surrounded by squamous tumor cells organizing glomerular-like structures known as Schiller-Duval bodies. Secretions from the epididymal duct, combined mainly with additional products of the prostate and seminal vesicles, contribute to the maturation and viability of the male gamete. This article starts by reviewing the major developmental steps of the gonads and the excurrent (efferent) ducts. This review leads to an understanding of the histology, function and clinical significance of the pathway followed by male and female gametes in the pursuit of fertilization. Recall that hematopoiesis and the development of melanocytes and mast cells depend on the c-kit receptor and its stem cell ligand. Coelomic epithelial cords grow into the mesenchyme of the gonadal ridge to form the outer cortex and inner medulla of the indifferent gonad. Development of the testes (21-1; see Primer 21-A) Until the seventh week of fetal development, there is one type of gonad common to both genders. Thereafter, in the female, the cortex develops into the ovary, and the medulla regresses. We have learned in Chapter 4, Connective Tissue, that Sox9 participates in chondrogenesis, by enabling cells in the perichondrium to differentiate into chondrocytes. Therefore, Sox9 is important for the development of the male reproductive system and the skeleton. The initial step of testicular development is the differentiation of the Sertoli cell population regulated by the Y chromosome. Fetal precursors of peritubular myoid cells and the vasculature develop around the testicular cords. Mutations of the Sox9 gene cause campomelic dysplasia involving skeletal abnormalities. Development of internal genitalia (21-1) In the absence of androgen, the wolffian duct regresses and the prostate fails to develop. If high levels of androgen are present in the female fetus, both müllerian and wolffian ducts can persist (see Box 21-A). Testicular descent the fetal testis consists of testicular cords connected to the rete testis by tubuli recti. Leydig cells, derived from the mesonephric mesenchyme, are present between the testicular cords. The cephalic end of the wolffian ducts (also called mesonephric ducts) forms the epididymis, vas deferens and ejaculatory duct. The prostate gland has a dual origin: the glandular epithelium forms from outgrowths of the prostatic urethral endoderm; the stroma and smooth muscle derive from the surrounding mesoderm. In month 9 of pregnancy or immediately after birth, the testes reach the scrotal sac after moving across the inguinal canal. The gubernaculum shortens, the vaginal process lengthens and each testis is drawn into the scrotum. As the vaginal process lengthens, it traps muscle fibers of the oblique internal muscle and the transverse muscle to form the cremaster muscle. For additional details, see Cryptorchidism (or undescended testis) in Chapter 20, Spermatogenesis. The testes may be removed after puberty (until feminization is complete) because of the risk of testicular cancer, just like in the undescended testis condition. Atrophic müllerian duct Developing wolffian duct At puberty, the production of both androgen and estradiol increases (the latter from peripheral aromatization of androgens). Although the external genitalia may be female, the vagina consists of only the lower two-thirds of a normal vagina, creating a blind-ending vaginal pouch (see Box 21-A). Efferent ductules, in turn, link the rete testis to the initial segment of the epididymal duct, an irregularly coiled duct extending to the ductus, or vas deferens. To rete testis Basal tight junctions linking columnar Sertoli cells change into apical tight junctions connecting cuboidal Sertoli cells at the straight tubule and rete testis. The apical domain of the cuboidal Sertoli cells displays microvilli and an occasional primary cilium. Leydig cells Blood vessel Lymphatic vessel Seminiferous epithelium Seminiferous epithelium Lymphatic vessel Aggregates of Leydig cells are in proximity to lymphatic and blood vessels, all supported by loose connective tissue Blood vessels Transition zone Spermatocyte Columnar Sertoli cells Straight tubules Straight tubules are shown in a cross section. The lining epithelium is cuboidal and peritubular smooth muscle cells continue the peritubular myoid cells layer of the seminiferous tubules. Straight tubule Cuboidal Sertoli cells Lymphatic vessel or vas deferens develop from the mesonephric duct (wolffian duct). Straight tubules (Latin tubulus rectus; plural tubuli recti) are located in the mediastinum of the testis. They are lined by a simple cuboidal epithelium with structural features similar to those of Sertoli cells, except that occluding junctions are now at the apical domain, instead of at the basal domain. The rete testis consists of irregularly anastomosing channels within the mediastinum of the testis. The wall, formed by fibroblasts 706 and smooth muscle cells, is surrounded by large lymphatic channels and