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The plate of matrix appears as a bar between the adjacent lacunae.Some of the lacunae in the cartilage are arranged in pairs separated by a thin plate of matrix.Elastic fibers (E) are also apparent in the adipose tissue (AT), between the adipocytes.It is found in the auricle of the exter-nal ear, in the auditory tube, in the epiglottis, and in part of the larynx. The elastic material imparts properties of elasticity, as distinguished from resiliency, which are not shared by hyaline cartilage. Elastic cartilage is surrounded by perichondrium, and it, too, increases in size by both ap-positional and interstitial growth. Unlike hyaline cartilage, however, elastic cartilage does not normally calcify. Elastic cartilage, epiglottis, human, H&E and orcein stains ×80. This section of the epiglottis contains elastic cartilage (EC) as the centrally located structure. The essential components of the cartilage, namely, the matrix that stains deep blue and the light, unstained lacunae surrounded by matrix, are evident in this low-magnification micrograph. The perimeter of the cartilage is covered PLATE 9 • E LASTIC CARTI LAG E KEY AT, adipose tissue E, elastic fiber EC, elastic cartilage MG, mucous gland PC, perichondrium SE, stratified squamous epithelium Elastic cartilage, epiglottis, human, H&E and orcein stains ×250; inset ×400. This shows an area of the elastic cartilage at higher magnification. The elastic fibers appear as the blue, elongate profiles within the matrix. They are most evident at the edges of the cartilage, but they are obscured in some deeper parts of the matrix, where they blend with the elastic material that forms a honeycomb about the lacunae. Elastic fibers (E) are also apparent in the adipose tissue (AT), between the adipocytes. Some of the lacunae in the cartilage are arranged in pairs separated by a thin plate of matrix. The plate of matrix appears as a bar between the adjacent lacunae.They have moved away from each other and secreted a plate of cartilage matrix by perichondrium (PC); its fibrous character is just barely visible in this figure.Also note the adipose tissue (AT) within the boundaries of the elastic cartilage.Both above and below the elastic cartilage is connective tissue, and each surface of the epiglottis is formed by stratified squamous epithelium (SE).

chEst roEntgEnography A normal or nearly normal chest x-ray often occurs in PE.Only the left upper lobe segmental artery is free of thrombus.There are filling defects in the main and segmental pulmonary arteries bilaterally (white arrows).He had developed sudden onset of chest heaviness and shortness of breath while at home.Noninvasive Imaging Modalities • vEnous ultrasonography Ultrasonography of the deep venous system relies on loss of vein compressibility as the primary criterion for DVT. When a normal vein is imaged in cross-section, it readily collapses with gentle manual pressure from the ultrasound transducer. This creates the illusion of a “wink.” With acute DVT, the vein loses its compressibility because of passive distention by acute thrombus. The diagnosis of acute DVT is even more secure when thrombus is directly visualized. It appears homogeneous and has low echogenicity (Fig. 300-4). The vein itself often appears mildly dilated, and collateral channels may be absent. Venous flow dynamics can be examined with Doppler imaging. Normally, manual calf compression causes augmentation of the Doppler flow pattern. Loss of normal respiratory variation is caused by an obstructing DVT or by any obstructive process within the pelvis. For patients with a technically poor or nondiagnostic venous ultrasound, one should consider alternative imaging modalities for DVT, such as computed tomography (CT) and magnetic resonance imaging. FIGURE 300-4 Venous ultrasound, with and without compression of the leg veins. CFA, common femoral artery; CFV, common femoral vein; GSV, great saphenous vein; LT, left. FIGURE 300-5 Large bilateral proximal PE on a coronal chest CT image in a 54-year-old man with lung cancer and brain metastases. He had developed sudden onset of chest heaviness and shortness of breath while at home. There are filling defects in the main and segmental pulmonary arteries bilaterally (white arrows). Only the left upper lobe segmental artery is free of thrombus. chEst roEntgEnography A normal or nearly normal chest x-ray often occurs in PE.chEst ct CT of the chest with intravenous contrast is the principal imaging test for the diagnosis of PE (Fig.300-5).Multidetector-row spiral CT acquires all chest images with ≤1 mm of resolution during a short breath hold.Sixth-order branches can be visualized with resolution superior to that of conventional invasive contrast pulmonary angiography.

He had severe headaches, hydrocephalus, and mental dullness.MRI with gadolinium infusion showing diffuse rheumatoid pachymeningitis in an older man with minimal systemic disease.Figure 29-7.Similar changes may be found in the spinal dura.B-waves are ballistic deflections that reflect entry of blood into the main basal arteries and conductance vessels of the brain during cardiac systole. The insert shows the dicrotic and reflected “notches” within a B-wave, (P1, P2, and P3 not all of which are always visible); an increase in P2 amplitude above P1 is indicative or reduced intracranial compliance. Figure 29-3. MRI of adult tension hydrocephalus from a congenital stenosis of the cerebral aqueduct. There is transependymal movement of water that appears as a T2 signal in a rim surrounding the lateral ventricles. The third ventricle, but not the fourth, is enlarged. Figure 29-4. CT of a patient with normal-pressure hydrocephalus. There is enlargement of all the ventricles, particularly of the frontal horns of the lateral ventricles (left), which is roughly disproportionate to the cortical atrophy (right). The frontal horn span is over 39 mm. Various formulas have been devised to quantitate the imaging features, but they are difficult to apply. Figure 29-5. Fluid-attenuated inversion recovery (FLAIR) MRI sequence in a patient man with hydrocephalus, shunt failure, and L-dopa-responsive parkinsonism. There is signal change in the dorsal midbrain and periaqueductal region. Figure 29-6. MRI after gadolinium infusion (T1 sequence) showing the widespread dural enhancement that is typical of low CSF pressure after lumbar puncture, spontaneous CSF leakage, or shunt overdrainage. Similar changes may be found in the spinal dura. Figure 29-7. MRI with gadolinium infusion showing diffuse rheumatoid pachymeningitis in an older man with minimal systemic disease. He had severe headaches, hydrocephalus, and mental dullness.Their importance derives from their great variety; the numerous neurologic symptoms caused by their size, location, and invasive qualities; the destruction and displacement of tissues in which they are situated; the elevation of intracranial pressure they cause; and, most of all, their lethality.

InsP3 then diffuses to the SR and opens the InsP3-gated Ca++ channel, thereby resulting in release of Ca++ from the SR into the myoplasm.PLC hydrolyzes the membrane phospholipid phosphatidylinositol bisphosphate (PIP2) into InsP3 and diacylglycerol.Inappropriatecontractionofsmoothmuscleisassociatedwithmanypathologicalsituations.Oneexampleissustainedvasospasmofacerebralarterythatdevelopsseveralhoursafterasubarachnoidhemorrhage.Itisthoughtthatfreeradicalsgeneratedasaresultofthehemorrhageraisemyoplasmic[Ca++]insurroundingarterialsmoothmusclecells.Theriseinmyoplasmic[Ca++]activatesMLCK,whichleadstocross-bridgephosphorylationandcontraction.Thevasoconstrictiondeprivesotherareasofthebrainofoxygenandmayleadtopermanentinjuryordeathofsurroundingneurons.Forafewdaysthecerebralarteryremainssensitivetovasoactiveagents,andthereforetreatmentwithvasodilatorsmayrestoreflow.AnincreaseinROKactivityandMPphosphorylationhasbeenobservedduringcerebralvasospasm.AdministrationofROKinhibitorspromotesrelaxationofthevasospasmanddecreasesthelevelofmyosinlight-chainphosphorylation.Thesmoothmusclecellsceasetorespondtothevasodilatorsafterseveraldays,andtheylosecontractileproteinsandsecreteextracellularcollagen.Thelumenofthearteryremainsconstrictedasaresultofstructuralandmechanicalchangesthatdonotinvolveactivecontraction. [Ca++] of smooth muscle. This differs from skeletal muscle, in which action potential–induced release of Ca++ from the SR fully activates the contractile apparatus. The role of smooth muscle SR in regulating myoplasmic [Ca++] is comparable to that of skeletal muscle. Stimulation of the cell opens SR Ca++ channels, and myoplasmic [Ca++] increases rapidly. This release is not linked to voltage sensors, as is the case in skeletal muscle, but to binding of the second messenger InsP3 to receptors in the SR. InsP3 is generated by a stimulus that acts on sarcolemmal receptors that are coupled via a guanine nucleotide–binding protein (G protein) to activate phospholipase C (PLC) (see ). PLC hydrolyzes the membrane phospholipid phosphatidylinositol bisphosphate (PIP2) into InsP3 and diacylglycerol. InsP3 then diffuses to the SR and opens the InsP3-gated Ca++ channel, thereby resulting in release of Ca++ from the SR into the myoplasm.Calcium is reaccumulated by the SR through the activity of the SERCA, although as indicated later, extrusion of Ca++ from the smooth muscle cell also contributes to the reduction in myoplasmic [Ca++].Refilling of the SR with Ca++ not only involves reaccumulation of cytosolic Ca++ but also depends on the extracellular [Ca++].

In theory, only the amount of the loading dose need be computed—not the rate of its administration—and, to a first approximation, this is so.When the time to reach steady state is appreciable, as it is for drugs with long half-lives, it may be desirable to administer a loading dose that promptly raises the concentration of drug in plasma to the target concentration.For oral dosing: If intermittent doses are given, the maintenance dose is calculated from: (See Box: Example: Maintenance Dose Calculations.) Note that the steady-state concentration achieved by continuous infusion or the average concentration following intermittent dosing depends only on clearance. The volume of distribution and the half-life need not be known in order to determine the average plasma concentration expected from a given dosing rate or to predict the dosing rate for a desired target concentration. Figure 3–6 shows that at different dosing intervals, the concentration-time curves will have different maximum and minimum values even though the average concentration will always be 10 mg/L. Estimates of dosing rate and average steady-state concentrations, which may be calculated using clearance, are independent of any specific pharmacokinetic model. In contrast, the determination of maximum and minimum steady-state concentrations requires further assumptions about the pharmacokinetic model. The accumulation factor (equation [7]) assumes that the drug follows a one-compartment model (Figure 3–2B), and the peak concentration prediction assumes that the absorption rate is much faster than the elimination rate. For the calculation of estimated maximum and minimum concentrations in a clinical situation, these assumptions are usually reasonable. When the time to reach steady state is appreciable, as it is for drugs with long half-lives, it may be desirable to administer a loading dose that promptly raises the concentration of drug in plasma to the target concentration. In theory, only the amount of the loading dose need be computed—not the rate of its administration—and, to a first approximation, this is so.If the patient is a nonsmoker and otherwise normal except for asthma, we may use the mean clearance given in Table 3–1, ie, 2.8 L/h/70 kg.Since the drug will be given as an intravenous infusion, F = 1.Dosing rate = CL × TC = 2.8 L/h/70 kg × 10 mg/L = 28 mg/h/70 kg Therefore, in this patient, the infusion rate would be 28 mg/h/ 70 kg.

A rare, peculiar, usually self-limited severe HA of the first month of life, called infantile poikilocytosis, may be associated with deficiency of glutathione peroxidase (GSHPX) due not to an inherited abnormality, but to transient nutritional deficiency of selenium, an element essential for the activity of GSHPX.When AHA develops and once its cause is recognized, in most cases, no specific treatment is needed. However, if the anemia is severe, it may be a medical emergency, especially in children, requiring immediate action, including blood transfusion. This has been the case with an antimalarial drug combination containing dapsone (called Lapdap, introduced in 2003) that has caused severe acute hemolytic episodes in children with malaria in several African countries; after a few years, the drug was taken off the market. If there is acute renal failure, hemodialysis may be necessary, but if there is no previous kidney disease, recovery is the rule. The management of NNJ associated with G6PD deficiency is no different from that of NNJ due to other causes. In cases with CNSHA, if the anemia is not severe, regular folic acid supplements and regular hematologic surveillance will suffice. It will be important to avoid exposure to potentially hemolytic drugs, and blood transfusion may be indicated when exacerbations occur, mostly in concomitance with intercurrent infection. In rare patients, regular blood transfusions may be required, in which case appropriate iron chelation should be instituted. Unlike in HS, there is no evidence of selective red cell destruction in the spleen; however, in practice, splenectomy has proven beneficial in severe cases. other abnormalities of the redox system As mentioned above, GSH is a key player in the defense against oxidative stress. Inherited defects of GSH metabolism are exceedingly rare, but each one can give rise to chronic HA (Table 129-4). A rare, peculiar, usually self-limited severe HA of the first month of life, called infantile poikilocytosis, may be associated with deficiency of glutathione peroxidase (GSHPX) due not to an inherited abnormality, but to transient nutritional deficiency of selenium, an element essential for the activity of GSHPX.How exactly its deficiency causes HA is not well understood, but a highly distinctive feature of this condition is a morphologic abnormality of the red cells known as basophilic stippling.The condition is rare, but it probably ranks third in frequency among red cell enzyme defects (after G6PD deficiency and PK deficiency).

23-8).The sheath acts to protect the vessel from injury as wires and catheters are introduced (Fig.The sheath also acts to protect the vessel from injury as guidewires (small arrows) and catheters are introduced.Hemostatic SheathsThe hemostatic sheath is a device through which endovascular procedures are performed.In addition to diameter size, guidewires come in varying lengths, usually ranging from 180 to 260 cm in length. Increasing the length of the wire always makes it more difficult to handle and increases the risk of contamination. While per-forming a procedure, it is important to maintain the guidewire across the lesion until the completion arteriogram has been sat-isfactorily completed.The stiffness of the guidewire is also an important charac-teristic. Stiff wires allow for passage of large aortic stent graft devices without kinking. They are also useful when trying to perform sheath or catheter exchanges around a tortuous artery. An example of a stiff guidewire is the Amplatz wire. Hydro-philic coated guidewires, such as the Glidewire, have become invaluable tools for assisting in difficult catheterizations. The coating is primed by bathing the guidewire in saline solution. The slippery nature of this guidewire along with its torque capa-bility significantly facilitate in difficult catheterizations. Guide-wires also come in various tip configurations. Angled tip wires like the angled Glidewire can be steered to manipulate a catheter across a tight stenosis or to select a specific branch of a vessel. The Rosen wire has a soft curled end, which makes it ideal for renal artery stenting. The soft curl of this wire prevents it from perforating small renal branch vessels.Brunicardi_Ch23_p0897-p0980.indd 90427/02/19 4:13 PM 905ARTERIAL DISEASECHAPTER 23Figure 23-8. All percutaneous endovascular procedures are per-formed through an introducer sheath (large arrow), which pro-vides an access conduit from skin to intravascular compartment. The sheath also acts to protect the vessel from injury as guidewires (small arrows) and catheters are introduced.Hemostatic SheathsThe hemostatic sheath is a device through which endovascular procedures are performed. The sheath acts to protect the vessel from injury as wires and catheters are introduced (Fig. 23-8).Sheaths are sized by their inner diameter.The most commonly used sheaths for percutaneous access have a 5to 9-French inner diameter, but with open surgical exposure of the CFA, sheaths as large as 26 French can be introduced.

Presents with shallow, rapid breathing; dyspnea with exercise; and a nonproductive cough.Causes include idiopathic interstitial pneumonias, collagen vascular disease, granulomatous disorders, drugs, hypersensitivity disorders, pneumoconiosis, and eosinophilic pulmonary syndromes.In advanced disease, cystic spaces develop in the lung periphery (“honeycombing”).Acute exacerbations: O2, inhaled β-agonists (albuterol) and anticholinergics (ipratropium, tiotropium), IV +/− inhaled corticosteroids, antibiotics. Severe cases may beneft from noninvasive ventilation. Consider intubation in the setting of severe hypoxemia or hypercapnia, impending respiratory fatigue, or changes in mental status. Chronic: Smoking cessation, supplemental O2 (if resting PaO2 is ≤ 55 mmHg or SaO2 is ≤ 89%, or in the setting of cor pulmonale, pulmonary hypertension, a hematocrit > 55%, or nocturnal hypoxia), inhaled β-agonists, AB F IGU R E 2.1 5-3. Chronic obstructive pulmonary disease. Note the hyperinfated and hyperlucent lungs, f at diaphragms, ↑ AP diameter, narrow mediastinum, and large upper bullae on (A) AP and (B) lateral CXRs. (Reproduced, with permission, from Stobo J et al. The Principles and Practice of Medicine, 23rd ed. Stamford, CT: Appleton & Lange, 1996: 135.) anticholinergics (tiotropium), systemic or inhaled corticosteroids. Give pneumococcal and fl u vaccines. Characterized by a loss of lung compliance, restrictive lung diseases result in ↑ lung stiffness and ↓ lung expansion. Table 2.15-1 and Figure 2.15-2 contrast obstructive with restrictive lung disease. The etiologies of restrictive lung disease are shown in the mnemonic PAINT. A heterogeneous group of disorders characterized by infl ammation and/or fibrosis of the interalveolar septum. In advanced disease, cystic spaces develop in the lung periphery (“honeycombing”). Causes include idiopathic interstitial pneumonias, collagen vascular disease, granulomatous disorders, drugs, hypersensitivity disorders, pneumoconiosis, and eosinophilic pulmonary syndromes. Presents with shallow, rapid breathing; dyspnea with exercise; and a nonproductive cough.■ CXR: Reticular, nodular, or ground-glass pattern; “honeycomb” pattern (severe disease).■↓TLC, ↓FVC, ↓DLCO (may be normal if the cause is extrapulmonary), normal FEV1/FVC.Serum markers of connective tissue diseases should be obtained if clinically indicated.Supportive.Avoid exposure to causative agents.

First onset in adulthood is relatively rare and is more likely to occur after a stressful or humiliating event or after life changes that require new social roles (e.g., marrying someone from a different social class, receiving a job promo- tion).Blushing is a hall- mark physical response of social anxiety disorder. The 12-month prevalence estimate of social anxiety disorder for the United States is ap- proximately 7%. Lower 12-month prevalence estimates are seen in much of the world us- ing the same diagnostic instrument, clustering around 0.5%—2.0%,' median prevalence in Europe is 2.3%. The 12-month prevalence rates in children and adolescents are comparable to those in adults. Prevalence rates decrease with age. The 12-month prevalence for older adults ranges from 2% to 5%. In general, higher rates of social anxiety disorder are found in females than in males in the general population (with odds ratios ranging from 1.5 to 2.2), and the gender difference in prevalence is more pronounced in adolescents and young adults. Gender rates are equivalent or slightly higher for males in clinical samples, and it is assumed that gender roles and social expectations play a significant role in ex- plaining the heightened help-seeking behavior in male patients. Prevalence in the United States is higher in American Indians and lower in persons of Asian, Latino, African Amer- ican, and Afro-Caribbean descent compared with non-Hispanic whites. Median age at Onset of social anxiety disorder in the United States is 13 years, and 75% of individuals have an age at onset between 8 and 15 years. The disorder sometimes emerges out of a childhood history of social inhibition or shyness in US. and European studies. On- set can also occur in early childhood. Onset of social anxiety disorder may follow a stress- ful or humiliating experience (e.g., being bullied, vomiting during a public speech), or it may be insidious, developing slowly. First onset in adulthood is relatively rare and is more likely to occur after a stressful or humiliating event or after life changes that require new social roles (e.g., marrying someone from a different social class, receiving a job promo- tion).Among individuals presenting to clinical care, the disor— der tends to be particularly persistent.Adolescents endorse a broader pattern of fear and avoidance, including of dating, compared with younger children.Older adults express social anxiety at lower levels but across a broader range of situations, whereas younger adults express higher levels of so- cial anxiety for specific situations.

The chloride channel is envisioned to have 10 membrane-spanning domains.It is also now recognized that some cases of thyrotoxic HypoKPP are caused by genetic variants in a potassium channel (Kir 2.6), whose expression is regulated by thyroid hormone.Ocular and bulbar muscles are less likely to be affected. Respiratory muscles are usually spared, but when they are involved, the condition may prove fatal. Weakness may take as long as 24 h to resolve. Life-threatening cardiac arrhythmias related to hypokalemia may occur during attacks. As a late complication, patients commonly develop severe, disabling proximal lower extremity weakness. Attacks of thyrotoxic periodic paralysis resemble those of primary HypoKPP. Despite a higher incidence of thyrotoxicosis in women, men, particularly those of Asian descent, are more likely to manifest this complication. Attacks abate with treatment of the underlying thyroid condition. A low serum potassium level during an attack, excluding secondary causes, establishes the diagnosis. Interattack muscle biopsies show the presence of single or multiple centrally placed vacuoles or tubular aggregates. Provocative tests with glucose and insulin to establish a diagnosis are usually not necessary and are potentially hazardous. type 1, the most common form, is inherited as an autosomal dominant disorder with incomplete penetrance. These patients have mutations in the voltage-sensitive, skeletal muscle calcium channel gene, CALCL1A3 (Fig. 462e-8). Approximately 10% of cases are HypoKPP type 2, arising from mutations in the voltage-sensitive sodium channel gene (SCN4A). In either instance, the mutations lead to an abnormal gating pore current that predisposes the muscle cell to depolarize when potassium levels are low. It is also now recognized that some cases of thyrotoxic HypoKPP are caused by genetic variants in a potassium channel (Kir 2.6), whose expression is regulated by thyroid hormone. The chloride channel is envisioned to have 10 membrane-spanning domains.The acute paralysis improves after the administration of potassium.Muscle strength and ECG should be monitored.Oral KCl (0.2–0.4 mmol/kg) should be given every 30 min.Only rarely is IV therapy necessary (e.g., when swallowing problems or vomiting is present).Administration of potassium in a glucose solution should be avoided because it may further reduce serum potassium levels.

More rarely, gram-negative bacilli and fungi are involved.Additional bacterial agents include enterococci and the so-called “HACEK group” (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella), all commensal in the oral cavity.The disease typically appears insidiously and—even if untreated— follows a protracted course of weeks to months; most patients recover after appropriate antibiotic therapy. Infective endocarditis can develop on previously normal valves, but cardiac abnormalities predispose to such infections; rheumatic heart disease, mitral valve prolapse, bicuspid aortic valves, and calcific valvular stenosis are all common substrates. Prosthetic heart valves (discussed later) now account for 10% to 20% of all cases of IE. Sterile platelet-fibrin deposits at sites of pacemaker lines, indwelling vascular catheters, or endocardium damage by flow “jets” stemming from preexisting cardiac disease all can be foci for bacterial seeding and development of endocarditis. Host factors such as neutropenia, immunodeficiency, malignancy, diabetes mellitus, and alcohol or intravenous drug abuse also increase the risk for IE and adversely affect outcomes. The causative organisms differ depending on the underlying risk factors; 50% to 60% of cases occurring on damaged or deformed valves are caused by Streptococcus viridans, a relatively banal group of normal oral flora. By contrast, the more virulent S. aureus (common to skin) can attack healthy as well as deformed valves and is responsible for 10% to 20% of cases overall; it also is the major offender in infections occurring in intravenous drug abusers. Additional bacterial agents include enterococci and the so-called “HACEK group” (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella), all commensal in the oral cavity. More rarely, gram-negative bacilli and fungi are involved.Foremost among the factors predisposing to endocarditis is seeding of the blood with microbes.

Of note, patients with ectopic ANP may have worsening hyponatremia if sodium intake is not concomitantly increased.Likewise, the cost of tolvaptan may be prohibitive (as high as $300 per tablet in some areas).However, there are significant limitations to the use of tolvaptan including liver injury and overly rapid correction of the hyponatremia, which can lead to irreversible neurologic injury.In some cases, the pathophysiology of the paraneoplastic syndrome is known, particularly when a hormone with biological activity is secreted by a tumor. However, in many cases, the pathophysiology is unknown. Systemic symptoms of anorexia, cachexia, weight loss (seen in 30% of patients), fever, and suppressed immunity are paraneoplastic syndromes of unknown etiology or at least not well defined. Weight loss greater than 10% of total body weight is considered a bad prognostic sign. Endocrine syndromes are seen in 12% of patients; hypercalcemia resulting from ectopic production of parathyroid hormone (PTH), or more commonly, PTH-related peptide, is the most common life-threatening metabolic complication of malignancy, primarily occurring with squamous cell carcinomas of the lung. Clinical symptoms include nausea, vomiting, abdominal pain, constipation, polyuria, 511 thirst, and altered mental status. Hyponatremia may be caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) or possibly atrial natriuretic peptide (ANP). SIADH resolves within 1-4 weeks of initiating chemotherapy in the vast majority of cases. During this period, serum sodium can usually be managed and maintained above 128 mEq/L via fluid restriction. Demeclocycline can be a useful adjunctive measure when fluid restriction alone is insufficient. Vasopressin receptor antagonists like tolvaptan also have been used in the management of SIADH. However, there are significant limitations to the use of tolvaptan including liver injury and overly rapid correction of the hyponatremia, which can lead to irreversible neurologic injury. Likewise, the cost of tolvaptan may be prohibitive (as high as $300 per tablet in some areas). Of note, patients with ectopic ANP may have worsening hyponatremia if sodium intake is not concomitantly increased.Ectopic secretion of ACTH by SCLC and pulmonary carcinoids usually results in additional electrolyte disturbances, especially hypokalemia, rather than the changes in body habitus that occur in Cushing’s syndrome from a pituitary adenoma.Treatment with standard medications, such as metyrapone and ketoconazole, is largely ineffective due to extremely high cortisol levels.

Dysarthria occasionally is the presenting symptom; rarely, progressive scoliosis, foot deformity, nystagmus, or cardiopathy is the initial sign.The lower extremities are more severely involved than the upper ones.SymptomS AnD SignS Friedreich’s ataxia presents before 25 years of age with progressive staggering gait, frequent falling, and titubation.One well-characterized family in North Carolina has a phenotypic variant known as the Haw River syndrome, now recognized to be due to the DRPLA mutation. EA types 1 and 2 are two rare dominantly inherited disorders that have been mapped to chromosomes 12p (a potassium channel gene) for type 1 and 19p for type 2. Patients with EA-1 have brief episodes of ataxia with myokymia and nystagmus that last only minutes. Startle, sudden change in posture, and exercise can induce episodes. Acetazolamide or anticonvulsants may be therapeutic. Patients with EA-2 have episodes 2629 of ataxia with nystagmus that can last for hours or days. Stress, exercise, or excessive fatigue may be precipitants. Acetazolamide may be therapeutic and can reverse the relative intracellular alkalosis detected by magnetic resonance spectroscopy. Stop codon, nonsense mutations causing EA-2 have been found in the CACNA1A gene, encoding the voltage-dependent calcium channel subunit (see “SCA6,” above). AUTOSOMAL RECESSIVE ATAXIAS Friedreich’s Ataxia This is the most common form of inherited ataxia, comprising one-half of all hereditary ataxias. It can occur in a classic form or in association with a genetically determined vitamin E deficiency syndrome; the two forms are clinically indistinguishable. SymptomS AnD SignS Friedreich’s ataxia presents before 25 years of age with progressive staggering gait, frequent falling, and titubation. The lower extremities are more severely involved than the upper ones. Dysarthria occasionally is the presenting symptom; rarely, progressive scoliosis, foot deformity, nystagmus, or cardiopathy is the initial sign.Extensor plantar responses (with normal tone in trunk and extremities), absence of deep tendon reflexes, and weakness (greater distally than proximally) are usually found.Loss of vibratory and proprioceptive sensation occurs.The median age of death is 35 years.Women have a significantly better prognosis than men.Cardiac involvement occurs in 90% of patients.

Activated TH17 cells secrete cytokines that recruit neutrophils and monocytes.In many cases, the specificity of the T cells and the mechanisms of tissue injury are inferred based on the similarity with experimental animal models of the diseases.The T cells differentiate into effector cells under the influence of various cytokines (see Figs. 5.9 5.10 ). Classical T cell–mediated hypersensitivity is a reaction of TH1 effector cells, but TH17 cells also may contribute to the reaction, especially when neutrophils are prominent in the inflammatory infiltrate. TH1 cells secrete cytokines, mainly IFN-γ, which are responsible for many of the manifestations of delayed-type hypersensitivity. IFNγ-activated (classically activated) macrophages produce substances that destroy microbes and damage tissues, and mediators that promote inflammation (Chapter 3). http://ebooksmedicine.net Hypersensitivity: Immunologically Mediated Tissue Injury143 Table 5.6 T Cell–Mediated Diseases Specificity of Pathogenic T Cells Collagen?Citrullinated self proteins? Protein antigens in myelin (e.g., myelin basic protein) Antigens of pancreatic islet β cells (insulin, glutamic acid decarboxylase, others) Enteric bacteria; self antigens? Various environmental chemicals (e.g., urushiol from poison ivy or poison oak, therapeutic drugs) Principal Mechanisms of Tissue Injury Inflammation mediated by TH17 (and TH1?) cytokines; role of antibodies and immune complexes? Inflammation mediated by TH1 and TH17 cytokines, myelin destruction by activated macrophages T cell–mediated inflammation, destruction of islet cells by CTLs Inflammation mediated by TH1 (and TH17?) cytokines Chronic arthritis with inflammation, destruction of articular cartilage Insulitis (chronic inflammation in islets), destruction of β cells; diabetes Chronic intestinal inflammation, obstruction Epidermal necrosis, dermal inflammation, causing skin rash and blisters Examples of human T cell–mediated diseases are listed. In many cases, the specificity of the T cells and the mechanisms of tissue injury are inferred based on the similarity with experimental animal models of the diseases. Activated TH17 cells secrete cytokines that recruit neutrophils and monocytes.In a previously exposed individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside.Morphologically, delayed-type hypersensitivity is characterized by the tion and inflammation.Drug reactions often manifest as skin rashes.

External to the muscle is an adventitia containing adipose tissue and blood vessels.The smooth muscle bundles of the muscularis externa are randomly oriented.There is no muscularis mucosae or submucosa.Beneath this layer is a relatively thick layer, the muscularis externa.The empty or partially filled gallbladder has numerous deep mucosal folds (Fig. 18.16). The mucosal surface consists of simple columnar epithelium (Fig. 18.17). The tall epithelial cells exhibit the following features:  Numerous, but short and not well-developed apical microvilli  Apical junctional complexes that join adjacent cells and form a barrier between the lumen and the intercellular compartment These cells closely resemble the absorptive cells of the intestine. Both cells share the above characteristics, as well as localization of Na/K–activated ATPase on their lateral plasma membranes and secretory vesicles filled with glycoproteins in their apical cytoplasm. The lamina propria of the mucosa is particularly rich in fenestrated capillaries and small venules, but there are no lymphatic vessels in this layer. The lamina propria is also very cellular, containing large numbers of lymphocytes and plasma cells. The characteristics of the lamina propria resemble those of the colon, another organ specialized for the absorption of electrolytes and water. Mucin-secreting glands are sometimes present in the lamina propria in the normal human gallbladder, especially near the neck of the organ, but they are more commonly found in FIGURE 18.16 • Photomicrograph of the wall of the gallbladder. The mucosa of the gallbladder consists of a lining of simple columnar epithelial cells and a lamina propria of loose connective tissue, which typically exhibits numerous deep folds in the mucosa. Beneath this layer is a relatively thick layer, the muscularis externa. There is no muscularis mucosae or submucosa. The smooth muscle bundles of the muscularis externa are randomly oriented. External to the muscle is an adventitia containing adipose tissue and blood vessels.175.FIGURE 18.17 • Electron micrographs of gallbladder epithelium.a.The tall columnar cells display features typical of absorptive cells, with microvilli on their apical surface, an apical junctional complex separating the lumen of the gallbladder from the lateral intercellular space, and numerous mitochondria in the apical portion of the cell.3,000. b.

New York: Garland Science; 2015.)6th ed.(Redrawn from Alberts B, et al: Molecular Biology of the Cell.These mechanisms are described in detail in the text.3.3 Cell-to-cell communication is mediated by five basic mechanisms: contact-dependent (A), paracrine (B), autocrine (C), synaptic (D), and endocrine signaling (E).• Fig.Endocrine signals are relatively slow (seconds to minutes) because time is required for diffusion and blood flow to the target cell, whereas synaptic signaling is extremely fast (milliseconds). If the response involves changes in the activity of proteins in the cell, the response may occur in milliseconds to seconds. However, if the response involves changes in gene expression and the de novo synthesis of proteins, the response may take hours to occur, and a maximal response may take days. For example, the stimulatory effect of aldosterone on sodium transport by the kidneys requires days to develop fully (see The response to a particular signaling molecule also depends on the ability of the molecule to reach a particular cell, on expression of the cognate receptor (i.e., receptors that recognize a particular signaling molecule or ligand with a high degree of specificity), and on the cytoplasmic signaling molecules that interact with the receptor. Thus signaling molecules frequently have many different effects that are dependent on the cell type. For example, the neurotransmitter acetylcholine stimulates contraction of skeletal muscle but decreases the force of contraction in heart muscle. This is because skeletal muscle and heart cells express different acetylcholine receptors. aThe acetylcholine receptor in skeletal muscle is termed nicotinic because nicotine can mimic this action of the neurotransmitter. In contrast, the acetylcholine receptor in cardiac muscle is termed muscarinic because this effect is mimicked by muscarine, an alkaloid derived from the mushroom Amanita muscaria. • Fig. 3.3 Cell-to-cell communication is mediated by five basic mechanisms: contact-dependent (A), paracrine (B), autocrine (C), synaptic (D), and endocrine signaling (E). These mechanisms are described in detail in the text. (Redrawn from Alberts B, et al: Molecular Biology of the Cell. 6th ed. New York: Garland Science; 2015.)

At therapeutic doses, about 80% of the activity of the transporter is inhibited.SSRIs allosterically inhibit the transporter by binding the SERT receptor at a site other than the serotonin binding site.Binding of intracellular K+ then results in the release of serotonin inside the cell and return of the transporter to its original conformation.For example, selegiline is available in both transdermal and sublingual forms that bypass both gut and liver. These routes decrease the risk of food interactions and provide substantially increased bioavailability. As previously noted, all currently available antidepressants enhance monoamine neurotransmission by one of several mechanisms. The most common mechanism is inhibition of the activity of SERT, NET, or both monoamine transporters (Table 30–2). Antidepressants that inhibit SERT, NET, or both include the SSRIs and SNRIs (by definition) and the TCAs. Another mechanism for increasing the availability of monoamines is inhibition of their enzymatic degradation (by the MAOIs). Additional strategies for enhancing monoamine tone include binding presynaptic autoreceptors (mirtazapine) or specific postsynaptic receptors (5-HT2 antagonists and mirtazapine). Ultimately, the increased availability of monoamines for binding in the synaptic cleft results in a cascade of events that enhance the transcription of some proteins and the inhibition of others. It is the net production of these proteins, including BDNF, glucocorticoid receptors, β adrenoceptors, and other proteins, that appears to determine the benefits as well as the toxicity of a given agent. A. Selective Serotonin Reuptake Inhibitors The serotonin transporter (SERT) is a glycoprotein with 12 trans-membrane regions embedded in the axon terminal and cell body membranes of serotonergic neurons. When extracellular serotonin binds to receptors on the transporter, conformational changes occur in the transporter and serotonin, Na+, and Cl− are moved into the cell. Binding of intracellular K+ then results in the release of serotonin inside the cell and return of the transporter to its original conformation. SSRIs allosterically inhibit the transporter by binding the SERT receptor at a site other than the serotonin binding site. At therapeutic doses, about 80% of the activity of the transporter is inhibited.SSRIs have modest effects on other neurotransmitters.Unlike TCAs and SNRIs, there is little evidence that SSRIs have prominent effects on β adrenoceptors or the norepinephrine transporter, NET.Binding to the serotonin transporter is associated with tonic TABLE 30–2 Blocking effects of some antidepressant drugs on several receptors and transporters.

1393 In Ethiopia, a combination of paromomycin (14 mg/kg per day) and sodium stibogluconate (10 mg/kg per day) is effective.Combinations should be tried.Miltefosine has been used for several months with a good initial response.In the New World, repeated 20-day courses of pentavalent antimonials are given, with an intervening drug-free period of 10 days.Diffuse Cutaneous Leishmaniasis (DCL) DCL is a rare form of leishmaniasis caused by L. amazonensis and L. mexicana in South and Central America and by L. aethiopica in Ethiopia and Kenya. DCL is characterized by the lack of a cell-mediated immune response to the parasite, the uncontrolled multiplication of which thus continues unabated. The DTH response does not develop, and lymphocytes do not respond to leishmanial antigens in vitro. DCL patients have a polarized immune response with high levels of immunosuppressive cytokines, including IL-10, transforming growth factor (TGF) β, and IL-4, and low concentrations of IFN-γ. Profound immunosuppression leads to widespread cutaneous disease. Lesions may initially be confined to the face or a limb but spread over months or years to other areas of the skin. They may be symmetrically or asymmetrically distributed and include papules, nodules, plaques, and areas of diffuse infiltration. These lesions do not ulcerate. The overlying skin is usually erythematous in pale-skinned patients. The lesions are teeming with parasites, which are therefore easy to recover. DCL does not heal spontaneously and is difficult to treat. If relapse and drug resistance are to be prevented, treatment should be continued for some time after lesions have healed and parasites can no longer be isolated. In the New World, repeated 20-day courses of pentavalent antimonials are given, with an intervening drug-free period of 10 days. Miltefosine has been used for several months with a good initial response. Combinations should be tried. 1393 In Ethiopia, a combination of paromomycin (14 mg/kg per day) and sodium stibogluconate (10 mg/kg per day) is effective.In L. (V.) braziliensis infections, cutaneous lesions may be simultaneously accompanied by mucosal spread of the disease or followed by spread years later.ML is typically caused by L. (V.) braziliensis and rarely by L. amazonensis, L. (V.) guyanensis, and L. (V.) panamensis.Young men with chronic lesions of CL are at particular risk.Overall, ~3% of infected persons develop ML.

However, there have been subsequent reports of high rates of anterior vaginal prolapse (63,64).Reported success for apical support has been good (89%–97%) with follow-up times ranging from 1 month to 11 years (51,62).Apical support procedures that have been described for use when the uterus or cervix is to be kept in place include Manchester and Gilliam procedures and fixation of the cervix to the sacrospinous ligament . The other procedures described in this section may also be used in women who desire uterine conservation. Adequate outcome data on such uterine-sparing procedures are not yet available. When the cervix is absent, in addition to repair of fibromuscular defects, both fibromuscular planes anterior and posterior to the vaginal cuff should be attached to whatever suspension is employed. The fixation of the vaginal apex to the sacrospinous ligament, the tendineus component of the coccygeus muscle, was first described in 1958 and was subsequently modified in Europe and the United States (53–56). Access is traditionally extraperitoneal via the rectovaginal space with penetration of the pararectal (Denonvillier’s fascia) at the level of the ischial spine to expose the muscle and ligament. Variations in this approach to the ligament include entrances through an anterior lateral access, an apical passage posterior to the uterosacral ligament, and a laparoscopic approach (57–59). Bilateral sacrospinous ligament suspensions have also been advocated; however, these techniques may impose a greater degree of tension on the sutures and, at times, create a band of apical vagina across the rectum at the level of the suspension (60,61). Whether this can cause defecatory dysfunction remains unknown. The advantages of the sacrospinous fixation procedure include (i) its transvaginal extraperitoneal approach, (ii) resultant posterior vaginal deflection, and (iii) the fact that it is a durable repair if performed correctly. Reported success for apical support has been good (89%–97%) with follow-up times ranging from 1 month to 11 years (51,62). However, there have been subsequent reports of high rates of anterior vaginal prolapse (63,64).Failure to address an anterior defect concurrently with suspension of the posterior apical vagina may predispose the patient to such a defect postoperatively.