blood vessels associated with large clusters of Leydig cells. About 12 to 20 efferent ductules (Latin ductuli efferentes) link the rete testis to the epididymis after piercing the testicular tunica albuginea (see 21-3). Columnar cells with microvilli/stereocilia, with a role in the reabsorption of fluid from the lumen. Ciliated cells, which contribute to the transport of non-motile sperm toward the epididymis. Basal cells, the cell precursor of the ciliated and non-ciliated epithelial cells. The efferent ductules are lined by a pseudostratified epithelium with a distinctive scalloped outline. The epithelium consists of: (1) principal cells with microvilli; (2) ciliated cells and (3) basal cells. Efferent ductule the smooth muscle layer increases in thickness the pseudostratified columnar epithelium of the epididymis consists of two major cell types: (1) principal cells with stereocilia/stereovilli; and (2) basal cells. The apical surface of the epithelial cells contains microvilli and a single cilium. Seminiferous tubules Epididymal duct (initial segment) Columnar cell with microvilli Ciliated cell Rete testis Stereocilia Smooth muscle cell layer Principal cell Basal cell Smooth muscle cell layer Basal cell the pseudostratified epithelium has a characteristic scalloped outline, which enables identification of the efferent ductules. A thin inner circular layer of smooth muscle cells underlies the epithelium and its basal lamina. The protein-steroid complex is present in the lumen of the rete testis and the initial segments of the epididymis. Consequently, the rete testis contains a larger concentration of androgens than arterial blood. Intraluminal androgens appear to favor the normal function of the head of the epididymis. The epididymal ducts (21-4 and 21-5; see 21-3) the epididymides (Greek epi, following; didymos, pair; plural epididymides) are highly elongated and coiled tubules (about 6 meters in length in the adult human) where sperm mature. Sperm maturation consists of the acquisition of forward motility, essential to sperm fertilizing ability. Mature sperm are stored in the terminal portion of the epididymal duct before ejaculation. The epididymal duct is classically subdivided into three major segments (see 21-4): 1. Circular smooth muscle cell layer Basal cells Sperm tail in the lumen of the epididymal duct Stereocilia/stereovilli Note that: (1) the circular smooth muscle cell layer thickens gradually from the head to the tail. Head (caput) Principal cell Stereocilia/stereovilli Principal cell the lumen to the basal lamina. The apical domain of principal cells displays branched stereocilia/ stereovilli and a well-developed Golgi apparatus, lysosomes and vesicles (see 21-5). Other cell types are the apical cells, rich in mitochondria and predominant in the head of the epididymis, and the clear cells, predominant in the tail of the epididymis. The height of the epithelium varies with respect to the segment of the epididymal duct. In an opposite fashion, the lumen of the epididymal duct is narrow in the head region and wider in the tail region. Regional differences exist in the organization of the smooth muscle cell layer, responsible for the rhythmic peristaltic contractions moving sperm along the epididymal duct (see Box 21-B). Pinocytotic vesicle Apical Multivesicular body cytoplasm Lysosome Lipid droplet Intraepithelial lymphocytes are abundant in all regions of the epididymal duct Basal cells rest on the basal lamina. Apical Golgi apparatus Principal cell Elongated and folded nucleus the principal cells have the following structural features: (1) They are tall in the caput and decrease in height along the epididymal duct to become low-columnar to cuboidal in the cauda region. Basal cell Basal rough endoplasmic reticulum Basal lamina Circular smooth muscle cell layer the initial portions of the epididymal duct are surrounded by a circular smooth muscle cell layer. The terminal portions (body and tail) display an increase in the thickness of the inner circular smooth muscle layer and the development of an outer longitudinal smooth muscle cell layer. Vas deferens, spermatic cord and ejaculatory duct (21-6 and 21-7) Box 21-B Epididymal duct · the epididymis has three main functions: · Sperm transport by peristalsis to the storage region, the tail of the epididymis. Mutations in the genes encoding bone morphogenetic protein (Bmp) 4, Bmp7 and Bmp8 result in the defective differentiation of specific segments of the epididymal duct. The vas deferens (ductus deferens) is a 45-cm-long muscular tube with the following features (see 21-6): 1. The lining epithelium is pseudostratified columnar with stereocilia/stereovilli similar to that of the epididymis and is supported by a connective tissue lamina propria with elastic fibers. The muscular wall consists of inner and outer layers of longitudinally oriented muscle separated by a middle circular layer. In addition to the vas deferens, the spermatic cord contains the following components (see 21-6): 1.