Back and neck pain and stiffness are also common in PsA.Rapid ankylosis of one or more proximal interphalangeal (PIP) joints early in the course of disease is not uncommon.384-3), and there is a much greater tendency than in RA for both fibrous and bony ankylosis of small joints.Shortening of digits because of underlying osteolysis is particularly characteristic of PsA (Fig.In the original scheme of Wright and Moll, five patterns are described: (1) arthritis of the DIP joints; (2) asymmetric oligoarthritis; (3) symmetric polyarthritis similar to RA; (4) axial involvement (spine and sacroiliac joints); and (5) arthritis mutilans, a highly destructive form of FIGUrE 384-3 Characteristic lesions of psoriatic arthritis. Inflammation is prominent in the distal interphalangeal joints (left 5th, 4th, 2nd; right 2nd, 3rd, and 5th) and proximal interphalangeal joints (left 2nd, right 2nd, 4th, and 5th). There is dactylitis in the left 2nd finger and thumb, with pronounced telescoping of the left 2nd finger. Nail dystrophy (hyperkeratosis and onycholysis) affects each of the fingers except the left 3rd finger, the only finger without arthritis. (Courtesy of Donald Raddatz, MD; with permission.) disease. These patterns frequently coexist, and the pattern that persists chronically often differs from thatofthe initialpresentation. A simpler scheme in recent use contains three patterns: oligoarthritis, polyarthritis, and axial arthritis. Nail changes in the fingers or toes occur in up to 90% of patients with PsA, compared with 40% of psoriatic patients without arthritis, and pustular psoriasis is said to be associated with more severe arthritis. Several articular features distinguish PsA from other joint disorders;such hallmark featuresinclude dactylitis and enthesitis.Dactylitis occurs in >30%; enthesitis and tenosynovitis are also common and are probably present in most patients, although often not appreciated on physical examination. Shortening of digits because of underlying osteolysis is particularly characteristic of PsA (Fig. 384-3), and there is a much greater tendency than in RA for both fibrous and bony ankylosis of small joints. Rapid ankylosis of one or more proximal interphalangeal (PIP) joints early in the course of disease is not uncommon. Back and neck pain and stiffness are also common in PsA.Accompanying nail changes in the affected digits are almost always present.These joints are also often affected in the other patterns of PsA.Approximately 30% of patients have asymmetric oligoarthritis.This pattern commonly involves a knee or another large joint with a few small joints in the fingers or toes, often with dactylitis.

This inhibitory, contact-dependent signaling is mediated by the ligand Delta, which appears on the surface of the future neural cell and binds to Notch receptor proteins on the neighboring cells.When individual cells in the epithelium begin to develop as neural cells, they signal to their neighbors not to do the same.The protease complex is thought to contribute to this and other forms of Alzheimer’s disease by generating extracellular peptide fragments from a transmembrane neuronal protein; the fragments accumulate in excessive amounts and form aggregates of misfolded protein called amyloid plaques, which may injure nerve cells and contribute to their degeneration and loss. Both Notch and Delta are glycoproteins, and their interaction is regulated by the glycosylation of Notch. The Fringe family of glycosyl transferases, in particular, adds extra sugars to the O-linked oligosaccharide (discussed in Chapter 13) on Notch, which alters the specificity of Notch for its ligands. This has provided the first example of the modulation of ligand–receptor signaling by differential receptor glycosylation. Wnt Proteins Bind to Frizzled Receptors and Inhibit the Degradation of β-Catenin Wnt proteins are secreted signal molecules that act as local mediators and morphogens to control many aspects of development in all animals that have been studied. They were discovered independently in flies and in mice: in Drosophila, the Wingless (Wg) gene originally came to light because of its role as a morphogen Figure 15–58 lateral inhibition mediated by Notch and Delta during neural cell development in Drosophila. When individual cells in the epithelium begin to develop as neural cells, they signal to their neighbors not to do the same. This inhibitory, contact-dependent signaling is mediated by the ligand Delta, which appears on the surface of the future neural cell and binds to Notch receptor proteins on the neighboring cells.In other cases, additional factors interact with Delta or Notch to make some cells susceptible to the lateral inhibition signal and others unresponsive to it.

70-10) or primary irritant dermatitis.Erythematous papules and vesicles can occur in many conditions, but their arrangement in a specific linear array suggests an external etiology such as allergic contact dermatitis (Fig.Likewise, the arrangement of individual lesions is important.70-9).Once the distribution of the lesions has been established, the nature of the primary lesion FIguRE 70-3 A schematic representation of several common primary skin lesions (see Table 70-1). must be determined. Thus, when lesions are distributed on elbows, knees, and scalp, the most likely possibility based solely on distribution is psoriasis or dermatitis herpetiformis (Figs. 70-7 and 70-8, respectively). The primary lesion in psoriasis is a scaly papule that soon forms erythematous plaques covered with a white scale, whereas that of dermatitis herpetiformis is an urticarial papule that quickly becomes a small vesicle. In this manner, identification of the primary lesion directs the examiner toward the proper diagnosis. Secondary changes in skin can also be quite helpful. For example, scale represents excessive epidermis, while crust is the result of a discontinuous epithelial cell layer. Palpation of skin lesions can yield insight into the character of an eruption. Thus, red papules on the lower extremities that blanch with pressure can be a manifestation of many different diseases, but hemorrhagic red papules that do not blanch with pressure indicate palpable purpura characteristic of necrotizing vasculitis (Fig. 70-4). The shape of lesions is also an important feature. Flat, round, erythematous papules and plaques are common in many cutaneous diseases. However, target-shaped lesions that consist in part of erythematous plaques are specific for erythema multiforme (Fig. 70-9). Likewise, the arrangement of individual lesions is important. Erythematous papules and vesicles can occur in many conditions, but their arrangement in a specific linear array suggests an external etiology such as allergic contact dermatitis (Fig. 70-10) or primary irritant dermatitis.As in other branches of medicine, a complete history should be obtained to emphasize the following features: 1.Evolution of lesions a.Site of onset b.Manner in which the eruption progressed or spread c. d. Periods of resolution or improvement in chronic eruptions 2.Symptoms associated with the eruption a. Itching, burning, pain, numbness b.

The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both quality of life and mortality.In many cases, patients whose primary complaint is dyspnea on exertion are frequently misdiagnosed with more common diseases such as asthma or chronic obstructive pulmonary 1655 disease.Microsurgical lymphaticovenous anastomotic procedures have been performed to rechannel lymph flow from obstructed lymphatic vessels into the venous system. Limb reduction procedures to resect subcutaneous tissue and excessive skin are performed occasionally in severe cases of lymphedema to improve mobility. Therapeutic lymphangiogenesis has been studied in rodent models of lymphedema, but not as yet in humans. Overexpression of vascular endothelial growth factor (VEGF) C generates new lymphatic vessels and improves lymphedema in a murine model of primary lymphedema, and administration of recombinant VEGF-C or VEGF-D stimulated lymphatic growth in preclinical models of post-surgical lymphedema. Clinical trials in patients with lymphedema are required to determine efficacy of gene transfer (cell-based) therapies for lymphedema. Pulmonary Hypertension Aaron B. Waxman, Joseph Loscalzo Pulmonary hypertension (PH) is a spectrum of diseases involving the pulmonary vasculature, and is defined as an elevation in pulmonary arterial pressures (mean pulmonary artery pressure >22 mmHg). Pulmonary arterial hypertension (PAH) is a relatively rare form of 304 PH and is characterized by symptoms of dyspnea, chest pain, and syncope. If left untreated, the disease carries a high mortality rate, with the most common cause of death being decompensated right heart failure. There have been significant advances in this field in regard to understanding the pathogenesis, diagnosis, and classification of PAH. Despite these significant advances, there is still a substantial delay in diagnosis of up to 2 years. In many cases, patients whose primary complaint is dyspnea on exertion are frequently misdiagnosed with more common diseases such as asthma or chronic obstructive pulmonary 1655 disease. The availability of newer drugs has resulted in a radical change in the management of this disease with significant improvement in both quality of life and mortality.Clinicians should be able to recognize the signs and symptoms of PH and to complete a systematic workup in patients suspected of having it.In this way, early diagnosis, prompt treatment, and improved outcomes for patients become achievable.Vasoconstriction, vascular proliferation, thrombosis, and inflammation appear to underlie the development of PAH (Fig.304-1).

Associated symptoms such as dys-phonia, dysphagia, and dyspnea are common.The typical patient has a long-standing neck mass, which rapidly enlarges and may be painful.Women are more commonly affected, and the majority of tumors present in the seventh and eighth decade of life.Children with MEN2A and mutations at codon 634 (designated high-risk) are advised to undergo thyroidectomy at <5 years of age, and those with MEN2B-related mutations (designated highest-risk) should undergo the procedure before age 1. Central neck dissection can be avoided in children who are RET-positive and calcitonin-negative with a normal ultrasound examination. When the cal-citonin is increased or the ultrasound suggests a thyroid cancer, a prophylactic central neck dissection is indicated.Postoperative Follow-Up and Prognosis. Patients are fol-lowed by annual measurements of calcitonin and CEA levels, in addition to history and physical examination. Other modalities used to localize recurrent disease include ultrasound, CT, MRI, and more recently, FDG-PET/CT scans. Prognosis is related to disease stage. The 10-year survival rate is approximately 80% but decreases to 45% in patients with lymph node involvement. Survival also is significantly influenced by disease type. It is best in patients with non-MEN familial MTC, followed by those with MEN2A, and then those with sporadic disease. Progno-sis is the worst (survival of 35% at 10 years) in patients with MEN2B. Performing prophylactic surgery in RET oncogene mutation carriers not only improves survival rates but also ren-ders most patients calcitonin free.Anaplastic Carcinoma Anaplastic carcinoma accounts for approximately 1% of all thyroid malignancies in the United States. Women are more commonly affected, and the majority of tumors present in the seventh and eighth decade of life. The typical patient has a long-standing neck mass, which rapidly enlarges and may be painful. Associated symptoms such as dys-phonia, dysphagia, and dyspnea are common.38-21).Lymph nodes usually are palpable at presentation.Evidence of metastatic spread also may be present.Diagnosis is confirmed by FNAB revealing char-acteristic giant and multinucleated cells.Differential diagnoses on FNA can include lymphomas, medullary carcinomas, direct extension from a laryngeal carcinoma, or other metastatic car-cinomas or melanoma.

The half-lives of many benzodiazepines and barbiturates increase by 50–150% between ages 30 and 70.Others relate to economic stresses associated with greatly reduced income and, frequently, increased expenses due to illness.One of the most important changes is the loss of a spouse.Clinical studies have supported the idea that the elderly are more sensitive to some sedative-hypnotics and analgesics. In addition, some data from animal studies suggest actual changes with age in the characteristics or numbers of a few receptors. The most extensive studies suggest a decrease in responsiveness to β-adrenoceptor agonists. Other examples are discussed below. Important homeostatic control mechanisms appear to be blunted in the elderly. Since homeostatic responses are often significant contributors to the overall response to a drug, these physiologic alterations may change the pattern or intensity of drug response. In the cardiovascular system, the cardiac output increment required by mild or moderate exercise is successfully provided until at least age 75 (in individuals without obvious cardiac disease), but the increase is the result primarily of increased stroke volume in the elderly and not tachycardia, as in young adults. Average blood pressure goes up with age (in most Western countries), but the incidence of symptomatic orthostatic hypotension also increases markedly. It is thus particularly important to check for orthostatic hypotension (>20 mm Hg drop in systolic blood pressure on standing) on every visit. Similarly, the average 2-hour postprandial blood glucose level increases by about 1 mg/ dL for each year of age above 50. Temperature regulation is also impaired, and hypothermia is poorly tolerated by the elderly. Major changes in the conditions of daily life accompany the aging process and have an impact on health. Some of these (eg, forgetting to take one’s pills) are the result of cognitive changes associated with vascular or other pathology. One of the most important changes is the loss of a spouse. Others relate to economic stresses associated with greatly reduced income and, frequently, increased expenses due to illness. The half-lives of many benzodiazepines and barbiturates increase by 50–150% between ages 30 and 70.For some of the benzodiazepines, both the parent molecule and its metabolites (produced in the liver) are pharmacologically active (see Chapter 22).The age-related decline in renal function and liver disease, if present, both contribute to the reduction in elimination of these compounds.In addition, an increased volume of distribution has been reported for some of these drugs.

Mechanisms of Graft Rejection Graft rejection is classified into hyperacute, acute, and chronic, on the basis of clinical and pathologic features.Predictably, these strong reactions can destroy grafts rapidly, and their control requires powerful immunosuppressive agents.For this reason, immune responses to allografts are stronger than responses to pathogens.The graft antigens are either presented directly to recipient T cells by graft APCs, or the graft antigens are picked up by host APCs, processed (like any other foreign antigen), and presented to host T cells. These are called the direct and indirect pathways of recognition of alloantigens. Both lead to the activation of CD8+ T cells, which develop into CTLs, and CD4+ T cells, which become cytokine-producing effector cells, mainly TH1 cells. We do not know the relative importance of these pathways in the rejection of allografts. The direct pathway may be most important for CTL-mediated acute rejection, and the indirect pathway may play a greater role in chronic rejection, described later. http://ebooksmedicine.net A 1.0 cm B C D Fig. 5.30 IgG4-relateddisease:representativelesions.(A)Bileductshowingsclerosingcholangitis.(B)Scleroticareaofthebileductwithstoriformfibrosis.(C)Submandibularglandwithinfiltratesoflymphocytesandplasmacellsandwhorlsoffibrosis.(D)SectionofaninvolvedlacrimalglandstainedwithanantibodyagainstIgG4,showinglargenumbersofIgG4-producingplasmacells. (From Kamisawa T,Zen Y,Pillai S,et al:IgG4-related disease. Lancet385:1460, 2015.) The frequency of T cells that can recognize the foreign antigens in a graft is much higher than the frequency of T cells specific for any microbe. For this reason, immune responses to allografts are stronger than responses to pathogens. Predictably, these strong reactions can destroy grafts rapidly, and their control requires powerful immunosuppressive agents. Mechanisms of Graft Rejection Graft rejection is classified into hyperacute, acute, and chronic, on the basis of clinical and pathologic features.Each type of rejection is mediated by a particular kind of immune response.In the following discussion, the description of the morphology of rejection is limited to kidney allografts, but similar changes are seen in other organ transplants.• Hyperacute rejection is mediated by preformed antibodies specific for antigens on graft endothelial cells.

The clinician develops rapport with the child by engaging the child in developmentally appropriate conversation or play, perhaps providingtoys while interviewing the parents, and being sensitive to thefears the child may have.Rapport usually can be established quickly if the parents sense that the clinician respects them and is genuinelyinterested in listening to their concerns.Nonetheless the health care provider should be the coordinator of the testing and evaluation performed by other specialists (e.g., psychologists, psychiatrists, developmental pediatricians, and educational professionals). Ignorance of the environmental influences on child behavior may result in ineffective or inappropriate management Congenital hearing loss in first cousin or closer relative Bilirubin level of ≥20 mg/dL Congenital rubella or other nonbacterial intrauterine infection Defects in the ear, nose, or throat Birth weight of ≤1500 g Multiple apneic episodes Exchange transfusion Meningitis Five-minute Apgar score of ≤5 Persistent fetal circulation (primary pulmonary hypertension) Treatment with ototoxic drugs (e.g., aminoglycosides and loop Health (past and current) Developmental status Temperament (e.g., difficult, slow to warm up) Coping mechanisms Misinterpretations of stage-related behaviors Mismatch of parental expectations and characteristics of child Mismatch of personality style between parent and child Parental characteristics (e.g., depression, lack of interest, rejection, Stress (e.g., marital discord, unemployment, personal loss) Support (e.g., emotional, material, informational, child care) Poverty Racism (or both). Table 8-4 lists some contextual factors that should be considered in the etiology of a child’s behavioral or developmental problem. Building rapport with the parents and the child is a prerequisite for obtaining the often sensitive information thatis essential for understanding a behavioral or developmentalissue. Rapport usually can be established quickly if the parents sense that the clinician respects them and is genuinelyinterested in listening to their concerns. The clinician develops rapport with the child by engaging the child in developmentally appropriate conversation or play, perhaps providingtoys while interviewing the parents, and being sensitive to thefears the child may have.Similar to their parents,children feel more comfortable if they are greeted by name and involved in pleasant interactions before they are askedsensitive questions or threatened with examinations.Youngchildren can be engaged in conversation on the parent’s lap,which provides security and places the child at the eye levelof the examiner.

B. Medial wall of right nasal cavity.A. Lateral wall of right nasal cavity.8.245 Innervation of the nasal cavities.Nasal vein in foramen cecumDrainage to cavernoussinus in cranial cavityDrainage to pterygoid plexusin infratemporal fossaDrainage to facial vein Fig.8.244 Venous drainage of the nasal cavities.NaresAMajor alar cartilageMinor alar cartilagesInferior nasal spine of maxillaConnective tissueSeptal cartilageBOrbitAttachment to frontalprocess of maxillaNasalis muscleAttachment to maxillaDepressor septi nasiNarisLevator labii superioris alaeque nasi Fig. 8.241 Choanae (posterior view). A. Overview. B. Magnified view. Ala of vomerSphenoidal rostrumSphenoidal process of palatine bonePalatine boneMaxillaPalatovaginal canalVomerBAVomerSphenoid boneMedial pterygoidplate of sphenoidHorizontal plate of palatine bonePyramidal process of palatine boneOral cavityChoanaeChoanaeVaginal process of medial pterygoid plate Fig. 8.242 Gateways to the nasal cavities. Fig. 8.243 Arterial supply of the nasal cavities. A. Lateral wall of the right nasal cavity. B. Septum (medial wall of right nasal cavity). ABAnterior ethmoidal arteryPosterior ethmoidal arterySuperior conchaMiddle conchaInferior conchaGreater palatine arteryPosterior lateral nasalbranches of sphenopalatine arterySphenopalatine arteryAlar branch oflateral nasal arteryExternal nasalartery from anteriorethmoidal arterySeptal branch ofanterior ethmoidal arterySeptal branch ofposterior ethmoidal arteryArea of significantanastomoses (proneto “nosebleeds”)Posterior septal branch ofsphenopalatine arteryTerminal part ofgreater palatine arterySeptal branch from nasalartery from superior labial artery Fig. 8.244 Venous drainage of the nasal cavities. Nasal vein in foramen cecumDrainage to cavernoussinus in cranial cavityDrainage to pterygoid plexusin infratemporal fossaDrainage to facial vein Fig. 8.245 Innervation of the nasal cavities. A. Lateral wall of right nasal cavity. B. Medial wall of right nasal cavity.8.246 Lymphatic drainage of the nasal cavities.Fig.8.247 Oral cavity.A.Relationship to other cavities.B.Oral vestibule and oral cavity proper.Fig.8.248 Base and lateral aspects of the skull.A.Features in the base of the skull related to structures associated with the oral cavity.B. Styloid process of the temporal bone.

The age-adjusted lower extremity amputation rate in diabet-ics (5.0 per 1000 diabetics) was approximately 28 times that of people without diabetes (0.2 per 1000 people).59 Improved patient education and medical management, early detection of foot problems, and prompt intervention play important roles in improving the chances of limb preservation.60The best approach to managing diabetic patients with lower extremity wounds is to involve a multidisciplinary team composed of a plastic and reconstructive surgeon, a vascular surgeon, an orthopedic surgeon, a podiatrist, an endocrinolo-gist specializing in diabetes, a nutritionist, and a physical or Brunicardi_Ch45_p1967-p2026.indd 201401/03/19 6:31 PM 2015PLASTIC AND RECONSTRUCTIVE SURGERYCHAPTER 45occupational therapist. This brings together the greatest level of expertise to manage bone and soft tissue issues as well as the underlying disease and medical comorbidities. Treatment begins with rigorous control of blood glucose levels and a thor-ough assessment of comorbidities. In addition to careful detail-ing of the extent of the wound and the tissues involved, physical examination documents sensory deficits and vascular status. Plain radiographs, MRI, bone scintigraphy, and angiography or duplex Doppler ultrasound imaging may be indicated. A patient with significant vascular disease may be a candidate for lower extremity endovascular revascularization or open bypass.61 Nerve conduction studies may diagnose surgically reversible neuropathies at compressive sites and aid in decisions about whether to perform sensory nerve transfers to restore plantar sensibility.60 Antibiotic and fungal therapies should be guided by tissue culture results.Surgical management starts with debridement of devital-ized tissues.Negative pressure wound dressings may be appropriate for superficial defects in an effort to allow secondary healing or as a temporizing measure until definitive wound closure can be achieved.Skin grafts might be indicated at times but cannot be expected to provide durable cov-erage in weight-bearing or high-shear areas.