The damaged tissue is replaced by new capillaries (angiogenesis) blood pressure chart elderly purchase plavix paypal, macrophages and fibroblasts prehypertension home remedies plavix 75 mg buy low price. Suppurative acute inflammation pulse pressure 73 plavix 75 mg purchase with visa, when neutrophils and debris of dead cells predominate and the affected tissue is liquefied by neutrophil-derived proteolytic enzymes to produce pus arrhythmia questions buy cheap plavix 75 mg line. Acute appendicitis and recurring otitis media in children are examples of suppurative acute inflammation prehypertension 20s order discount plavix on-line. Specific bacteria produce suppurative acute inflammation, which can evolve into a pustule (at the skin surface) or an abscess, an enclosed collection of purulent tissue. Fibrinous acute inflammation, when fibrin is the predominant component of the fluid or effusion deposited on the surface of the meninges, peritoneum, pleura and pericardium. A fibrous repair process, converting the fibrinous effusion into scar tissue, causes the thickening of the affected surface and even the possible occlusion of a space (such as the pericardial space). The transudate of a blister of the skin, caused by a burn, viral or toxic agent (poison ivy, poison oak, or poison sumac), or effusion of fluid in pleural, peritoneal and pericardial cavities (caused by congestive heart failure or blocked blood or lymphatic vessels) are examples of serous acute inflammation. Chronic inflammation (10-15) the persistence of tissue damage caused by a pathogen can determine chronic inflammation, a process in which tissue necrosis and repair are simultaneous and persistent for many years. A chronic peptic ulcer is an example of chronic inflammation caused by the persistence of a pathogen (Helicobacter pylori), excessive production of gastric acid or the effect of non-steroidal anti-inflammatory drugs (see Chapter 15, Upper Digestive Segment). Macrophages fuse to form multinucleated giant cells (known as Langhans cells in tuberculosis infection). A connective tissue boundary is seen in contact with lymphocytes of the lymph node (*). Multinucleated giant cells 1 giant cells Caseous necrosis * Added to the characteristic cellular and tissue aspects of acute inflammation is the involvement in chronic inflammation of the immune system, represented by lymphocytes and macrophages. Macrophages have a dual function: they are phagocytic cells, clearing necrotic tissue and dead cells, and also antigen-presenting cells as part of their immunologic function. From a histopathology perspective, chronic inflammation displays fibrous repair, represented by fibrous granulation tissue, overlapping with lymphocytes and macrophages (see 10-14). Lymphocytes, macrophages and plasma cells are regarded as the typical combination of chronic inflammatory cells. Macrophages, derived from monocytes in the presence of interferon-, have a prevalent function in chronic inflammation. A granuloma (see 10-15) consists of a typical central necrotic zone surrounded by a zone of activated epithelial-like macrophages coexisting with multinucleated giant cells. The pathogen can elicit a significant immune response (lymphocytes interacting with macrophages/ antigen-presenting cell) but without significant pathogenic potential. Human diseases that fulfill this condition are tuberculosis (produced by Mycobacterium tuberculosis); leprosy (caused by Mycobacterium leprae); and syphilis (produced by Treponema pallidum). The physical and biochemical characteristics of the central zone of a granuloma depends on the pathogen. For example, the tuberculous granuloma has a central caseation soft cheese-like mass zone, surrounded by scattered multinucleated giant cells called Langhans cells. The sarcoidosis granuloma, displays a fibrosis center, and the multinucleated giant cells may contain calcified spherical deposits, called Schaumann bodies. The nature of the pathogen, a non-biological foreign body, such as silicone in lungs, which is resistant to the action of enzymes released by neutrophils, or an unknown pathogen in the disease sarcoidosis (affecting lungs, lymph nodes, spleen and liver). Lymphoid organs are the sites where immune protective responses occur when the body is confronting immunological challenges. Lymph nodes (10-16 and 10-17) the function of lymph nodes is to filter the lymph, maintain and differentiate B cells and house T cells. A lymph node is surrounded by a capsule and the parenchyma is divided into a cortex and a medulla (see 10-16). The capsule consists of dense irregular connective tissue surrounded by adipose tissue. The capsule at the convex surface of the lymph node is pierced by numerous afferent lymphatic vessels. Afferent lymphatic vessels have valves to prevent the reflux of lymph entering a lymph node. The stroma, or parenchyma, of a lymph node consists of interconnected fibroblastic