The swollen infected liver cells eventually burst, discharging motile merozoites into the bloodstream.By this amplification process (known as intrahepatic or preerythrocytic schizogony or merogony), a single sporozoite eventually may produce from 10,000 to >30,000 daughter merozoites.Although there are many successful new control initiatives as well as promising research initiatives, malaria remains today, as it has been for centuries, a heavy burden on tropical communities, a threat to nonendemic countries, and a danger to travelers. Six species of the genus Plasmodium cause nearly all malarial infections in humans. These are P. falciparum, P. vivax, two morphologically identical sympatric species of P. ovale (as suggested by recent evidence), P. malariae, and—in Southeast Asia—the monkey malaria parasite P. knowlesi (Table 248-1). While almost all deaths are caused aIn Southeast Asia, the monkey malaria parasite P. knowlesi also causes disease in humans. Young ring forms resemble those of P. falciparum, while older trophozoites resemble those of P. malariae. Reliable identification requires molecular genotyping. bParasitemias of >2% are suggestive of P. falciparum infection. Antibodies to sporozoites block invasion of hepatocytes Antibodies to merozoites block invasion of RBCs Antibodies to malaria "toxins" Antibodies to parasite antigens on infected RBCs block cytoadherence to endothelium Antibodies block fertilization, development, and invasion by falciparum malaria, P. knowlesi and occasionally P. vivax also can cause severe illness. Human infection begins when a female anopheline mosquito inoculates plasmodial sporozoites from its salivary gland during a blood meal (Fig. 248-1). These microscopic motile forms of the malaria parasite are carried rapidly via the bloodstream to the liver, where they invade hepatic parenchymal cells and begin a period of asexual reproduction. By this amplification process (known as intrahepatic or preerythrocytic schizogony or merogony), a single sporozoite eventually may produce from 10,000 to >30,000 daughter merozoites. The swollen infected liver cells eventually burst, discharging motile merozoites into the bloodstream.When the parasites reach densities of ~50/μL of blood (~100 million parasites in the blood of an adult), the symptomatic stage of the infection begins.In P. vivax and P. ovale infections, a proportion of the intrahepatic forms do not divide immediately but remain inert for a period ranging from 3 weeks to ≥1 year before reproduction begins.

Reports of successful pregnancy in women with GSD III suggest that fertility is normal.Polycystic ovaries are common in GSD III, and some patients develop features of polycystic ovarian syndrome, such as hirsutism and irregular menstrual cycles.Patients with type IIIa disease may experience muscle weakness in childhood that can become severe after the third or fourth decade of life.Type III GSD (Debrancher Deficiency, Limit Dextrinosis) Type III GSD is an autosomal recessive disorder caused by a deficiency of glycogen debranching enzyme. Debranching and phosphorylase enzymes are responsible for complete degradation of glycogen. When the debranching enzyme is defective, glycogen breakdown is incomplete. Abnormal glycogen accumulates with short outer chains and resembles dextrin. CliniCal and laboratory findings Deficiency of glycogen debranching enzyme causes hepatomegaly, hypoglycemia, short stature, variable skeletal myopathy, and cardiomyopathy. The disorder usually involves both liver and muscle and, in such cases, is termed type IIIa GSD. However, in ~15% of patients, the disease appears to involve only the liver and is classified as type IIIb. Hypoglycemia and hyperlipidemia occur in children. In type III disease (as opposed to type I disease), fasting ketosis can be prominent, aminotransferase levels are elevated, and blood lactate and uric acid concentrations are usually normal. Serum creatine kinase (CK) levels can sometimes be used to identify patients with muscle involvement, but normal levels do not rule out muscle enzyme deficiency. In most patients with type III disease, hepatomegaly improves with age; however, liver cirrhosis and hepatocellular carcinoma may occur in late adulthood. Hepatic adenomas may occur, although less commonly than in GSD I. Left ventricular hypertrophy and life-threatening arrhythmias have been reported. Patients with type IIIa disease may experience muscle weakness in childhood that can become severe after the third or fourth decade of life. Polycystic ovaries are common in GSD III, and some patients develop features of polycystic ovarian syndrome, such as hirsutism and irregular menstrual cycles. Reports of successful pregnancy in women with GSD III suggest that fertility is normal.In contrast, patients with type IIIb have debranching enzyme deficiency in the liver but not in muscle.The liver has distended hepatocytes due to glycogen buildup; areas of fibrosis are also noted very early in the disease course.In the past, definitive assignment of subtype required enzyme assays in both liver and muscle.

This means that there are physical changes within the nervous system that perpetuate the pain cycles, and these can be targeted both by medications (chronic pain drugs) and mind skills including CBT and mindfulness.PVD is considered a chronic pain syndrome, with features suggesting both central and peripheral sensitization within the nervous system.Inclusion of the partner in the assessment and evaluation of chronic dyspareunia allows his feelings to be addressed and his compliance with nonpenetrative sex encouraged. The couple rendered emotionally distant because of chronic dyspareunia may find it difficult to adapt to alternative forms of lovemaking. Provoked Vestibulodynia PVD is defined as pain on vestibular touch (from tampon, examining finger, penis, tight seam on clothing, etc.) where physical findings are limited to variable (possibly absent) vestibular erythema and the presence of allodynia (feeling a burning pain from the touch Descending excitation? Descending inhibition? Tricyclics, sensory nerves WBC releaseIncreased afferent input cytokines tryptase,from hypertonic pelvic bradykinin, stimulatingmuscles sensory nerves Cromolyn, lidocaine Figure 11.4 Schematic of proposed pathophysiological mechanisms underlying the chronic pain of vulvar vestibulitis syndrome and therapeutic interventions. WBC, white blood cells. stimulus) on localized areas around the outer edge of the hymen and inner edge of the labia minora where the two meet. The whole introital circumference may be affected: typically the lower part (lower horseshoe or 4 to 8 o’clock location) is involved along with the areas immediately around the openings of Skene’s ducts. Typically pelvic muscle tone is heightened. This is the most common cause of dyspareunia seen in clinics, with at least 50% of women reporting lifelong symptoms and others acquiring them after possibly multiple occasions of painless intercourse. PVD is considered a chronic pain syndrome, with features suggesting both central and peripheral sensitization within the nervous system. This means that there are physical changes within the nervous system that perpetuate the pain cycles, and these can be targeted both by medications (chronic pain drugs) and mind skills including CBT and mindfulness.Women with PVD report higher levels of perfectionism, reward dependency, fear of negative evaluation, and harm avoidance, higher levels of trait anxiety, and shyness (55).Higher rates of depression and anxiety disorders are found in women with PVD compared to controls.

This is termed a patent or persistent ductus arteriosus (PDA).Occasionally, the ductus arteriosus, which connects the left branch of the pulmonary artery to the inferior aspect of the aortic arch, fails to close at birth.The advent of cardiopulmonary bypass was crucial in delivering highly satisfactory surgical results.Most affected infants require surgical intervention.These lesions are most frequent in the membranous portion of the septum and they allow blood to flow from the left ventricle (higher pressure) to the right ventricle (lower pressure), leading to an abnormal communication between the systemic and pulmonary circulation. This leads to right ventricular hypertrophy, increased pulmonary blood flow, elevated arterial pulmonary pressure, and increased blood volume returning to the left ventricle, causing its dilation. Increased pulmonary pressure in most severe cases may cause pulmonary edema. If large enough and left untreated, VSDs can produce marked clinical problems that might require surgery. VSD may be an isolated abnormality or part of a syndromic constellation, such as the tetralogy of Fallot. The tetralogy of Fallot, the most common cyanotic congenital heart disorder diagnosed soon after birth, classically consists of four abnormalities: pulmonary stenosis, VSD, overriding aorta (originating to a varying degree from the right ventricle), and right ventricular hypertrophy. The underdevelopment of the right ventricle and pulmonary stenosis reduce blood flow to the lungs, leading to reduced volume of oxygenated blood returning to the heart. The defect in the interventricular septum causes mixing of oxygenated and nonoxygenated blood. The mixed blood is then delivered by the aorta to the major organs, resulting in poor oxygenation and cyanosis. Infants can present with cyanosis at birth or develop episodes of cyanosis while feeding or crying (tet spells). Most affected infants require surgical intervention. The advent of cardiopulmonary bypass was crucial in delivering highly satisfactory surgical results. Occasionally, the ductus arteriosus, which connects the left branch of the pulmonary artery to the inferior aspect of the aortic arch, fails to close at birth. This is termed a patent or persistent ductus arteriosus (PDA).The prognosis in patients with isolated PDA is extremely good, as most do not have any major sequelae after surgical closure.All of these defects produce a left-to-right shunt, indicating that oxygenated blood from the left side of the heart is being mixed with deoxygenated blood from the right side of the heart before being recirculated into the pulmonary circulation.

Combination of first and second line therapies c. Combination chemotherapyBrunicardi_Ch04_p0103-p0130.indd 10829/01/19 11:05 AM 109HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia.Chemotherapy or radiation therapye. Acute alcohol intoxicationf. Viral infections2. Decreased survivala. Immune-mediated1) Idiopathic thrombocytopenia (ITP)2) Heparin-induced thrombocytopenia3) Autoimmune disorders or B-cell malignancies4) Secondary thrombocytopeniab. Disseminated intravascular coagulation (DIC)c. Related to platelet thrombi1) Thrombocytopenic purpura (TTP)2) Hemolytic uremic syndrome (HUS)3. Sequestrationa. Portal hypertensionb. Sarcoidc. Lymphomad. Gaucher’s DiseaseB. Qualitative Disorders1. Massive transfusion2. Therapeutic platelet inhibitors3. Disease statesa. Myeloproliferative disordersb. Monoclonal gammopathiesc. Liver diseaseTable 4-2Management of idiopathic thrombocytopenic purpura (ITP) in adultsFirst line: a. Corticosteroids: Longer courses of corticosteroids are preferred over shorter courses of corticosteroids b. Intravenous immunoglobulin (IVIG) or anti-D immunoglobulin: the dose should initially be 1 g/kg as a one-time dose. This dosage may be repeated if necessarySecond line: a. Splenectomy b. Rituximab, an anti-CD 20 monoclonal antibody c. Thrombopoietin (TPO) receptor agonists d. Immunosuppressive agentsThird line: (failing first and second line therapy) a. Thrombopoietin (TPO) receptor agonists b. Combination of first and second line therapies c. Combination chemotherapyBrunicardi_Ch04_p0103-p0130.indd 10829/01/19 11:05 AM 109HEMOSTASIS, SURGICAL BLEEDING, AND TRANSFUSIONCHAPTER 4Heparin-induced thrombocytopenia (HIT) is a form of drug-induced immune thrombocytopenia.HIT should be suspected if the platelet count falls to less than 100,000 or if it drops by 50% from baseline in a patient receiv-ing heparin.While HIT is more common with full-dose unfrac-tionated heparin (1% to 3%), it can also occur with prophylactic doses or with low molecular weight heparins.

terminator Signal in bacterial DNA that halts transcription; in eukaryotes, transcription terminates after cleavage and polyadenylation of the newly synthesized RNA.terminally differentiated A cell at the limit of cell determination, being one of the highly specialized cell types of the adult body.Typically the result either of cell fusion or of a series of incomplete division cycles in which the nuclei divide but the cell does not. TATA box Sequence in the promoter region of many eukaryotic genes that binds a general transcription factor (TFIID) and hence specifies the position at which transcription is initiated. (Figure 6–14) T cell receptor (TCR) Transmembrane receptor for antigen on the surface of T lymphocytes, consisting of an immunoglobulin-like heterodimer. (Figure 24–32) T-cell-mediated immune response Any adaptive immune response mediated by antigen-specific T cells. telomerase Enzyme that elongates telomere sequences in DNA, which occur at the ends of eukaryotic chromosomes. telomere End of a chromosome, associated with a characteristic DNA sequence that is replicated in a special way. Counteracts the tendency of the chromosome otherwise to shorten with each round of replication. From Greek telos, end, and meros, portion. telomere End of a chromosome, associated with a characteristic DNA sequence that is replicated in a special way. Counteracts the tendency of the chromosome otherwise to shorten with each round of replication. From Greek telos, end. telophase Final stage of mitosis in which the two sets of separated chromosomes decondense and become enclosed by nuclear envelopes. (Panel 17–1, pp. 980–981) template Single strand of DNA or RNA whose nucleotide sequence acts as a guide for the synthesis of a complementary strand. (Figure 1–3) terminal differentiation The limit of cell determination when a cell forms one of the highly specialized cell types of the adult body. terminally differentiated A cell at the limit of cell determination, being one of the highly specialized cell types of the adult body. terminator Signal in bacterial DNA that halts transcription; in eukaryotes, transcription terminates after cleavage and polyadenylation of the newly synthesized RNA.TH1 cell A type of effector helper T cell that secretes interferon-γ to help activate macrophages and induces B cells to switch the class of antibody they make.(Figure 24–44) TH17 cell A type of effector helper T cell that secretes IL17, which recruits neutrophils and stimulates an inflammatory response.

This condition may require supplementation with vitamin K to correct the bleeding tendency.If the bacterial population in the gut is decreased (for example, by antibiotics), the amount of endogenously formed vitamin is decreased, and this can lead to hypoprothrombinemia in the marginally malnourished individual (for example, a debilitated geriatric patient).Prothrombin interaction with membranes: The Gla residues are good chelators of positively charged calcium ions, because of their two adjacent, negatively charged carboxylate groups. With prothrombin, for example, the prothrombin–calcium complex is able to bind to negatively charged membrane phospholipids on the surface of damaged endothelium and platelets. Attachment to membrane increases the rate at which the proteolytic conversion of prothrombin to thrombin can occur (Fig. 28.27). 3. γ-Carboxyglutamate residues in other proteins: Gla residues are also present in proteins other than those involved in forming a blood clot. For example, osteocalcin and matrix Gla protein of bone and proteins C and S (involved in limiting the formation of blood clots) also undergo γcarboxylation. Figure28.27RoleofvitaminKinbloodcoagulation.CO2=carbondioxide. B. Distribution and requirement Vitamin K is found in cabbage, kale, spinach, egg yolk, and liver. The adequate intake for vitamin K is 120 µg/day for adult males and 90 µg for adult females. There is also synthesis of the vitamin by the gut microbiota. C. Clinical indications for vitamin K 1. Deficiency: A true vitamin K deficiency is unusual because adequate amounts are generally obtained from the diet and produced by intestinal bacteria. If the bacterial population in the gut is decreased (for example, by antibiotics), the amount of endogenously formed vitamin is decreased, and this can lead to hypoprothrombinemia in the marginally malnourished individual (for example, a debilitated geriatric patient). This condition may require supplementation with vitamin K to correct the bleeding tendency.Consequently, their use in treatment is usually supplemented with vitamin K. Deficiency can also affect bone health.2.

The WHO estimates that ~6 million people have been blinded by trachoma and that ~1.3 million people in developing countries still suffer from preventable blindness due to trachoma; certainly hundreds of millions live in trachoma-endemic areas.In Seattle, women at a large health maintenance organization who were screened for chlamydial infection on a routine basis had a lower incidence of symptomatic PID than did women who received standard care and underwent more selective screening. In settings with low to moderate prevalence, the prevalence at which selective screening becomes more cost-effective than universal screening must be defined. Most studies have concluded that universal screening is preferable in settings with a chlamydial prevalence of >3–7%. Depending on the criteria used, selective screening is likely to be more cost-effective when prevalence falls below 3%. Nearly all regions of the United States have now initiated screening programs, particularly in family planning and STD clinics. Along with single-dose therapy, the availability of highly sensitive and specific diagnostic NAATs using urine specimens and self-obtained vaginal swabs makes it feasible to mount an effective nationwide Chlamydia control program, with screening of high-risk individuals in traditional health-care settings and in novel outreach and community-based settings. The U.S. Preventive Services Task Force has given C. trachomatis screening a Grade A recommendation, which means that private insurance and Medicare will cover its cost under the Affordable Care Act. TRACHOMA Epidemiology Trachoma—a sequela of ocular disease in developing countries—continues to be a leading cause of preventable infectious blindness worldwide. The WHO estimates that ~6 million people have been blinded by trachoma and that ~1.3 million people in developing countries still suffer from preventable blindness due to trachoma; certainly hundreds of millions live in trachoma-endemic areas.Serovars A, B, Ba, and C are isolated from patients with clinical trachoma in areas of endemicity in developing countries in Africa, the Middle East, Asia, and South America.The trachoma-hyperendemic areas of the world are in northern and sub-Saharan Africa, the Middle East, drier regions of the Indian subcontinent, and Southeast Asia.

With these arguments, the surgeon-leader’s vision remains susceptible to rejection for many of the same reasons.This is the “how,” and once again it appeals to the rational and analytical side of the team.)Generating Belief in Your VisionSurgical leaders with great visions will inevitably require help from colleagues, other healthcare professionals, scientists, administrators, patients, and nonmedical personnel. To get this help, surgical leaders must inspire their team and understand motivation. For the surgeon-leader, it is critical to know that people do not follow leaders because of what they do; people follow leaders because of why they do what they do. The people who help the leader execute the vision are motivated by the leader’s beliefs and attitudes more than the leader’s policy or agenda. This concept, based on Simon Sinek’s Start With Why, is rooted in understanding of the anatomy and function of the human brain.13 See figure 1-6.For example, take a surgeon-leader who wants to imple-ment a new perioperative checklist to reduce surgical errors. The “what” is very simple: a checklist to reduce errors. The operating room team may make a rational decision to adapt the checklist; however, it is also possible that the checklist may be perceived as “another piece of paperwork” and rejected, or that the checklist may have its implementation fought, undermined, delayed, or ignored. A surgeon-leader who does not understand how people are motivated might argue rationally, telling the team that the checklist was created with great care, that all of the best evidence was incorporated in its creation, and that the checklist is short and efficient. This is the “how,” and once again it appeals to the rational and analytical side of the team. With these arguments, the surgeon-leader’s vision remains susceptible to rejection for many of the same reasons.With these argu-ments, which constitute an emotional appeal to the team’s belief system, the leader can expect this vision for better patient care via a new surgical checklist to be adapted by the team.

These include Hartnup disorder, maple syrup urine disease, mitochondrial disorders, abetalipoproteinemia, and vitamin E deficiency.Several rare inborn errors of metabolism can present with intermittent episodes of ataxia and somnolence.The presence of opsoclonus-myoclonus in a child should prompt a vigorous search for an occult neuroblastoma.Brain magnetic resonance imaging may reveal cerebellar enhancement. No specific therapy is available except to prevent injury during the ataxic phase. Brain tumors are the second most common neoplasm in children. About 50% arise from within the posterior fossa. Tumors that arise in the posterior fossa or brainstem produce progressive ataxia with headache that may be acute or gradual in onset. There is a progressive worsening over days, weeks, or months, typically with associated signs and symptoms of elevated intracranial pressure. The ataxia and dysmetria may result from primary cerebellar invasion or from obstruction of the CSF pathways (aqueduct of Sylvius or fourth ventricle) with resultant hydrocephalus. The most common tumors in this region include medulloblastoma, ependymoma, cerebellar astrocytoma, and brainstem glioma. Rarely, a neuroblastoma located in the adrenal medulla or anywhere along the paraspinal sympathetic chain in the thorax or abdomen is associated with degeneration of Purkinje cells and the development of severe ataxia, dysmetria, irritability, myoclonus, and opsoclonus. An immunologic reaction directed toward the tumor may be misdirected to attack Purkinje cells and other neuronal elements. The myoclonic movements are irregular, lightning-like movements of a limb or the head. Opsoclonus is a rapid, multidirectional, conjugate movement of the eyes, which suddenly dart in random directions. The presence of opsoclonus-myoclonus in a child should prompt a vigorous search for an occult neuroblastoma. Several rare inborn errors of metabolism can present with intermittent episodes of ataxia and somnolence. These include Hartnup disorder, maple syrup urine disease, mitochondrial disorders, abetalipoproteinemia, and vitamin E deficiency.Ataxia-telangiectasia, an autosomal recessive genetic disorder, is the most common of the degenerative ataxias.Affected patients present with ataxia around age 2 years, progressing to loss of ambulation by adolescence.In mid-childhood, telangiectasia is evident over the sclerae, nose, ears, and extremities.