reticular cells and fibers forming an open network, which enables B-cell and T-cell compartmentalization and survival, as well as the transport of antigens and signaling molecules deep in the lymph node. Cell compartmentalization ensures adaptive immune responses to antigen and inflammation. Activated B cells, with high-affinity surface Igs, migrate to the medullary cords and differentiate into plasma cells secreting IgM or IgG into the medullary sinuses and efferent lymphatic vessels (see 10-17). They are located under the capsule (subcapsular sinus) and along trabeculae of connective tissue derived from the capsule and entering the cortex (paratrabecular sinus). Highly phagocytic macrophages are distributed along the subcapsular and paratrabecular sinuses to remove particulate matter present in the percolating lymph. Lymph entering the paratrabecular sinus through the subcapsular sinus percolates to the medullary sinuses and exits through a single efferent lymphatic vessel. Lymphatic follicle is a B-cell zone 1 4 Efferent lymphatic vessel Medullary sinus Lymph circulation through the lymph node 1 Afferent lymphatic vessels pierce the capsule and open into the subcapsular sinus. Deep or inner cortex is a T-cell zone the medulla contains medullary cords surrounding medullary sinuses; medullary cords contain mainly macrophages and plasma cells. B cell Mature B cells that are not specific for an antigen accumulate in the mantle zone, forming a cap on top of the lymphoid follicle. Proliferation occurs after B cells have been activated by helper T cells, presenting to them a specific antigen. The hilum is a concave surface of the lymph node where efferent lymphatic vessels and a single vein leave and an artery enters the lymph node. Medullary sinusoids, spaces lined by endothelial cells surrounded by reticular cells and macrophages. Activated B cells migrate from the cortex, enter the medullary cords and become plasma cells. This is a strategic location, because plasma cells can secrete immunoglobulins directly into the lumen of the medullary sinuses without leaving the lymph node. In Chapter 12, Cardiovascular System, we indicate that the interstitial fluid, representing plasma filtrate, is transported into blind sacs corresponding to lymphatic capillaries. This interstitial fluid, entering the lymphatic capillaries as lymph, flows into collecting lymphatic vessels, becoming afferents to regional lymph nodes Box 10-G Lymph flow and dendritic cell migration · Terminal afferent lymphatic vessels, transporting lymph to the lymph nodes, derive from collecting lymphatic vessels. They are distributed as sentinels in the periphery to monitor the presence of foreign antigens. They relocate to secondary lymphoid organs, lymph nodes in particular, to interact with memory T cells present in the deep cortex. Lymph nodes are linked in series by the lymphatic vessels in such a way that the efferent lymphatic vessel of a lymph node becomes the afferent lymphatic vessel of a downstream lymph node in the chain. Soluble and particulate antigens drained with the interstitial fluid, as well as antigen-bearing dendritic cells in the skin (Langerhans cells; see Chapter 11, Integumentary System), enter the lymphatic vessels and are transported to lymph nodes. Soluble and particulate antigens are detected in the percolating lymph by resident macrophages and dendritic cells strategically located along the subcapsular and paratrabecular sinuses. When the immune reaction is acute in response to locally drained bacteria (for example, infections of the teeth or tonsils), local lymph nodes enlarge and become painful because of the distention of the capsule by cellular proliferation and edema. Most of the lymphomas are of B-cell origin (80%); the remainder are of T-cell origin. They are clinically characterized by non-tender enlargement of localized or generalized lymph nodes (nodal disease). Another group in the lymphoma category includes the plasma cell tumors, consisting of plasma cells, the terminally differentiated B cells. Plasma cell tumors (multiple myeloma) originate in bone marrow and cause bone destruction with pain due to fractures (see Box 10-E). The mesenchyme from the pharyngeal arch gives rise to the capsule, trabeculae and vessels of the thymus. The thymic epithelial rudiment attracts bone marrow­derived thymocyte precursors, dendritic cells and macrophages required for normal thymic function. Philadelphia, Mosby, 2000 Electron microscopy image from Damjanov I, Linder J: Pathology: A Color Atlas. After puberty, the thymus begins to involute and the production of T cells in the adult decreases. The progenies of T cells become established and immunity is maintained without the need to produce new T cells. These self-proteins permit the disposal of autoreactive thymocytes in the medulla of the thymus. The mechanism of self-tolerance is not operational, because self-reactive T cells are not eliminated by clonal deletion. In contrast to the thymus, the stroma of the lymph node and the spleen contains reticular cells and reticular fibers. Differentiation includes the expression of cytokeratins and establishment of desmosome intercellular linkages, two typical features of epithelial cells. Capsule-derived trabeculae extending into the future corticomedullary region of the thymus divide the thymus into incomplete lobules. Parathyroid gland tissue, developing from the same pouch, migrates with the thymus and becomes the inferior parathyroid glands. Box 10-I DiGeorge syndrome · DiGeorge syndrome is an inherited immunodeficiency disease in which thymic epithelial cells fail to develop. The expression of these proteins permits the elimination of thymocytes, which recognize specific tissue antigens. Structure of the thymus (10-20 to 10-22) the thymus consists of two lobes subdivided into several incomplete lobules, each consisting of an independent cortex and a shared medulla (see 10-20). Each lobule contains an independent outer cortical region, but the central medullary region is shared by adjacent lobules. Trabeculae, extensions of the capsule down the corticomedullary region, form the boundary of each lobule. The cortex consists of stromal cells and developing T cells (thymocytes), macrophages and cortical thymic epithelial cells. The characteristic deep-blue nuclear staining of the cortex in histologic preparations reflects the predominant population of T cells as compared with the less basophilic medulla containing a lower number of thymocytes. Macrophages adjacent to the capillaries ensure that antigens escaping from blood vessels into the thymus do not react with developing thymocytes in the cortex, thus preventing the risk of an autoimmune reaction. The medulla contains the remaining 15% to 20% of thymocytes undergoing clonal deletion (elimination of autoreactive thymocytes). Abundant macrophages in the cortex of the thymus Immunohistochemistry panel from Martín-Lacave I, García-Caballero T: Atlas of Immunohistochemistry. The red pulp is associated with blood filtration by removing damaged or senescent red blood cells. The white pulp is associated with immune responses by screening blood-borne pathogens or antigens entering the marginal channel from the red pulp. The vascularization of the human spleen consists of branching arterial vessels derived from the splenic artery, ending in macrophage-sheathed capillaries opening into the red pulp space. Blood vessels reach the white pulp and red pulp through connective tissue trabeculae derived from the spleen capsule. The central artery/arteriole leaves the white pulp as the penicillar arteriole gives rise to macrophage-sheathed capillaries that open into the cords of Billroth in the red pulp. In the human spleen, blood circulation is open: circulating blood merges freely from the capillaries into the red pulp. Macrophage-sheathed capillaries are not continuous with the venous splenic sinusoids. The reticular cell stroma, blood, cords and splenic sinusoids constitute the red pulp of the spleen. Blood percolates through the reticular cell stroma of the cords before reaching the splenic sinusoids. Venous splenic sinusoids are lined by elongated endothelial cells in a parallel arrangement and separated by slits. Blood from the sinusoids converges to collecting veins that will form the splenic vein. About 95% of the developing thymocytes die within the cortex of the thymus without ever maturing. In the absence of a surviving signal, doublepositive thymocytes undergo apoptosis within three days; trophic signaling enables the progression of double-positive thymocytes into single-positive. Within 1 week, single-positive thymocytes will be eliminated by apoptosis unless they receive a positive signal for survival and export to the periphery. Maturation of the thymocytes is completed in the medulla and func374 tional thymocytes enter postcapillary venules in the corticomedullary junction to exit the thymus. The spherical structures are splenic follicles; they are part of the white pulp of the spleen. The red pulp consists of splenic sinusoids filled with blood and the splenic cords, plates of lymphoid-reticular cell tissue. Note that, in contrast to lymph node and thymus, the spleen lacks a cortex and a medulla. As discussed later, the white and red pulp interact at the marginal channel, a permeable gate between the red pulp compartment and the white pulp compartment. The red pulp receives a significant blood supply, including antigens entering the spleen from the blood. This differs from the lymph node, where antigens enter through the afferent lymphatic vessels. Although the splenic follicle mimics a lymphatic nodule of the lymph node cortex, the central artery/ arteriole is a distinctive feature. The cell components of the white pulp are similar to those of the lymph node, except that antigens enter the spleen from the blood rather than from the lymph. The red pulp is a filter, which removes aged and damaged red blood cells and microorganisms from circulating blood. Red pulp Rodent Periarteriolar lymphoid sheath White pulp Central arteriole Radial arteriole the red pulp is formed by (1) the penicillar arteriole; (2) macrophage-sheathed capillaries; (3) splenic sinusoids; (4) reticular cells, the stroma of the splenic cords (or cords of Billroth); and (5) all cell types of the circulating blood. This function is particularly important during bacteremia (presence of viable bacteria in blood circulation) because macrophages can trap bacteria in the red pulp and present their antigens to lymphocytes in the spleen to stimulate a specific immune response.