Consequently, a marked decline in the use of the PAC from 5.66 per 1000 medical admissions in 1993 to 1.99 per 1000 medical admissions in 2004 has been seen.31 Based upon the results and exclusion criteria in these pro-spective randomized trials, reasonable criteria for perioperative monitoring without use of a PAC are presented in Table 13-3.One of the reasons for using a PAC to monitor critically ill patients is to optimize cardiac output and systemic oxygen delivery. Defining what constitutes the optimum cardiac out-put, however, has proven to be difficult. A number of random-ized trials evaluating the effect on outcome of goal-directed as compared to conventional hemodynamic resuscitation have 2Table 13-3Suggested criteria for perioperative monitoring without use of a pulmonary artery catheter in patients undergoing cardiac or major vascular surgical proceduresNo anticipated need for suprarenal or supraceliac aortic cross-clampingNo history of myocardial infarction during 3 months prior to operationNo history of poorly compensated congestive heart failureNo history of coronary artery bypass graft surgery during 6 weeks prior to operationNo history of ongoing symptomatic mitral or aortic valvular heart diseaseNo history of ongoing unstable angina pectorisbeen published.

This means that there is misclassification error of 30% that limits the value in predicting the severity of acute pancreatitis in indi-vidual patients.The accuracy of this approach appears to be over 90% and triages most patients away from intensive care.Unfortunately, these and many other single and combined predictors of severity have an accuracy of around 70%66.When there are three or more positive criteria, the disease is considered “predicted severe.” There are many other approaches to predicting severity. At 24 hours after admission an APACHE II score of 8 or more or a serum C-reactive protein level of >150 mg/dL has a similar accuracy in predicting severity as Ranson’s criteria.66 The more recently proposed Bedside Index for Severity of Acute Pancreatitis (BISAP) is calculated from blood urea nitrogen (> 25 mg/dL), impaired mental status (GCS <15), presence of systemic inflammatory response syndrome, age >60 years, and pleural effusion. Although it has the advantage of simplicity and can be performed within the first 24 hours of admission, it performed no better than other predictors.67 The presence of SIRS also has prognostic significance.68 There remains some controversy as to how important obesity is as a risk factor for severe and critical acute pancreatitis.69 Another approach has been taken in seeking to predict those with the “harmless acute pancreatitis score”70 using three factors that can be determined on admission: absence of rebound tenderness or guarding, normal hematocrit, and normal serum creatinine. The accuracy of this approach appears to be over 90% and triages most patients away from intensive care.Unfortunately, these and many other single and combined predictors of severity have an accuracy of around 70%66. This means that there is misclassification error of 30% that limits the value in predicting the severity of acute pancreatitis in indi-vidual patients.The wide spectrum of pancreatitis severity was not captured in the previous binary classifica-tions (mild or severe).

MRI or lumbar puncture may be helpful to exclude a specific medical condition such as cryptococcus infection or herpes en- cephalitis that may contribute to CNS changes in the context of AIDS.As individuals treated for HIV survive into older age, additive and interactive neurocognitive effects of HIV and aging, including other NCDs (e.g., due to Alzheimer’s disease, due to Parkinson’s dis- ease), are possible. Risk and prognostic factors for HIV infection. Risk factors for HIV infection include injec- tion drug use, unprotected sex, and unprotected blood supply and other iatrogenic factors. Risk and prognostic factors for major or mild neurocognitive disorder due to HIV in- fection. Paradoxically, NCD due to HIV infection has not declined significantly with the advent of combined antiretroviral therapy, although the most severe presentations (con- sistent with the diagnosis of major NCD) have decreased sharply. Contributory factors may include inadequate control of HIV in the central nervous System (CNS), the evolution of drug-resistant viral strains, the effects of chronic long-term systemic and brain inflam- mation, and the effects of comorbid factors such as aging, drug abuse, past history of CNS trauma, and co-infections, such as with the hepatitis C virus. Chronic exposure to antiret- roviral drugs also raises the possibility of neurotoxicity, although this has not been defin- itively established. Serum HIV testing is required for the diagnosis. In addition, HIV characterization of the cere- fluid versus in the plasma. Neuroimaging (i.e., magnetic resonance imaging [MRI]) may reveal reduction in total brain volume, cortical thinning, reduction in white matter volume, and patchy areas of abnormal white matter (hyperintensities). MRI or lumbar puncture may be helpful to exclude a specific medical condition such as cryptococcus infection or herpes en- cephalitis that may contribute to CNS changes in the context of AIDS.Functional Consequences of Major or Mild Neurocognitive Disorder Due to HIV Infection Functional consequences of major or mild NCD due to HIV infection are variable across individuals.

Mineralization of the matrix, both in trabecular bone and in osteones of compact cortical bone (Haversian systems), begins soon after the matrix is secreted (primary mineralization) but is not completed for several weeks or even longer (secondary mineralization).Remarkably, osteocytes also secrete fibroblast growth factor 23 (FGF23), a major regulator of phosphate metabolism (see below).Transcription factors and other markers specific for various stages of development are depicted below the arrows. BMPs, bone morphogenic proteins; IGFs, insulin-like growth factors; IL-1, interleukin 1; IL-6, interleukin 6; M-CSF, macrophage colony-stimulating factor; NFκB, nuclear factor κB; PTH, parathyroid hormone; PU-1, a monocyteand B lymphocyte–specific ets family transcription factor; RANK ligand, receptor activator of NFκB ligand; Runx2, Runt-related transcription factor 2; TRAF, tumor necrosis factor receptor–associated factors; Vit D, vitamin D; wnts, wingless-type mouse mammary tumor virus integration site. (Modified from T Suda et al: Endocr Rev 20:345, 1999, with permission.) forming bone. As an osteoblast secretes matrix, which then is mineralized, the cell becomes an osteocyte, still connected with its blood supply through a series of canaliculi. Osteocytes account for the vast majority of the cells in bone. They are thought to be the mechanosensors in bone that communicate signals to surface osteoblasts and their progenitors through the canalicular network and thereby serve as master regulators of bone formation and resorption. Remarkably, osteocytes also secrete fibroblast growth factor 23 (FGF23), a major regulator of phosphate metabolism (see below). Mineralization of the matrix, both in trabecular bone and in osteones of compact cortical bone (Haversian systems), begins soon after the matrix is secreted (primary mineralization) but is not completed for several weeks or even longer (secondary mineralization).Genetic studies in humans and mice have identified several key genes that control osteoblast development.Runx2 is a transcription factor expressed specifically in chondrocyte (cartilage cells) and osteoblast progenitors as well as in hypertrophic chondrocytes and mature osteoblasts.

Venkatachalam, Department of Pathology, University of Texas Health Science Center, San Antonio,Texas.)(Courtesy of Dr. M.A.Diabeticmicroangiopathy.Oneofthemostconsistentmorphologicfeaturesofdiabetesisdiffusethickeningofbasementmembranes.Thethickeningismostevidentinthecapillariesoftheskin,skeletalmuscle,retina,renalglomeruli,andrenalmedulla.However,italsomaybeseeninnonvascularstructuressuchasrenaltubules,theBowmancapsule,peripheralnerves,andplacenta.Bybothlightandelectronmicroscopy,thebasallaminaseparatingparenchymalorendothelialcellsfromthesurroundingtissueismarkedlythickenedbyconcentriclayersofhyalinematerialcomposedpredominantlyoftypeIVcollagen( Fig.20.28 ).Ofnote,despitetheincreaseinthethicknessofbasementmembranes,diabeticcapillariesareleaky,leadingtoextravasationofplasmaproteins.Themicroangiopathyunderliesthedevelopmentofdiabeticnephropathy,retinopathy,andsomeformsofneuropathy.Anindistinguishablemicroangiopathycanbefoundinagednondiabeticpatients,butrarelytotheextentseeninindividualswithlong-standingdiabetes. Diabeticnephropathy.Thekidneysareprimetargetsofdiabetes(seealsoChapter14).Renalfailureissecondonlytomyocardialinfarctionasacauseofdeathfromthisdisease.Thelesionsincludemainly:(1)glomerularlesions;(2)renalvascularlesions,principallyarteriolosclerosis;and(3)pyelonephritis,includingnecrotizingpapillitis. Themostimportantglomerularlesionsarecapillarybasementmembranethickening,diffusemesangialsclerosis,andnodularglomerulosclerosis.Theglomerularcapillarybasementmembranesarethickenedalongtheirentirelength.Thischangecanbedetectedbyelectronmicroscopywithinafewyearsoftheonsetofdiabetes,sometimeswithoutanyassociatedchangeinrenalfunction( Fig.20.29 Fig.20.27Severerenalhyalinearteriolosclerosisinaperiodicacid–Schiffstainedspecimen.Notethemarkedlythickened,tortuousafferentarteriole.Theamorphousnatureofthethickenedvascularwallisevident. (Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Science Center, San Antonio,Texas.)Diffusemesangialsclerosisreferstoanincreaseinmesangialmatrixassociatedwithmesangialcellproliferationandbasementmembranethickening.Itisfoundinmostindividualswithdiseaseofmorethan10years’duration.Whenglomerulosclerosisissevere,patientsdevelopthenephroticsyndrome,characterizedbyproteinuria,hypoalbuminemia,andedema(Chapter14).

It is likely that leukoaraiosis exist in a continuum with Binswanger disease and many elderly individuals who have these changes show cognitive impairment as discussed below.The term leukoaraiosis describes the imaging appearance of hypointense periventricular tissues, presumably damaged by chronic ischemia.Certain surgical measures have been employed, including transplantation of a vascular muscle flap, omentum, or pedicle containing the superficial temporal artery to the pial surface of the frontal lobe temporal pial synangiosis with the idea of creating neovascularization of the cortical convexity. These measures have reportedly reduced the number of ischemic attacks, but whether they alter the natural history of the illness cannot be stated. Anticoagulation is considered risky in view of the possibility of cerebral hemorrhage, but there have not been systematic studies. The reader is referred to a review of the clinical features and surgical treatments by Scott and Smith. This entity was mentioned briefly in the discussion of the course and prognosis of atherothrombotic infarction and as a cause of dementia in Chaps. 20 and 38 but it has appeared in the literature with decreasing frequency. The term has come to denote a widespread degeneration of cerebral white matter having a vascular causation and observed in the context of hypertension, atherosclerosis of the small blood vessels, and multiple strokes. Hemiparesis, dysarthria, TIAs, and typical lacunar or cortical strokes are admixed in many cases. The process has been associated with a particular radiologic appearance that reflects confluent areas of white matter signal change. The term leukoaraiosis describes the imaging appearance of hypointense periventricular tissues, presumably damaged by chronic ischemia. It is likely that leukoaraiosis exist in a continuum with Binswanger disease and many elderly individuals who have these changes show cognitive impairment as discussed below.Dementia, a pseudobulbar state, and a gait disorder, alone or in combination, are the main features of Binswanger cases.They have been attributed to the cumulative effects of the ischemic changes producing white matter degeneration.

“Wrong-way eyes” a paradoxical conjugate deviation to the side opposite a large hemispherical lesion may occur with thalamic and upper brainstem lesions.Serum concentrations of opiates that are high enough to cause coma have as a consistent sign pinpoint pupils, with constriction to light that may be so slight that it is detectable only with a magnifying glass. High-dose barbiturates may act similarly, but the pupillary diameter tends to be 1 mm or more. Systemic poisoning with atropine or with drugs that have atropinic qualities, especially the tricyclic antidepressants, but also, through another mechanism the selective serotonin reuptake inhibitors is characterized by dilatation and relative unresponsiveness to light of the pupils. Hippus, or fluctuating pupillary size, is a characteristic but not invariant sign of metabolic encephalopathy. Movements of Eyes and Eyelids and Corneal Responses These are altered in a variety of ways in coma. In stupor or light coma of metabolic origin, the eyes rove conjugately from side to side in seemingly random fashion, sometimes resting briefly in an eccentric position. These movements disappear as coma deepens, and the eyes then remain motionless and slightly exotropic. In bihemispheral coma, the eyes may rove smoothly from side-to-side (windshield wiper” eyes). A lateral and slight downward deviation of one eye suggests the presence of third-nerve palsy on that side, and a medial deviation, of sixth-nerve palsy. There is persistent conjugate deviation of the eyes to one side—away from the side of the paralysis with a large cerebral lesion (looking toward the lesion) and toward the side of the paralysis with a unilateral pontine lesion (looking away from the lesion). “Wrong-way eyes” a paradoxical conjugate deviation to the side opposite a large hemispherical lesion may occur with thalamic and upper brainstem lesions.The globes turn down and inward (looking at the nose) with hematomas or ischemic lesions of the thalamus and upper midbrain (a variant of Parinaud syndrome).Retraction and convergence nystagmus and “ocular bobbing,” described in Chap.13, occur with lesions in the tegmentum of the mid-brain and pons, respectively.

Lesions of the cauda equina alone, always difficult to separate from those of the lumbosacral plexuses and multiple nerves, are usually attended in the early stages by sciatic and other root pain and lumbar ache, which are variously combined with a bilaterally asymmetrical, atrophic, areflexic paralysis, radicular sensory loss, and sphincteric disorder.Sacral sparing of sensation may be found as described in Chap. 8 on the sensory syndromes but is of less value in distinguishing intramedullary from extramedullary lesions. A dissociation of thermal pain and tactile sensory loss over several contiguous segments on the trunk is a more dependable sign of an intramedullary lesion. Rarely, an extramedullary tumor may give rise to a syringomyelic sensory syndrome, possibly by causing vascular insufficiency in the central portion of the cord. Special spinal syndromes Unusual clinical syndromes may be found in patients with tumors in the region of the foramen magnum, as discussed in Chap. 3. They produce quadriparesis with pain in the back of the head and stiff neck, weakness and atrophy of the hands and dorsal neck muscles, marked imbalance, and variable sensory changes or, if they spread intracranially, there may be signs of cerebellar and lower cranial nerve involvement. Slowly growing tumors in this region, such as meningiomas, characteristically produce an “around the clock” progression of weakness beginning in one limb and proceeding to the adjacent one in a clockwise or counterclockwise direction. Lesions at the level of the lowermost thoracic and the first lumbar vertebrae may result in mixed cauda equina and spinal cord symptoms. A Babinski sign indicates that the spinal cord is involved above the fifth lumbar segment. Lesions of the cauda equina alone, always difficult to separate from those of the lumbosacral plexuses and multiple nerves, are usually attended in the early stages by sciatic and other root pain and lumbar ache, which are variously combined with a bilaterally asymmetrical, atrophic, areflexic paralysis, radicular sensory loss, and sphincteric disorder.Sensory abnormalities may precede motor and reflex changes by many months.Very rarely, for unclear reasons, tumors of the thoracolumbar cord (intramedullary, as a rule) are associated with markedly elevated spinal fluid protein and hydrocephalus; these respond to shunting and removal of the spinal tumor (Feldman et al).Less often, these tumors are associated with a pseudotumor cerebri syndrome.

Insulingeneexpressionandisletcellbiogenesisaredependentonseveraltranscriptionfactorsspecifictothepancreas,liver,andkidney.Thesetranscriptionfactorsincludehepatocyte nuclear factor 4α (HNF-4α), HNF-1α, insulin promoter factor 1 (IPF-1), HNF-1β, and neurogenic differentiation 1/beta cell E-box trans-activator 2 (NeuroD1/β2).BothDPP-4–resistant analogues of GLP-1 andinhibitors of DPP-4 arecurrentlyapprovedfortreatmentofpatientswithtype2DMwithsomebetacellfunction.Importantlythesedrugsarepermissive totheactionsofglucoseonthebetacellandthusonlyweaklyincreaseinsulinsecretionintheabsenceofglucose.ThusGLP-1analoguesinducehypoglycemiamuchlessfrequentlythansulfonylureadrugs. The insulin receptor (InsR) is a member of the receptor tyrosine kinase (RTK) gene family (see ). Most of the actions of insulin on metabolism involve activation of the protein kinase Akt, which in turn has pleiotropic actions on cell metabolism. The InsR is expressed on the cell membrane as a homodimer, with each monomer containing a tyrosine kinase B InsRec IRS protein Metabolic actions Anabolic actions of insulin • Utilization of glucose for ATP & anabolic pathways • Storage of FFAs as TG • Protein synthesis from AAs • Macromolecular synthesis (e.g., RNA, DNA, lipids) • Organelle formation • Cell proliferation/renewal Mitogenic actions Merabolic actions PIP2PIP3 RAS/ RAF MAPK/ ERK PI3K Akt GLUT 4 Translocation Glucose import Glycolysis, Glycogenesis, PDH, DNL Glucogenolysis Gluconeogensis FFA ˜ oxidation Ketogenesis Lipolysis Proteolysis autophagy Protein synthesis Gycolysis, PPP, DNL Gluconeo-genesis, VLDL export Protein phoshatases mTORC1 SREBP-1C FOX01 Akt •Fig. 39.9 A,Structureofdimerizedinsulinreceptorincellmembrane.B,SimplifieddiagramoftheAktkinaseandMAPKpathwaysdownstreamoftheInsR.C,Summarizedactionsofinsulin/InsR-activatedAktkinase. Insulingeneexpressionandisletcellbiogenesisaredependentonseveraltranscriptionfactorsspecifictothepancreas,liver,andkidney.Thesetranscriptionfactorsincludehepatocyte nuclear factor 4α (HNF-4α), HNF-1α, insulin promoter factor 1 (IPF-1), HNF-1β, and neurogenic differentiation 1/beta cell E-box trans-activator 2 (NeuroD1/β2).•Fig.39.10 Divergentproteolyticcleavagepatternsoftheproglucagonmolecule.GLUC,glucagon;GLP,glucagon-likepeptide;GRPP,glucagon-relatedpolypeptide.domain on the cytosolic side (see Fig.39.10A ).Binding of insulin to the receptor induces cross-phosphorylation of the subunits.

9-1) plotted his own visual aura, calculated that the cortical impairment progressed at a rate of 2 to 3 mm/min over the surface of the brain.Lashley, who as noted earlier (see Fig.The relationship between the vascular changes and evolving neurologic symptoms of migraine are noteworthy.Sophisticated measurements showed a reduction in blood flow that started in the occipital cortex and spread slowly forward on both sides, in a manner much like spreading cortical depression (see below) and Cutrer and colleagues, using perfusion-weighted MRI, corroborated the finding of diminished occipital cerebral blood flow during the aura. However, a study using single-photon emission computed tomography (SPECT) in 20 patients during and after attacks of migraine without aura disclosed no focal changes of cerebral blood flow; also, no changes occurred after treatment of the attacks with 6 mg of subcutaneous sumatriptan (Ferrari et al, 1995). In reference to the extracranial vessels, Iversen and associates, by means of ultrasonography, documented a dilatation of the superior temporal artery on the side of the migraine during the headache period. The same dilatation in the middle cerebral arteries has been inferred from observations with transcranial Doppler insonation. The complication of cerebral infarction is also in keeping with a vascular hypothesis, but it involves only a tiny proportion of migraineurs. The vascular hypothesis for migraine must be regarded as uncertain, but, clearly, there is frequently a reduction in posterior cortical blood flow during an aura. What is not established is whether the blood flow changes are fundamental or simply the result in a reduction in cortical activity. The original opinion expressed by Wolff that a vascular element is responsible for the cranial pain of migraine is also unconfirmed. The relationship between the vascular changes and evolving neurologic symptoms of migraine are noteworthy. Lashley, who as noted earlier (see Fig. 9-1) plotted his own visual aura, calculated that the cortical impairment progressed at a rate of 2 to 3 mm/min over the surface of the brain.Both of these events are intriguingly similar to the above-mentioned phenomenon of “spreading cortical depression,” observed by Leão in experimental animals.He demonstrated that a noxious stimulus applied to the rat cortex was followed by vasoconstriction and slowly spreading waves of inhibition of the electrical activity of cortical neurons, moving at a rate of approximately 3 mm/min.

For cannabis intoxication delirium, see the criteria and discussion of delirium in the chapter ”Neurocog- nitive Disorders.” These cannabis-induced disorders are diagnosed instead of cannabis in- toxication or cannabis withdrawal when the symptoms are sufficiently severe to warrant independent clinical attention.A substantial proportion of adults and adolescents in treatment for moderate to severe cannabis use disorder acknowledge mod- erate to severe withdrawal symptoms, and many complain that these symptoms make ces- sation more difficult. Cannabis users report having relapsed to cannabis use or initiating use of other drugs (e.g., tranquilizers) to provide relief from cannabis withdrawal symp— toms. Last, individuals living with cannabis users observe significant withdrawal effects, suggesting that such symptoms are disruptive to daily living. Because many of the symptoms of cannabis withdrawal are also symptoms of other sub- stance withdrawal syndromes or of depressive or bipolar disorders, careful evaluation should focus on ensuring that the symptoms are not better explained by cessation from an- other substance (e.g., tobacco or alcohol withdrawal), another mental disorder (general— ized anxiety disorder, major depressive disorder), or another medical condition. The following cannabis—induced disorders are described in other chapters of the manual with disorders with which they share phenomenology (see the substance/medication-induced mental disorders in these chapters): cannabis-induced psychotic disorder ("Schizophrenia Disorders”); and cannabis-induced sleep disorder (”Sleep-Wake Disorders"). For cannabis intoxication delirium, see the criteria and discussion of delirium in the chapter ”Neurocog- nitive Disorders.” These cannabis-induced disorders are diagnosed instead of cannabis in- toxication or cannabis withdrawal when the symptoms are sufficiently severe to warrant independent clinical attention.A.A pattern of phencyclidine (or a pharmacologically similar substance) use leading to clinically significant impairment or distress, as manifested by at least two of the follow- ing, occurring within a 12-month period: 1.2.10.Phencyclidine is often taken in larger amounts or over a longer period than was in- tended.

Among patients who survived and remained vegetative until death, J.H.All showed extensive zones of necrosis and hemorrhage in the upper brainstem.Adams examined the brains of 14 patients who remained in coma and in vegetative states from 1 to 14 years.Our colleague R.D.The lesions in these cases consisted of surface contusions (48 percent), lacerations of the cerebral cortex (28 percent), subarachnoid hemorrhage (72 percent), subdural hematoma (15 percent), extradural hemorrhage (20 percent), and skull fractures (72 percent). As these figures indicate, several pathologic entities were found in the same patient. There is that relatively small, distressing group of severely brain-injured patients in whom the vital signs become normal but who never regain full consciousness. As the weeks pass, the prospects become bleaker. Such a patient, especially if a child, may still emerge from coma after 6 to 12 weeks or longer and make a relatively good, although usually incomplete, recovery. Some of those who survive for long periods open their eyes and move their heads and eyes from side to side but betray no evidence of seeing or recognizing even the closest members of their families. They do not speak and are capable of only primitive postural or reflex withdrawal movements. Jennett and Plum referred to this as the “persistent vegetative state” (see Chap. 16 for a full discussion of this subject). Fourteen percent of the patients in the Traumatic Coma Data Bank remained in this state. Hemiplegia or quadriplegia with varying degrees of decerebrate or decorticate posturing are usually present. Life is sometimes terminated after several months or years by some medical complication but may patients have survived for decades. Our colleague R.D. Adams examined the brains of 14 patients who remained in coma and in vegetative states from 1 to 14 years. All showed extensive zones of necrosis and hemorrhage in the upper brainstem. Among patients who survived and remained vegetative until death, J.H.Moreover, trauma of extracranial organs and tissues is frequent and obviously contributes to the fatal outcome.Recent functional studies have shown that a limited proportion of patients who are in a vegetative or minimally conscious state can be trained to purposefully engage parts of the cerebrum.

Organ System Effects 1.B.However, hexamethonium actually produces most of its blockade by occupying sites in or on the nicotinic ion channel, not by occupying the cholinoceptor itself.Blockade can be surmounted by increasing the concentration of an agonist, eg, acetylcholine.Drugs now used as ganglion-blocking drugs are classified as non-depolarizing competitive antagonists.The ganglion-blocking drugs are important and used in pharmacologic and physiologic research because they can block all autonomic outflow. However, their lack of selectivity confers such a broad range of undesirable effects that they have limited clinical use. All ganglion-blocking drugs of interest are synthetic amines. Tetraethylammonium (TEA), the first to be recognized as having this action, has a very short duration of action. Hexamethonium (“C6”) was developed and was introduced clinically as the first drug effective for management of hypertension. As shown in Figure 8–7, there is an obvious relationship between the structures of the agonist acetylcholine and the nicotinic antagonists tetraethylammonium and hexamethonium. Decamethonium, the “C10” analog of hexamethonium, is a depolarizing neuromuscular blocking agent. Mecamylamine, a secondary amine, was developed to improve the degree and extent of absorption from the gastrointestinal tract because the quaternary amine ganglion-blocking compounds were poorly and erratically absorbed after oral administration. Trimethaphan, a short-acting, polar, ganglion-blocking drug, is no longer available for clinical use. FIGURE 8–7 Some ganglion-blocking drugs. Acetylcholine is shown for reference. A. Mechanism of Action Ganglionic nicotinic receptors, like those of the skeletal muscle neuromuscular junction, are subject to both depolarizing and nondepolarizing blockade (see Chapters 7 and 27). Nicotine itself, carbamoylcholine, and even acetylcholine (if amplified with a cholinesterase inhibitor) can produce depolarizing ganglion block. Drugs now used as ganglion-blocking drugs are classified as non-depolarizing competitive antagonists. Blockade can be surmounted by increasing the concentration of an agonist, eg, acetylcholine. However, hexamethonium actually produces most of its blockade by occupying sites in or on the nicotinic ion channel, not by occupying the cholinoceptor itself. B. Organ System Effects 1.Sedation, tremor, choreiform movements, and mental aberrations have been reported as effects of mecamylamine.2.Eye—The ganglion-blocking drugs cause a predictable cycloplegia with loss of accommodation because the ciliary muscle receives innervation primarily from the parasympathetic nervous system.

Many of the remain-ing colorectal carcinomas are thought to arise from mutations in the MSI pathway, which is characterized by errors in mismatch repair during DNA replication.Loss of either of these genes is thought to promote cancer progression.82The Microsatellite Instability Pathway.The mutations involved in colorectal cancer pathogenesis and progression are now recognized to accumulate via one of three major genetic pathways: the loss of heterozygosity (LOH; chromosomal instability) pathway, the microsatellite instability (MSI) pathway, and the CpG island methylation (CIMP; serrated methylated) pathway.The Loss of Heterozygosity Pathway The LOH pathway is characterized by chromosomal deletions and tumor aneu-ploidy. Eighty percent of colorectal carcinomas appear to arise from mutations in the LOH pathway. This pathway was first described in patients with FAP in whom mutations of the APC gene were found to be inherited.Another example of LOH occurs in the region of chromo-some 18q. This region has been found to be deleted in up to 70% of colorectal cancers. Two tumor suppressor genes, DCC and SMAD4, are located in this region, and as such, deletion of 18q may result in the loss of one or both of these genes. DCC is a tumor suppressor gene, and loss of both alleles is required for malignant degeneration. The main role of this molecule appears to be in the central nervous system, where it is involved in neural differentiation and axonal migration. This observa-tion has led to the hypothesis that DCC may be involved in differentiation and cellular adhesion in colorectal cancer, but this theory remains unproven. DCC mutations are present in more than 70% of colorectal carcinomas and may negatively impact prognosis. SMAD4 functions in the signaling cascade of transforming growth factor beta and beta-catenin (also a down-stream effector of the APC gene). Loss of either of these genes is thought to promote cancer progression.82The Microsatellite Instability Pathway. Many of the remain-ing colorectal carcinomas are thought to arise from mutations in the MSI pathway, which is characterized by errors in mismatch repair during DNA replication.A number of genes have been identified that appear to be crucial for recognizing and repairing DNA replication errors.These mismatch repair genes include MSH2, MLH1, PMS1, PMS2, and MSH6/GTBP.A mutation in one of these genes predisposes a cell to mutations, which may occur in proto-oncogenes or tumor suppressor genes.

The goal of the peripheral blood karyotype is to identify an absent or abnormal X chromosome and to identify whether or not any portion of a Y chromosome is present.FMR1 premutation testing will reveal women at risk for bearing a child with fragile X syndrome, which may be important information for other family members.21-hydroxylase antibody.Karyotype 3.FMR1 premutation 2.Prolactin is most accurately obtained in a patient who is fasting and who has not had any recent breast stimulation to avoid concluding that a patient is hyperprolactinemic on the basis of a transient prolactin elevation. If a patient still has some menstrual cycles, it is advisable to obtain the prolactin level in the follicular phase. Assessment of serum FSH levels is required to determine whether the patient has hypergonadotropic, hypogonadotropic, or eugonadotropic amenorrhea. A circulating FSH level of greater than 25 to 40 mIU/mL indicated on at least two blood samples is indicative of hypergonadotropic amenorrhea. Hypergonadotropism implies that the cause of amenorrhea is ovarian insufficiency. The history should establish whether the cause of ovarian insufficiency is chemotherapy or radiation therapy. One test that is likely to be performed increasingly frequently is serum AMH. AMH is a product of the granulosa cells. AMH levels are low in women with POI and high in women with PCOS. AMH may be used more commonly in the evaluation of amenorrhea, but its assessment is not yet part of routine evaluation. If the diagnosis of POI is confirmed, the patient should be tested for: 1. FMR1 premutation 2. Karyotype 3. 21-hydroxylase antibody. FMR1 premutation testing will reveal women at risk for bearing a child with fragile X syndrome, which may be important information for other family members. The goal of the peripheral blood karyotype is to identify an absent or abnormal X chromosome and to identify whether or not any portion of a Y chromosome is present.It is important to identify Y chromosomal material so it may be removed to prevent malignant degeneration.Although commonly suggested that Assessment of the Pituitary and Hypothalamus karyotype only be performed if the patient is under age 30, it should be noted that rare patients with Turner syndrome developed amenorrhea after age 35.

Despite a greater proportion of poststerilization failures resulting in ectopic pregnancy, the absolute rate of ectopic pregnancy is decreased after sterilization (40).The 10-year cumulative incidence of pregnancy after any form of tubal sterilization is 18.5 per 1,000 woman-years and the likelihood of sterilization failure does not decrease with time since the procedure (39).Hormonal control of the muscular activity in the fallopian tube may explain the increased incidence of tubal pregnancy associated with failures of the morning-after pill, minipill, progesterone-containing IUDs, and ovulation induction. There is no increase in the incidence of chromosomal abnormalities in ectopic pregnancies (37). Tubal Surgery As would be expected, factors that disrupt normal tubal anatomy are the primary etiology for ectopic pregnancy. Women with prior tubal surgery have a more than 20-fold increased risk of subsequent ectopic pregnancy (32). Tubal repair or reconstruction may be performed to correct an obstruction, lyse adhesions, or evacuate an unruptured ectopic pregnancy. Although it is clear that tubal surgery is associated with an increased risk for ectopic pregnancy, it is unclear whether the increased risk results from the surgical procedure or from the underlying problem. A four-to fivefold increased risk is associated with salpingostomy, neosalpingostomy, fimbroplasty, anastomosis, and lysis of complex peritubal and periovarian adhesions (38). After tubal surgery, the overall rate of ectopic pregnancy is 2% to 7%, and the viable intrauterine pregnancy rate is 50% (38). Though tubal sterilization remains one of the most effective forms of contraception, failures do occur; when they do, they are more likely to result in ectopic gestation. The 10-year cumulative incidence of pregnancy after any form of tubal sterilization is 18.5 per 1,000 woman-years and the likelihood of sterilization failure does not decrease with time since the procedure (39). Despite a greater proportion of poststerilization failures resulting in ectopic pregnancy, the absolute rate of ectopic pregnancy is decreased after sterilization (40).The 10-year cumulative incidence of tubal pregnancy after any sterilization procedure is 7.3 per 1,000 procedures (41).

ABC generally occurs during the first 2 decades of life and has Fig.21.25Radiographically,giantcelltumoroftheproximalfibulaispre-dominantlylytic,expansilewithdestructionofthecortex.Apathologicfractureisalsopresent.Aneurysmal bone cyst (ABC) is a benign tumor characterized by multiloculated blood-filled cystic spaces.The RANKL inhibitor, Denosumab, has shown promise in treating giant cell tumor.Giant cell tumors arise in the epiphyses of long bones, most commonly the distal femur and proximal tibia. The typical location of these tumors near joints frequently causes arthritis-like symptoms. Occasionally, they present with pathologic fractures. Fig.21.24Ewingsarcomacomposedofsheetsofsmallroundcellswithsmallamountsofclearcytoplasm. http://ebooksmedicine.net Experimental evidence suggests that the neoplastic cells of the giant cell tumor are osteoblast precursors, which represent only a minority of the cells in the tumor. The neoplastic cells express high levels of RANKL, which promotes the proliferation and differentiation of normal osteoclast precursors into osteoclasts. The osteoclasts in turn cause localized but highly destructive resorption of bone. MORPHOLOGYGiantcelltumorsoftendestroytheoverlyingcortex,producingabulgingsofttissuemassdelineatedbyathinshellofreactivebone( Fig.21.25 ).Grossly,theyarered-brownmassesthatfrequentlyundergocysticdegeneration.Microscopically,thetumorconspicuouslylacksboneorcartilage,consistingofnumerousosteoclast-typegiantcellswith100ormorenucleiwithuniform,ovalmononucleartumorcellsinbetween( Fig.21.26 Giant cell tumors are typically treated with curettage, but 40% to 60% recur locally. Up to 4% of tumors metastasize to the lungs, but these sometimes spontaneously regress and they are seldom fatal. The RANKL inhibitor, Denosumab, has shown promise in treating giant cell tumor. Aneurysmal bone cyst (ABC) is a benign tumor characterized by multiloculated blood-filled cystic spaces. ABC generally occurs during the first 2 decades of life and has Fig.21.25Radiographically,giantcelltumoroftheproximalfibulaispre-dominantlylytic,expansilewithdestructionofthecortex.Apathologicfractureisalsopresent.no sex predilection.It most frequently develops in the metaphysis of long bones and the posterior elements of vertebral bodies.Pain and swelling are common.Radiographically, ABC is usually an eccentric, expansile, lytic, metaphyseal lesion with well-defined margins ( Fig.21.27A ).

Rising temperatures also can have differential effects on parasite development during external incubation and on the mosquitoes’ gonotrophic cycle.While mosquitoes and parasites may adapt to a warming climate, the present optimal temperature for malaria transmission is ~25°C, with a range of transmission temperatures between 16°C and 34°C.In addition, insects tend to be sensitive to water availability. Mosquitoes that transmit malaria, dengue, and other infections may breed in pools of water created by heavy downpours. As has been observed in the Amazon, breeding pools can also appear during periods of drought when rivers recede and leave behind stagnant pools of water for Anopheles mosquitoes. These circumstances have raised interest in the potentially favorable impact of water-cycle intensification on the spread of mosquito-borne disease. Malaria • TEMPERATURE Higher temperatures promote higher mosquito-biting rates, shorter parasite reproductive cycles, and the potential for the survival of mosquito vectors of Plasmodium infection in locations previously too cold to sustain them. Recent modeling experiments identify highland areas of East Africa and South America as perhaps most vulnerable to increased malarial incidence as a result of rising temperatures. In addition, a recent analysis of interannual malaria in Ecuador and Colombia has documented a greater incidence of malaria at higher altitudes in warmer years. Highland populations may be more vulnerable to malaria epidemics because they lack immunity. Although rising temperature has the potential to expand the viable range of disease, malaria incidence is not associated with temperature in a strictly linear fashion. While mosquitoes and parasites may adapt to a warming climate, the present optimal temperature for malaria transmission is ~25°C, with a range of transmission temperatures between 16°C and 34°C. Rising temperatures also can have differential effects on parasite development during external incubation and on the mosquitoes’ gonotrophic cycle.PRECIPITATION The abundance of Anopheles mosquitoes is strongly correlated with the availability of surface water pools for mosquito breeding, and biting rates have been linked to soil moisture (a surrogate for breeding pools).

Reports of treatment of this condition have appeared in medical journals, mostly from Asian countries and some in the United States.Internet gaming has been reportedly defined as an ”addiction” by the Chinese govern- ment, and a treatment system has been set up..0’ Note: Only nongambling Internet games are included in this disorder. Use of the Internet for required activities in a business or profession is not included; nor is the disorder intend- ed to include other recreational or social Internet use. Similarly, sexual Internet sites are excluded. Specify current severity: Internet gaming disorder can be mild, moderate, or severe depending on the degree of disruption of normal activities. Individuals with less severe Internet gaming disorder may exhibit fewer symptoms and less disruption of their lives. Those with severe Inter- net gaming disorder will have more hours spent on the computer and more severe loss of relationships or career or school opportunities. There are no well-researched subtypes for Internet gaming disorder to date. Internet gam- ing disorder most often involves specific Internet games, but it could involve non-Internet computerized games as well, although these have been less researched. It is likely that pre- ferred games will vary over time as new games are developed and popularized, and it is unclear if behaviors and consequence associated with Internet gaming disorder vary by game type. Gambling disorder is currently the only non-substance-related disorder proposed for in- clusion with DSM-S substance—related and addictive disorders. However, there are other behavioral disorders that show some similarities to substance use disorders and gambling disorder for which the word addiction is commonly used in nonmedical settings, and the one condition with a considerable literature is the compulsive playing of Intemet games. Internet gaming has been reportedly defined as an ”addiction” by the Chinese govern- ment, and a treatment system has been set up. Reports of treatment of this condition have appeared in medical journals, mostly from Asian countries and some in the United States.The literature suffers, however, from lack of a standard definition from which to derive prev- alence data.An understanding of the natural histories of cases, with or without treatment, is also missing.

These two cytokines are important contributors to the chronic inflammation in psoriasis plaques, PsA, and Crohn’s disease.It is a fully human IgG monoclonal antibody to the p40 protein subunit, which is part of both IL-12 and IL-23.Mechanism of Action: Ustekinumab is an IL-12 and IL-23 antagonist.1.The precipitating drug should be discontinued in such cases.On the other hand, there is no clear evidence of increased risk of solid malignancies or lymphomas with TNF-α–blocking agents, and their incidence may not be different compared with other bDMARDs or active RA itself. A low incidence of newly formed dsDNA antibodies and antinuclear antibodies (ANAs) has been documented when using TNF-α–blocking agents, but clinical lupus is extremely rare and the presence of ANA and dsDNA antibodies per se does not contraindicate the use of TNF-α–blocking agents. In patients with borderline or overt heart failure (HF), TNF-α–blocking agents can exacerbate HF. TNF-α–blocking agents can induce the immune system to develop antidrug antibodies in about 17% of cases. These antibodies may interfere with drug efficacy and correlate with infusion site reactions. Injection site reactions occur in 20–40% of patients, although they rarely result in discontinuation of therapy. Cases of alopecia areata, hypertrichosis, and erosive lichen planus have been reported. Cutaneous pseudo-lymphomas are reported rarely with TNF-α–blocking agents, especially infliximab. TNF-α–blocking agents may increase the risk of gastrointestinal ulcers and large bowel perforation including diverticular and appendiceal perforation. Nonspecific interstitial pneumonia, psoriasis, and sarcoidosislike syndrome are among the rare reported toxicities associated with TNF-α blockers. Rare cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia have also been reported. The precipitating drug should be discontinued in such cases. 1. Mechanism of Action: Ustekinumab is an IL-12 and IL-23 antagonist. It is a fully human IgG monoclonal antibody to the p40 protein subunit, which is part of both IL-12 and IL-23. These two cytokines are important contributors to the chronic inflammation in psoriasis plaques, PsA, and Crohn’s disease.This interruption interferes with IL-12 and IL-23 signal transduction and suppresses the formation of proinflammatory TH1 and TH17 cells.2.Pharmacokinetics: Ustekinumab is available as a 45and 90-mg SC injection for PsA and plaque psoriasis.Its bioavailability is 57% following SC injection; time to peak plasma concentration is 7–13.5 days and elimination half-life is 10–126 days.