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Cholecystokinin cells (duodenum) 6 It stimulates bile release from the gallbladder and the secretion of pancreatic enzymes arteria 23 buy plavix 75 mg online. Microbiota includes bacteria prehypertension nhs purchase plavix 75 mg visa, archaea arrhythmia while sleeping best buy for plavix, fungi blood pressure chart software free order discount plavix, parasites and viruses that reside in the lumen and mucosal surface of the intestine pulse pressure under 20 order plavix discount. We discuss in Chapter 15, Upper Digestive Segment, the role of the mucus blanket in the protection of the surface of the stomach during Helicobacter pylori infection. In the small and large intestines, goblet cells secrete mucin glycoproteins assembled into a viscous gel-like blanket, limiting direct bacterial contact with enterocytes. Several defensive mechanisms operate in the alimentary tube to limit tissue invasion of pathogens and avoid potentially harmful overreactions that could damage intestinal tissues. The intestinal tight junction barrier, formed by apical tight junctions linking enterocytes. The barrier of pathogens is monitored by the immune­ competent cells residing in the subjacent lamina propria. Polymeric immunoglobulin A(IgA), a secretory product of plasma cells located in the lamina propria. Paneth cells, whose bacteriostatic secretions of antimicrobial proteins control the resident microbiota of the small intestine. In addition, keep in mind the defensive roles of the acidity of the gastric juice, which inactivates ingested microorganism, and the propulsive intestinal motility (peristalsis), which prevents bacterial colonization. Intestinal tight junction barrier (16-12) Intestinal tight junctions link adjacent enterocytes and provide a barrier function impermeable to most hydrophilic solutes in the absence of specific transporters. Tight junctions establish a separation between the intestinal luminal content and the mucosal immune function, which occurs within the lamina propria. Plasma cells, lymphocytes, eosinophils, mast cells and macrophages are present in the intestinal lamina propria. Flux of dietary proteins and bacterial lipopolysaccharides across leaky tight junctions can increase in the presence of tumor necrosis factor ligand and interferon-, two proinflammatory cytokines that affect tight junction integrity. Many diseases associated with intestinal epithelial dysfunction, including inflammatory bowel disease and intestinal ischemia, are associated with increased levels of tumor necrosis factor ligand. A minor defect of the tight junction barrier can allow bacterial products or dietary antigens to cross the epithelium and enter the lamina propria. If the mucosa immune cell activation response proceeds unchecked, proinflammatory cytokines will continue enhancing further leakage across the tight junction barrier, a condition leading to intestinal chronic inflammatory diseases. Therefore, these structures serve important functions associated with inflammation or immunotolerance. Follicle-associated epithelium formed by M cells and enterocytes the dome contains B cells, T cells, macrophages and dendritic cells. The lymphoid follicles, each showing a germinal center and a subepithelial dome area. M cells form an enterocyte specialized cell layer that takes up antigens and replace the brush border with short microfolds (hence the name M cell). Dendritic cells migrate to mesenteric local lymph nodes to also elicit immune responses. In the lumen, the secretory component is cleaved from its transmembrane anchorage. M cells form intraepithelial pockets, where a subpopulation of intraepithelial B cells resides and express IgA receptors, allowing the capture and phagocytosis of IgA-bound bacteria. Antigens are transported by M cells and presented to the immunocompetent B cells residing in the intraepithelial pockets. The population of M cells increases rapidly in the presence of pathogenic bacteria in the intestinal lumen (for example, Salmonella typhimurium). When confronting Salmonella, the microfolds of M cells change into large ruffles and, within 30 to 60 minutes, M cells undergo necrosis and the population of M cells is depleted. Dendritic cells, extending cytoplasmic processes between tight junctions linking enterocytes. Intestinal mucus blanket In the intestine, goblet cells secrete a mucus glycoprotein blanket consisting of stratified outer and inner layers. Microorganisms predominate in the outer mucus layer, whereas the inner mucus layer, resistant to microorganism penetration, contains antimicrobial proteins secreted by Paneth cells and enterocytes. Enteroendocrine cell Muscularis mucosae Paneth cells Lymphocytes Enteroendocrine cell presenting cells and follicular dendritic cells. The subepithelial dome contains B cells, T cells, macrophages and dendritic cells. Intestinal antigens, bound to immunoglobulin receptors on the surface of B cells, interact with antigen-presenting cells at the subepithelial dome region. Polymeric IgA (16-15) Plasma cells secrete polymeric IgA into the intestinal lumen, the respiratory epithelium, the lactating mammary gland and salivary glands. Most plasma cells are present in the lamina propria of the intestinal villi, together with lymphocytes, eosinophils, mast cells and macrophages. Polymeric IgA molecules secreted by plasma cells are transported from the lamina propria to the intestinal lumen by a transcytosis mechanism consisting of the following steps: 1. Polymeric IgA is secreted as a dimeric molecule joined by a peptide called the J chain. Polymeric IgA binds to a specific receptor, called the polymeric immunoglobulin receptor (pIgR), available on the basal surfaces of the enterocytes. The polymeric IgA­pIgR­secretory component complex is internalized and transported across the cell to the apical surface of the epithelial cell. IgA attaches to bacteria and soluble antigens, preventing a direct damaging effect to intestinal cells and penetration into the lamina propria. One last point: IgA regulates the composition and the function of the intestinal microbiota by affecting bacterial gene expression. By this mechanism, IgA keeps a congenial relationship between the host and the microbiota. The pyramid-shaped Paneth cells have a basal domain containing the rough endoplasmic reticulum. By creating a barrier that limits direct access of luminal bacteria to the epithelium. Pores cause swelling and membrane rupture, enabling the entrance of water into the pathogen. Defensins enhance the recruitment of dendritic cells to the site of infection and facilitate the uptake of antigens by forming defensin-antigen complexes. Recall that selectins, a member of the group of Ca2+-dependent cell adhesion molecules, belong to the C-type lectin family that have carbohydrate-recognition domains. Lysozyme is a proteolytic enzyme that cleaves glycosidic linkages that maintain the integrity of cell wall peptidoglycan. It is important to emphasize that the expression Box 16-B Lgr5+-intestinal stem cells are regulated by FoxL1+-telocytes located in the lamina propria · As was discussed in Chapter 3, Cell Signaling Cell Biology Pathology, a stem cell niche is a local environment that provides molecular signaling and physical support for the replication of stem cells and their differentiation into functional cells. Glands of Lieberkühn 1 Photomicrograph from Cotran R, et al: Robbins Pathologic Basis of Disease, 6th ed. Inflammatory cells (neutrophils, lymphocytes and macrophages) produce cytokines that cause damage to the intestinal mucosa. The initial alteration of the intestinal mucosa consists of an infiltration of neutrophils into the crypts of Lieberkühn. This process results in the destruction of the intestinal glands by the formation of crypt abscesses and the progressive atrophy and ulceration of the mucosa. Patients with intestinal bowel disease have an increased number of bacteria associated with the epithelial cell surface, suggesting a failure of mechanisms limiting direct contact between microorganisms and the epithelium. A contributing factor is the reactive immune response of the intestinal mucosa, determined by an abnormal signaling exchange with the resident bacteria (microbiota). In genetically susceptible individuals, inflammatory bowel disease occurs when the mucosal immune machinery regards the microbiota present in normal and healthy individuals as pathogenic and triggers an immune response. Cytokines produced by helper T cells within the intestinal mucosa cause a proinflammatory response that characterizes inflammatory bowel disease. Abnormal digestion of fats and proteins by pancreatic diseases (pancreatitis or cystic fibrosis) or lack of solubilization of fats by defective bile secretion (hepatic disease or obstruction of the flow of bile into the duodenum). Enzymatic abnormalities at the brush border, where disaccharidases and peptidases cannot hydrolyze carbohydrates (lactose intolerance) and proteins, respectively. Disturbances of the musculoskeletal system are observed when proteins, calcium and vitamin D fail to be absorbed. Plicae circulares and intestinal villi cannot be found beyond the ileocecal valve. Instead, the mucosa