The diagnosis of MELAS is based on a combination of clinical findings and molecular genetic testing.Muscle biopsy typically shows ragged red fibers with the modified Gomori trichrome stain or “ragged blue fibers” resulting from the hyperintense reaction with the histochemical staining for succinate dehydrogenase.In contrast to the other classic mtDNA disorders, it is of interest that patients with this syndrome Neurologic: stroke, epilepsy, migraine headache, peripheral neuropathy, cranial neuropathy (optic atrophy, sensorineural deafness, dysphagia, dysphasia) Skeletal myopathy: ophthalmoplegia, exercise intolerance, myalgia Cardiac: conduction block, cardiomyopathy Respiratory: hypoventilation, aspiration pneumonitis Endocrine: diabetes mellitus, premature ovarian failure, hypothyroidism, hypoparathyroidism Ophthalmologic: cataracts, pigment retinopathy, neurologic and myopathic (optic atrophy, ophthalmoplegia) ophthalmoplegia, diabetes mellitus, hir sutism, gastrointestinal dysmotility, and nephropathy. The typical age of death ranges from 10 to 35 years, but some individuals live into their sixth decade. Intercurrent infections or intestinal obstructions are often the terminal events. Laboratory investigation commonly demonstrates elevated lactate concentrations at rest with excessive increase after moderate exercise. Brain imaging during stroke-like episodes shows areas of increased T2 signal, typically involving the posterior cerebrum and not conforming to the distribution of major arteries. Electrocardiogram (ECG) may show evidence of cardiomyopathy, preexcitation, or incomplete heart block. Electromyography and nerve conduction studies are consistent with a myopathic process, but axonal and sensory neuropathy may coexist. Muscle biopsy typically shows ragged red fibers with the modified Gomori trichrome stain or “ragged blue fibers” resulting from the hyperintense reaction with the histochemical staining for succinate dehydrogenase. The diagnosis of MELAS is based on a combination of clinical findings and molecular genetic testing.The most common mutation, present in approximately 80% of individuals with typical clinical findings, is an A-to-G transition at nucleotide 3243 (m.3243A>G).Mutations can usually be detected in mtDNA from leukocytes in individuals with typical MELAS; however, the occurrence of heteroplasmy can result in varying tissue distribution of mutated mtDNA.

There are several reasons for this.Most advocate the routine addition of an antireflux procedure follow-ing repair of the hernia defect.Controversy remains as to whether to perform an antireflux procedure at all, in selected cases only, or in all patients.Mindful of these difficulties, and given appropriate experience, patients with PEH may be approached laparoscopi-cally, with expectation of success in the majority.Diaphragmatic RepairIt has been shown that PEH repair has a relatively high incidence of recurrence (10–40%) when the crura is closed primarily with permanent suture. Techniques to reduce hernia recurrence con-tinue to evolve. Most surgeons believe that recurrence may be reduced with the use of synthetic or biologic mesh to reinforce the standard crural closure. Randomized controlled studies have 4Brunicardi_Ch25_p1009-p1098.indd 104801/03/19 6:04 PM 1049ESOPHAGUS AND DIAPHRAGMATIC HERNIACHAPTER 25demonstrated a reduction in PEH recurrence rate when mesh was used. Nonabsorbable synthetic mesh must be used carefully and not in a keyhole fashion at the hiatus because of a potential risk of esophagus or gastric erosion and mesh infection. Bio-logic mesh (acellular porcine dermis, acellular human dermis, porcine small intestinal submucosa) has become more widely used, but these meshes are significantly more expensive than synthetic mesh, and the only randomized study supporting bio-logic mesh usage failed to demonstrate superiority over suture alone after 5 years of rigorous follow-up.Role of Fundoplication in Giant Hiatal Hernia Repair. Controversy remains as to whether to perform an antireflux procedure at all, in selected cases only, or in all patients. Most advocate the routine addition of an antireflux procedure follow-ing repair of the hernia defect. There are several reasons for this.Furthermore, there is no relation between the symptoms experienced by the patient with a PEH and the competency of the cardia.

*Average in parentheses.The bacteria causing infectious arthritis are similar to bacteria causing osteomyelitis (Table 118-1). Lyme disease also may cause arthritis (see Chapter 122). The arthritis of disseminated gonococcal infectionsincludes both reactive and suppurative forms in early and late gonococcal disease, respectively. With untreated genital infection, gonococcemia may occur with fever and a polyarticular, symmetric arthritis and rash, known as the arthritis-dermatitis syndrome. Bacterial cultures of the synovium are sterile at this stage, despite a relatively high prevalence of bacteremia. Monarticular arthritis of large, weight-bearing joints develops S. aureus Anaerobic bacteria Streptococcus pneumoniae Pseudomonas aeruginosa Group A streptococci Enterobacteriaceae Kingella kingae Haemophilus influenzae type b* N. gonorrhoeae Mycobacterium tuberculosis *The incidence of invasive infections caused by H. influenzae type b has diminished greatly with universal childhood Hib vaccination. days to weeks later. Cultures of affected synovial fluid at this stage often yield the pathogen. Reactive arthritis is immune-mediated synovial inflammation that follows a bacterial or viral infection, especially Yersinia and other enteric infections. Reactive arthritis of the hip joints in children 3 to 6 years of age is known as toxic or transient synovitis (see Chapter 200). Infectious arthritis occurs most commonly in children younger than 5 years of age and adolescents. Available @ StudentConsult.com The typical features of suppurative arthritis include monarticular involvement with erythema, warmth, swelling, and tenderness over the affected joint with a palpable effusion Normal Clear, yellow 0–200 (200)* <10 Good No difference — Trauma Clear, turbid, or 50–4000 (600) <30 Good No difference Common in hemorrhagic LE, Lupus erythematosus; PMN, polymorphonuclear cell; PPD, purified protein derivative of tuberculin; WBC, white blood cell. *Average in parentheses.The onset may be sudden or insidious with symptoms noted when the joint is moved only, such as during a diaper change, or if parents become aware of decreased voluntary movement of a joint or limb.Toddlers may exhibit a limp or refuse to walk.

Either open or laparoscopic repair can be performed.Given the high rate of incar-ceration, surgical repair is usually recommended.Incarceration is common as up to 20% of patients present with a nonreducible hernia.Most patients present with pain and swelling in the mid to lower abdomen.35-6).In this case, mesh should be placed as a sublay technique (below the fascia) and sutured in place to prevent migration.Patients with cirrhosis and associated ascites with an umbilical hernia pose a significant clinical dilemma. Umbilical defects enlarge in these patients because of high intra-abdominal pressure associated with uncontrolled ascites. With severe liver disease, these patients are at high risk of operative complica-tions. Most hernias contain ascites; however, omentum and bowel may also enter the defect. Given the high pressure, skin breakdown may ensue leading to hernia rupture or weeping as well as risk of spontaneous bacterial peritonitis. All attempts should be made to control the patient’s ascites prior to repair. Therefore, asymptomatic patients should be managed conserva-tively with aggressive management of ascites. Liver transplant candidates should undergo repair at the time of transplanta-tion as pretransplant repair has high morbidity and mortality. Patients with incarcerated hernias or with thinning or ruptured skin overlying the hernia should be treated emergently.Hernias that occur along the arcuate line are known as Spigelian hernias. While rare, these hernias form due to the anatomic weakness of lack of a posterior rectus sheath below the arcuate line. As the hernia develops, peritoneum that passes through the arcuate line will pass laterally toward the external oblique muscle given the overlying aponeurosis (Fig. 35-6). Most patients present with pain and swelling in the mid to lower abdomen. Incarceration is common as up to 20% of patients present with a nonreducible hernia. Given the high rate of incar-ceration, surgical repair is usually recommended. Either open or laparoscopic repair can be performed.Hernias that develop at sites of pre-vious abdominal incisions are known as incisional hernias.Hernias can develop at the site of any previous abdominal incision.Up to 20% of midline incisions will develop her-nias eventually.Vertical incisions may have a higher risk of hernia formation than transverse or oblique incisions.

The tethering complex that docks COPII-coated Figure 13–16 Tethering of a transport vesicle to a target membrane.as the result, a large tubular vesicle is formed that can accommodate the large cargo molecules. The packaging proteins are not part of the budding vesicle but remain in the er. (Modified from g. Zanetti et al., eLife 2:e00951, 2013.) cytosol; in their GTP-bound state, they are active and tightly associated with the membrane of an organelle or transport vesicle. Membrane-bound Rab-GEFs activate Rab proteins on both transport vesicle and target membranes; for some membrane fusion events, activated Rab molecules are required on both sides of the reaction. Once in the GTP-bound state and membrane-bound through a now-exposed lipid anchor, Rab proteins bind to other proteins, called Rab effectors, which are the downstream mediators of vesicle transport, membrane tethering, and membrane fusion (Figure 13–16). The rate of GTP hydrolysis sets the concentration of active Rab and, consequently, the concentration of its effectors on the membrane. In contrast to the highly conserved structure of Rab proteins, the structures and functions of Rab effectors vary greatly, and the same Rab proteins can often bind to many different effectors. Some Rab effectors are motor proteins that propel vesicles along actin filaments or microtubules to their target membrane. Others are tethering proteins, some of which have long, threadlike domains that serve as “fishing lines” that can extend to link two membranes more than 200 nm apart; other tethering proteins are large protein complexes that link two membranes that are closer together and interact with a wide variety of other proteins that facilitate the membrane fusion step. The tethering complex that docks COPII-coated Figure 13–16 Tethering of a transport vesicle to a target membrane.In the example shown here, the rab effector is a filamentous tethering protein (dark green).next, snare proteins on the two membranes (red and blue) pair, docking the vesicle to the target membrane and catalyzing the fusion of the two apposed lipid bilayers.

Common inflammatory diseases with pain include peptic ulcer, appendicitis, diverticulitis, inflammatory bowel disease, and infectious enterocolitis.Visceral pain generally is midline in location and vague in character, whereas parietal pain is localized and precisely described.Disorders Without Obvious Organic Abnormalities The most common GI disorders show no abnormalities on biochemical or structural testing and include irritable bowel syndrome, functional dyspepsia, functional chest pain, and functional heartburn. These disorders exhibit altered gut motor function; however, the pathogenic relevance of these abnormalities is uncertain. Exaggerated visceral sensory responses to noxious stimulation may cause discomfort in these disorders. Symptoms in other patients result from altered processing of visceral pain sensations in the central nervous system. Functional bowel patients with severe symptoms may exhibit significant emotional disturbances on psychometric testing. Subtle immunologic defects may contribute to functional symptoms as well. Genetic Influences Although many GI diseases result from environmental factors, others exhibit hereditary components. Family members of inflammatory bowel disease patients show a genetic predisposition to disease development themselves. Colonic and esophageal malignancies arise in certain inherited disorders. Rare genetic dysmotility syndromes are described. Familial clustering is even observed in the functional bowel disorders, although this may be secondary learned familial illness behavior rather than a true hereditary factor. The most common GI symptoms are abdominal pain, heartburn, nausea and vomiting, altered bowel habits, GI bleeding, and jaundice (Table 344-1). Others are dysphagia, anorexia, weight loss, fatigue, and extraintestinal symptoms. Abdominal Pain Abdominal pain results from GI disease and extra-intestinal conditions involving the genitourinary tract, abdominal wall, thorax, or spine. Visceral pain generally is midline in location and vague in character, whereas parietal pain is localized and precisely described. Common inflammatory diseases with pain include peptic ulcer, appendicitis, diverticulitis, inflammatory bowel disease, and infectious enterocolitis.Noninflammatory visceral sources include mesenteric ischemia and neoplasia.The most common causes of abdominal pain are irritable bowel syndrome and functional dyspepsia.Heartburn Heartburn, a burning substernal sensation, is reported intermittently by at least 40% of the population.Classically, heartburn is felt to result from excess gastroesophageal reflux of acid.

During antigen-driven B-cell differentiation, the immunoglobulin genes undergo further changes, such as class switching and somatic hypermutation (see Chapter 5), which are evident in the immunoglobulins produced by memory cells and plasma cells.B-1 cells are best thought of as a partly activated self-renewing pool of lymphocytes that are selected by ubiquitous self and foreign antigens. Because of this selection, and possibly because the cells are produced early in life, the B-1 cells have a restricted repertoire of variable regions and antigen-binding specificities. Marginal zone B cells also have a restricted repertoire of V-region specificities that may be selected by a set of antigens similar to those that select B-1 cells. B-1 cells seem to be the major population of B cells in certain body cavities, most probably because of exposure at these sites to antigens that drive B-1 cell proliferation. Marginal zone B cells remain in the marginal zone of the spleen and are not thought to recirculate. Partial activation of B-1 cells leads to the secretion of mainly IgM antibody; B-1 cells contribute much of the IgM that circulates in the blood. The limited diversity of both the B-1 and marginal zone B-cell repertoire and the propensity of these cells to react with common bacterial carbohydrate antigens suggest that they carry out a more primitive, less adaptive immune response than follicular B cells (B-2 cells). In this regard they are comparable to γ:δ T cells. Fig. 8.14 A summary of the development of human conventional B-lineage cells. The state of the immunoglobulin genes, the expression of some essential intracellular proteins, and the expression of some cell-surface molecules are shown for successive stages of conventional B-2 B-cell development. During antigen-driven B-cell differentiation, the immunoglobulin genes undergo further changes, such as class switching and somatic hypermutation (see Chapter 5), which are evident in the immunoglobulins produced by memory cells and plasma cells.Somatic hypermutation Alternative splicing yields both membrane and secreted Ig lgM Lympho-blast lgMlgD Mature naive B cell CD45R MHC class II IgM, IgD CD19, CD20 CD21, CD40 CD45R MHC class II IgG, IgA CD19, CD20 CD21, CD40 CD45R MHC class II CD19, CD20 CD21, CD40 VDJ rearranged.˝chain produced in membrane form.

Sometimes these small molecules are attached covalently and permanently to their protein, thereby becoming an integral part of the protein molecule itself.By binding reversibly to oxygen gas through its iron atom, heme enables hemoglobin to pick up oxygen in the lungs and release it in the tissues.Heme gives hemoglobin (and blood) its red color.Because it cannot be synthesized by humans, and must therefore be supplied in small quantities in our diet, biotin is a vitamin. Many other coenzymes are either vitamins or derivatives of vitamins (Table 3–2). Other proteins also frequently require specific small-molecule adjuncts to function properly. Thus, the signal receptor protein rhodopsin, which is made by the photoreceptor cells in the retina, detects light by means of a small molecule, retinal, embedded in the protein (Figure 3–53A). Retinal, which is derived from vitamin A, changes its shape when it absorbs a photon of light, and this change causes the protein to trigger a cascade of enzymatic reactions that eventually lead to an electrical signal being carried to the brain. Figure 3–53 Retinal and heme. (A) The structure of retinal, the light-sensitive molecule attached to rhodopsin in the eye. The structure shown isomerizes when it absorbs light. (B) The structure of a heme group. The carbon-containing heme ring is red and the iron atom at its center is orange. A heme group is tightly bound to each of the four polypeptide chains in hemoglobin, the oxygen-carrying protein whose structure is shown in Figure 3–19. Another example of a protein with a nonprotein portion is hemoglobin (see Figure 3–19). Each molecule of hemoglobin carries four heme groups, ring-shaped molecules each with a single central iron atom (Figure 3–53B). Heme gives hemoglobin (and blood) its red color. By binding reversibly to oxygen gas through its iron atom, heme enables hemoglobin to pick up oxygen in the lungs and release it in the tissues. Sometimes these small molecules are attached covalently and permanently to their protein, thereby becoming an integral part of the protein molecule itself.And membrane proteins exposed on the surface of the cell, as well as proteins secreted outside the cell, are often modified by the covalent addition of sugars and oligosaccharides.Multienzyme Complexes Help to Increase the Rate of Cell Metabolism The efficiency of enzymes in accelerating chemical reactions is crucial to the maintenance of life.

Insulin secretagogues, biguanides, α-glucosidase inhibitors, thiazolidinediones, GLP-1 receptor agonists, DPP-IV inhibitors, SLGT2 inhibitors, and insulin are approved for monotherapy of type 2 DM.If this occurs, the insulin may be discontinued.Other insulin formulations that have a combination of short-acting and long-acting insulin (Table 418-4) are sometimes used in patients with type 2 DM because of convenience but do not allow independent adjustment of short-acting and long-acting insulin dose and often do not achieve the same degree of glycemic control as basal/bolus regimens. In selected patients with type 2 DM, insulin-infusion devices may be considered. cHoice of initial GlucoSe-loWerinG aGent The level of hyperglycemia and the patient’s individualized goal (see “Establishment of Target Level of Glycemic Control”) should influence the initial choice of therapy. Assuming that maximal benefit of MNT and increased physical activity has been realized, patients with mild to moderate hyperglycemia (FPG <11.1–13.9 mmol/L [200–250 mg/dL]) often respond well to a single, oral glucose-lowering agent. Patients with more severe hyperglycemia (FPG >13.9 mmol/L [250 mg/dL]) may respond partially but are unlikely to achieve normoglycemia with oral monotherapy. A stepwise approach that starts with a single agent and adds a second agent to achieve the glycemic target can be used (see “Combination therapy with glucose-lowering agents,” below). Insulin can be used as initial therapy in individuals with severe hyperglycemia (FPG <13.9–16.7 mmol/L [250–300 mg/dL]) or in those who are symptomatic from the hyperglycemia. This approach is based on the rationale that more rapid glycemic control will reduce “glucose toxicity” to the islet cells, improve endogenous insulin secretion, and possibly allow oral glucose-lowering agents to be more effective. If this occurs, the insulin may be discontinued. Insulin secretagogues, biguanides, α-glucosidase inhibitors, thiazolidinediones, GLP-1 receptor agonists, DPP-IV inhibitors, SLGT2 inhibitors, and insulin are approved for monotherapy of type 2 DM.Considerable clinical experience exists with metformin and sulfonylureas because they have been available for several decades.It is assumed that the α-glucosidase inhibitors, GLP-1 agonists, DPP-IV inhibitors, thiazolidinediones, and SLGT2 inhibitors will reduce DM-related complications by improving glycemic control, but longterm data are not yet available.

Pelvic Floor The pelvic floor includes all of the structures closing the pelvic outlet from the skin inferiorly to the peritoneum superiorly.Even with severe intraperitoneal disease, the ureter can always be identified using a retroperitoneal approach and noting fundamental landmarks and relationships.As the ureter descends into the pelvis, it runs within the broad ligament just lateral to the uterosacral ligament, separating the uterosacral ligament from the mesosalpinx, mesovarium, and ovarian fossa. Figure 5.25 The course of the ureter and its relationship to the sites of greatest vulnerability. Pubovesical lig. Bladder Obturator a. Uterine a. Ureter Sup. vesical a. Vagina Uterosacral lig. Ureter Ovarian a. (infundibulopelvic lig.) 3. At about the level of the ischial spine, the ureter crosses under the uterine artery in its course through the cardinal ligament; the ureter divides this area into the supraureteric parametrium surrounding the uterine vessels and the infraureteric paracervix molded around the vaginal vessels and extending posteriorly into the uterosacral ligament. In this location, the ureter lies 2 to 3 cm lateral to the cervix and in proximity to the insertion of the uterosacral ligament at the cervix. This proximity warrants caution when using the uterosacral ligament for vaginal vault suspension (44,45). 4. The ureter then turns medially to cross the anterior upper vagina as it traverses the bladder wall. About 75% of all iatrogenic injuries to the ureter result from gynecologic procedures, most commonly abdominal hysterectomy (46). Distortions of pelvic anatomy, including adnexal masses, endometriosis, other pelvic adhesive disease, or fibroids, may increase susceptibility to injury by displacement or alteration of usual anatomy. Careful identification of the course of the ureter before securing the infundibulopelvic ligament and uterine artery is the best protection against ureteric injury during hysterectomy or adnexectomy. Even with severe intraperitoneal disease, the ureter can always be identified using a retroperitoneal approach and noting fundamental landmarks and relationships. Pelvic Floor The pelvic floor includes all of the structures closing the pelvic outlet from the skin inferiorly to the peritoneum superiorly.The pelvic diaphragm is spread transversely in a hammocklike fashion across the true pelvis, with a central hiatus for the urethra, vagina, and rectum.Anatomically and physiologically, the pelvic diaphragm can be divided into two components: the internal and external components.The external component originates from the arcus tendineus, extending from the pubic bone to the ischial spine.