of the colon shows numerous openings of the straight tubular glands or crypts of Lieberkühn. As in the small intestine, the tissue layers of the large intestine are: mucosa (epithelium, lamina propria and muscularis mucosae), submucosa, muscularis and serosa. The simple columnar epithelial lining of the mucosa derives from the self-renewing intestinal stem cell population. Driven by a Wnt protein concentration gradient along the tubular gland axis, intestinal stem cells give rise to all the cell types lining the tubular gland (see Box 16-B). All regions of the colon absorb Na+ and Cl­ ions, facilitated by plasma membrane channels that are regulated by mineralocorticoids. Aldosterone increases the number of Na+ channels, thus facilitating the absorption of Na+. Na+ ions entering the absorptive enterocytes leave the enterocyte through Na+ pumps. Goblet cells secrete mucus to lubricate the mucosal surface and serve as a protective barrier. Enteroendocrine cells, which accumulate their secretory products in cytoplasmic granules and release them by exocytosis at the basolateral membrane upon mechanical, chemical or neural stimulation. Cells of the stem cell progeny exit the niche, initially as proliferating cells before differentiating gradually into post-mitotic specialized cells (enterocytes and goblet cells). Keep in mind that differentiated enterocytes and goblet cells are shed into the lumen within 5 days. The main function of the mucosa is the absorption of water, sodium, vitamins and minerals. The transport of sodium is active (energy-dependent), causing water to move along an osmotic gradient. As a result, the fluid chyme entering the colon is concentrated into semisolid feces. The absorptive capacity of the colon favors the uptake of many substances, including sedatives, anesthetics, and steroids. This property is of considerable therapeutic importance when medication cannot be administered through the mouth (for example, because of vomiting). Mucosa Submucosa Muscularis Serosa Tubular glands, or crypts of Lieberkühn, are oriented perpendicular to the long axis of the colon, are much deeper than in the small intestine and have a higher proportion of goblet cells. Mucosa of the large intestine the mucosa of the large intestine lacks folds or villi and contains tubular glands of Lieberkühn. Four cell types are present in the surface epithelium and tubular glands: (1) Simple columnar absorptive enterocytes with apical microvilli (striated apical border). Submucosa Mucosa Tubular gland Taeniae coli Fascicles of the outer longitudinal layer aggregate into three spaced bands called taeniae coli. Lymphatic follicles extend into the mucosa and submucosa and disrupt the continuity of the muscularis mucosae. The inner circular layers of the muscularis is well developed in contrast with the outer longitudinal layer covered by the serosa. The rectum (16-22) Lumen Lymphatic follicles are observed in the mucosa and submucosa. The follicles resemble the lymphatic follicles surrounding the crypts of the palatine tonsils. A clear difference is that the tubular glands, lined by predominant goblet cells, are not seen in the tonsils. Tubular glands are lined by abundant goblet cells the stem cell progeny at the base of the tubular glands have been considered the cells of origin of colorectal cancer. One last point: Paneth cells may be seen in the cecum, but not in the other segments of the large intestine. The muscularis has a particular feature: the bundles of its outer longitudinal layer fuse to form the taeniae coli. The taeniae coli consist of three longitudinally oriented ribbon-like bands, each 1 cm wide. The contraction of the taeniae coli and circular muscle layer draws the colon into sacculations called haustra. The serosa has scattered sacs of adipose tissue, the appendices epiploicae, which, together with the haustra, are typical of the colon. The appendix (16-21) the appendix is a diverticulum of the cecum and has layers similar to those of the large intestine. The characteristic features of the appendix are the 566 the rectum, the terminal portion of the intestinal tract, is a continuation of the sigmoid colon. The mucosa is thicker, with prominent veins, and the crypts of Lieberkühn are longer (0. At the level of the anal canal, the crypts gradually disappear and the serosa is replaced by an adventitia. A characteristic feature of the mucosa of the anal canal are 8 to 10 longitudinal anal columns. When the canal is distended with feces, the columns, sinuses and valves flatten and mucus is discharged from the sinuses to lubricate the passage of the feces. Beyond the pectinate line, the simple columnar epithelium of the rectal mucosa is replaced by a stratified squamous epithelium. Colorectal adenocarcinoma (gland-like) originates above the transformation zone; epidermoid (epidermis-like) carcinoma originates below the transformation zone (anal canal).

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