In many cases, it shifts the reading frame to produce a nonfunctional gene, in which case the developing B cell fails to make a functional Ig molecule and consequently dies in the bone marrow.This increased diversification comes at a price, however.Any of the 35 or so functional V segments in our κ light-chain locus, for example, can be joined to any of the 5 J segments (see Figure 24–28), so that this locus can encode at least 175 (35 × 5) different κ-chain V regions. Similarly, any of the 40 V segments in the human heavy-chain locus can be joined to any of the 23 or so D segments and to any of the 6 J segments to encode at least 5520 (40 × 23 × 6) different heavy-chain V regions. By this mechanism alone, called V(D)J recombination, a human can produce 295 different VL regions (175 κand 120 λ) and 5520 different VH regions. In principle, these could then be combined to make over 1.5 × 106 (295 × 5520) different antigen-binding sites. V(D)J recombination is mediated by an enzyme complex called V(D)J recombinase, which recognizes recombination signal sequences in the DNA that flanks each gene segment to be joined. Although the process ensures that only appropriate gene segments recombine, a variable number of nucleotides are often lost from the ends of the recombining gene segments, and one or more randomly regions of DNA to be joined chosen nucleotides are also inserted. This random loss and gain of nucleotides at joining sites is called junctional diversification, and it enormously increases the diversity of V-region coding sequences created by V(D)J recombination (up to about 108-fold), specifically in the third hypervariable region. This increased diversification comes at a price, however. In many cases, it shifts the reading frame to produce a nonfunctional gene, in which case the developing B cell fails to make a functional Ig molecule and consequently dies in the bone marrow.B cells making BCRs that bind strongly to self antigens in the bone marrow would be dangerous.

Everolimus (an mTOR inhibitor) in coordination with endocrine agents is now being explored as front-line therapy and in the adjuvant setting.A series of studies with aromatase inhibitors, tamoxifen, and fulvestrant have all shown that the addition of everolimus to the hormonal treatment can lead to significant benefit after progression on the endocrine agent alone.If neither receptor is present, the objective response rates are <5%. Receptor analyses provide information as to the correct ordering of endocrine therapies as opposed to chemotherapy. Because of their lack of toxicity and because some patients whose receptor analyses are reported as negative respond to endocrine therapy, an endocrine treatment should be attempted in virtually every patient with metastatic breast cancer. Potential endocrine therapies are summarized in Table 108-4. The choice of endocrine therapy is usually determined by toxicity profile and availability. In most postmenopausal patients, the initial endocrine therapy should be an aromatase inhibitor rather than tamoxifen. For the subset of postmenopausal women who are estrogen receptor–positive but also HER2/neu-positive, response rates to aromatase inhibitors are substantially higher than to tamoxifen. Aromatase inhibitors are not used in premenopausal women because their hypothalamus can respond to estrogen deprivation by producing gonadotropins that promote estrogen synthesis. Newer “pure” antiestrogens that are free of agonistic effects are also effective. Cases in which tumors shrink in response to tamoxifen withdrawal (as well as withdrawal of pharmacologic doses of estrogens) have been reported. A series of studies with aromatase inhibitors, tamoxifen, and fulvestrant have all shown that the addition of everolimus to the hormonal treatment can lead to significant benefit after progression on the endocrine agent alone. Everolimus (an mTOR inhibitor) in coordination with endocrine agents is now being explored as front-line therapy and in the adjuvant setting.luteinizing hormone–releasing hormone in premenopausal women.Additive endocrine therapies, including treatment with progestogens, estrogens, and androgens, may also be tried in patients who respond to initial endocrine therapy; the mechanism of action of these latter therapies is unknown.

Symbol key Breast cancer 52 Breast ca 44 46 Ovarian ca 43 Ovarian cancer 2 40 Ovarian ca 38 42 Breast ca 38 24 Pneumonia 56 36 62 69 Breast ca 44 55 Ovarian ca 54 6210 Accident 6 40 5 2 2 intensive and ideally involves interviews of additional family members or reviewing medical records, autopsy reports, and death certificates.The physical examination may also provide important clues about the risk for a specific inherited disorder. A patient presenting with xanthomas at a young age should prompt consideration of familial hypercholesterolemia. The presence of trichilemmomas in a woman with breast cancer raises concern for Cowden syndrome, associated with PTEN mutations. Recall of family history is often inaccurate. This is especially so when the history is remote and families lose contact or separate geographically. It can be helpful to ask patients to fill out family history forms before or after their visits, because this provides them with an opportunity to contact relatives. Ideally, this information should be embedded in electronic health records and updated intermittently. Attempts should be made to confirm the illnesses reported in the family history before making important and, in certain circumstances, irreversible management decisions. This process is often labor FIGURE 84-1 A 36-year-old woman (arrow) seeks consultation because of her family history of cancer. The patient expresses concern that the multiple cancers in her relatives imply an inherited predisposition to develop cancer. The family history is recorded, and records of the patient’s relatives confirm the reported diagnoses. Symbol key Breast cancer 52 Breast ca 44 46 Ovarian ca 43 Ovarian cancer 2 40 Ovarian ca 38 42 Breast ca 38 24 Pneumonia 56 36 62 69 Breast ca 44 55 Ovarian ca 54 6210 Accident 6 40 5 2 2 intensive and ideally involves interviews of additional family members or reviewing medical records, autopsy reports, and death certificates.As a result, the pedigree obtained in such families may not exhibit a clear Mendelian inheritance pattern, because not all family members carrying the disease-associated alleles will manifest clinical evidence of the condition.Furthermore, genes associated with some of these disorders often exhibit variable disease expression.

This complication is believed to be a rare example of a long-term adverse efect of pregnancy.Progression was identiied in only 14 percent (Rasmussen, 2010).The same group of investigators evaluated 80 type 2 diabetics and identified retinopathy, mostly mild, in 14 percent during early pregnancy.A fourth of these women developed progression of retinopathy in at least one eye during pregnancy.In the United States, diabetic retinopathy is the most important cause ofvisual impairment in working-aged adults. he first and most common visible lesions are small microaneurysms followed by blot hemorrhages that form when erythrocytes escape from the aneurysms. hese areas leak serous fluid that creates hard exudates. Such features are termed backgroundor nonprolierative retinopathy. With increasingly severe retinopathy, the abnormal vessels of background eye disease become occluded, leading to retinal ischemia and infarctions that appear as cotton wool exuates. hese are considered preprolerative retinopathy. In response to ischemia, neovascularization begins on the retinal surface and out into the vitreous cavity. Vision is obscured when these vessels bleed. Laser photocoagulation before hemorrhage reduces the rate of visual loss progression and blindness by half. The procedure may be performed during pregnancy when indicated. Vestgaard and coworkers (2010) reported that almost two thirds of 102 pregnant women with type 1 diabetes examined by 8 weeks' gestation had background retinal changes, proliferative retinopathy, or macular edema. A fourth of these women developed progression of retinopathy in at least one eye during pregnancy. The same group of investigators evaluated 80 type 2 diabetics and identified retinopathy, mostly mild, in 14 percent during early pregnancy. Progression was identiied in only 14 percent (Rasmussen, 2010). This complication is believed to be a rare example of a long-term adverse efect of pregnancy.The American Academy of Ophthalmology (2016) recommends that pregnant women with preexisting diabetes should routinely be ofered retinal assessment after the first prenatal visit.Subsequent eye examinations depend on severity of retinopathy and level of diabetes control.

The broader definition would include all wounds drain-ing pus, whether or not the bacteriologic studies are positive; wounds that are opened by the surgeon; and wounds that the surgeon considers infected.92Anatomically, wound infections can be classified as superficial incisional, deep incisional, and organ/space wound infections, involving fascia, muscle, or the abdominal cavity.Most surgical wound infections become apparent within 7 to 10 days postoperatively, although a small number manifest years after the original operative intervention. With the hospital stay becoming shorter and shorter, many infections are detected in the outpatient setting, leading to underreporting of the true incidence of wound infections absent intensive sur-veillance. There has been much debate about the actual defini-tion of wound infection. The narrowest definition would include wounds that drain purulent material with bacteria identified on culture. The broader definition would include all wounds drain-ing pus, whether or not the bacteriologic studies are positive; wounds that are opened by the surgeon; and wounds that the surgeon considers infected.92Anatomically, wound infections can be classified as superficial incisional, deep incisional, and organ/space wound infections, involving fascia, muscle, or the abdominal cavity.aureus, S. epidermidisCefazolin1–2 g IV2OphthalmicS.epidermidis, S. aureus, streptococci, enteric gram-negative bacilli, Pseudomonas spp.Gentamicin, tobramycin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin or neomycin-gramicidin-polymyxin BOR cefazolinMultiple drops topically over 2 to 24 hours100 mg subconjuctivallyOrthopedicS.

670.e2 670.e1 In the clinic—cont’d Table 6.1 Branches of the lumbosacral plexus associated with the lower limb—cont’d Regional Anatomy • Deep Fascia and the Saphenous Opening Fig.6.145), which had to be repaired surgically.Unfortunately for this patient there was a tear of the anterior talofibular ligament (eFig.As each of these ligaments is disrupted, the severity of the soft tissue injury is significantly enhanced and the chance of permanent ankle instability is increased. On examination any positive anterior drawer test of the ankle (4–5 mm compared to the opposite side) suggests an injury to the anterior talofibular ligament. The anterior talofibular ligament can be assessed by placing the foot in marked plantarflexion. If there is over 10° of difference between the affected foot and nonaffected foot, an anterior talofibular ligament disruption is suspected. It is extremely rare for all three ligaments to be disrupted, and if so there are usually other significant ankle injuries. Magnetic resonance imaging (MRI) was carried out to assess ligament damage. MRI is excellent for demonstrating the medial and lateral ligament complexes of the ankle as well as the soft tissues that support the bones of the posterior foot. Unfortunately for this patient there was a tear of the anterior talofibular ligament (eFig. 6.145), which had to be repaired surgically. 670.e2 670.e1 In the clinic—cont’d Table 6.1 Branches of the lumbosacral plexus associated with the lower limb—cont’d Regional Anatomy • Deep Fascia and the Saphenous Opening Fig.It is suspended from the trunk by muscles and a small skeletal articulation between the clavicle and the sternum—the sternoclavicular joint.Based on the position of its major joints and component bones, the upper limb is divided into shoulder, arm, forearm, and hand (Fig.7.1A).The shoulder is the area of upper limb attachment to the trunk (Fig.7.1B).

This low level of surface immunoglobulin on plasma cells may still be physiologically important, since their survival seems to be determined in part by their ability to continue to bind antigen.Plasmablasts have relatively large numbers of B-cell receptors on the cell surface, whereas plasma cells have many fewer.Some of these proliferating B cells differentiate into antibody-synthesizing plasmablasts in the primary focus. Not all B cells activated by the initial interaction with TFH cells will move into the primary focus. Some will migrate into the lymphoid follicle, where they may eventually differentiate into plasma cells, as described below. Plasmablasts are cells that have begun to secrete antibody, yet are still dividing and express many of the characteristics of activated B cells that allow their interaction with T cells. After a few more days, the plasmablasts in the primary focus stop dividing and may eventually die. Subsequently, long-lived plasma cells will develop and migrate to the bone marrow, where they will continue antibody production. Since many long-lived plasma cells are generated long after the primary focus has dissipated, it is likely that they do not arise directly from plasmablasts in the primary focus, but rather from B cells that entered the germinal center reaction. The properties of resting B cells, plasmablasts, and plasma cells are compared in Fig. 10.9. The differentiation of a B cell into a plasma cell is accompanied by many morphological changes that reflect a commitment to the production of large amounts of secreted antibody, which can constitute up to 20% of all the protein synthesized by a plasma cell. Plasmablasts and plasma cells have a prominent perinuclear Golgi apparatus and an extensive rough endoplasmic reticulum that is rich in immunoglobulin molecules that are being synthesized and exported into the lumen of the endoplasmic reticulum for secretion. Plasmablasts have relatively large numbers of B-cell receptors on the cell surface, whereas plasma cells have many fewer. This low level of surface immunoglobulin on plasma cells may still be physiologically important, since their survival seems to be determined in part by their ability to continue to bind antigen.Nevertheless, T cells still provide important signals for plasma-cell differentiation and survival, such as IL-6 and CD40 ligand.Fig.10.9 Plasma cells secrete antibody at a high rate but can no longer respond to antigen.Resting naive B cells have membrane-bound immunoglobulin (usually IgM and IgD) and MHC class II molecules on their surface.

Primary isolation usually requires 5–7 days under anaerobic conditions but may take as long as 2–4 weeks.For optimal yield, the avoidance of even a single dose of antibiotics is mandatory.Microbiologic identification of actinomycetes is often precluded by prior antimicrobial therapy or failure to perform appropriate micro-biologic cultures.All too often, actinomycosis is first mentioned by the pathologist after extensive surgery. Since medical therapy alone is frequently sufficient for cure, the challenge for the clinician is to consider the possibility of actinomycosis, to diagnose it in the least invasive fashion, and to avoid unnecessary surgery. The clinical and radiographic presentations that suggest actinomycosis are discussed above. Of note, hypermetabolism has been demonstrated by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in actinomycotic disease. Aspirations and biopsies (with or without CT or ultrasound guidance) are being used successfully to obtain clinical material for diagnosis, although surgery may be required. The diagnosis is most commonly made by microscopic identification of sulfur granules (an in vivo matrix of bacteria, calcium phosphate, and host material) in pus or tissues. Occasionally, these granules are identified grossly from draining sinus tracts or pus. Although sulfur granules are a defining characteristic of actinomycosis, granules also are found in mycetoma (Chaps. 199 and 243) and botryomycosis (a chronic suppurative bacterial infection of soft tissue or, in rare cases, visceral tissue that produces clumps of bacteria resembling granules). These entities can easily be differentiated from actinomycosis with appropriate histopathologic and microbiologic studies. Microbiologic identification of actinomycetes is often precluded by prior antimicrobial therapy or failure to perform appropriate micro-biologic cultures. For optimal yield, the avoidance of even a single dose of antibiotics is mandatory. Primary isolation usually requires 5–7 days under anaerobic conditions but may take as long as 2–4 weeks.Because actinomycetes are components of the normal oral and genital-tract flora, their identification in the absence of sulfur granules in sputum, bronchial washings, and cervicovaginal secretions is of little significance.FIGuRE 200-4 Computed tomogram showing pelvic actinomy-cosis associated with an intrauterine contraceptive device.

Furthermore, individual cells function as part of a community of interacting tissues, not in isolation.METABOLISM REGULATION The pathways of metabolism must be coordinated so that the production of energy or the synthesis of end products meets the needs of the cell.II.Catabolism, then, is a convergent process (that is, a wide variety of molecules are transformed into a few common end products). 1. Hydrolysis of complex molecules: In the first stage, complex molecules are broken down into their component building blocks. For example, proteins are degraded to amino acids, polysaccharides to monosaccharides, and fats (triacylglycerols) to free fatty acids and glycerol. 2. Conversion of building blocks to simple intermediates: In the second stage, these diverse building blocks are further degraded to acetyl coenzyme A (CoA) and a few other simple molecules. Some energy is captured as ATP, but the amount is small compared with the energy produced during the third stage of catabolism. 3. Oxidation of acetyl coenzyme A: The tricarboxylic acid (TCA) cycle (see p. 109) is the final common pathway in the oxidation of fuel molecules that produce acetyl CoA. Oxidation of acetyl CoA generates large amounts of ATP via oxidative phosphorylation as electrons flow from NADH and flavin adenine dinucleotide (FADH2) to oxygen ([O2] see p. 73). C. Anabolic pathways In contrast to catabolism, anabolism is a divergent process in which a few biosynthetic precursors (such as amino acids) form a wide variety of polymeric, or complex, products (such as proteins [Fig. 8.4]). Anabolic reactions require energy (are endergonic), which is generally provided by the hydrolysis of ATP to adenosine diphosphate (ADP) and inorganic phosphate (Pi). [Note: Catabolic reactions generate energy (are exergonic).] Anabolic reactions often involve chemical reductions in which the reducing power is most frequently provided by the electron donor NADPH (phosphorylated NADH, see p. 147). II. METABOLISM REGULATION The pathways of metabolism must be coordinated so that the production of energy or the synthesis of end products meets the needs of the cell. Furthermore, individual cells function as part of a community of interacting tissues, not in isolation.Regulatory signals that inform an individual cell of the metabolic state of the body as a whole include hormones, neurotransmitters, and the availability of nutrients.These, in turn, influence signals generated within the cell (Fig.8.5).A. Intracellular communication The rate of a metabolic pathway can respond to regulatory signals that arise from within the cell.

Accordingly, mucosal tissues have developed specialized “noninflammatory” defense mechanisms, which form the basis of the mucosal immune system and can function independently of the systemic immune system.Insomelungdiseases—forexample,thosecausedbyinhalationofsilicaparticles(silicosis) orcoaldustparticles(pneumoconiosis, the“blacklung”diseaseofcoalminers)—alveolarmacrophagesphagocytizetheparticlesbutareunabletodestroythem,andthemacrophageseventuallydie.Alveolarmacrophageshavelocalizedandconcentratedtheparticlesinthe“Achillesheel”regionofthelung.Theseparticlesarenotremovedviamucociliaryclearanceandeventuallyenterthelunginterstitium.Theensuinginflammatoryresponseleadstoagranulomatouslikelesionwithfibrosis,arestrictivelungdisease.Silicosisandpneumoconiosisareclassicalexamplesofdiseasesoriginatingthroughenvironmentalworkplaceexposure.Increasedawarenessofthecauseofthesediseasesandimprovedworkplaceenvironmentshaveledtoreductionintheincidenceofthesetypesoflungdiseases. Mucosal Immune System: Adaptive and Innate Immunity In nonmucosal tissues (e.g., spleen, liver, kidney), the body’s primary defense is the classical proinflammatory adaptive, antigen-specific immune response orchestrated in the local draining lymph nodes with afferent and efferent lymph flow. The major adaptive immune cells in the systemic immune system are T lymphocytes with αβ T cell receptors (TCRαβ T cells) for specific antigen recognition and plasma B cells that synthesize immunoglobulin M (IgM) and immunoglobulin G (IgG) complement–binding antibodies, which can induce inflammation. However, mucosal tissues (i.e., those of the respiratory, gastrointestinal, and urinary systems, as well as the eyes, nose, throat, and mouth) must constantly discriminate between what is harmful and what is not, and although inflammation is protective, it usually disrupts the normal physiologic processes and is not desirable unless absolutely necessary. Accordingly, mucosal tissues have developed specialized “noninflammatory” defense mechanisms, which form the basis of the mucosal immune system and can function independently of the systemic immune system.These innate and unique adaptive responses can prevent or limit responses to foreign nonpathological agents while eliminating pathological agents/substances with little or no inflammation.

Tendon reflexes are usually preserved.Weakness of the flexor muscles of the forearm may be present in advanced cases.There is slight wasting and weakness of the hypothenar, interosseous, adductor pollicis, and deep flexor muscles of the fourth and fifth fingers (i.e., the muscles innervated by the lower trunk of the brachial plexus and ulnar nerve).Compression of the subclavian artery, which results in ischemia of the limb, may be complicated by digital gangrene and retrograde embolization, also is a rare entity. A unilateral Raynaud phenomenon, brittle nails, and ulceration of the fingertips are important diagnostic findings. A supraclavicular bruit is suggestive but not in itself diagnostic of subclavian artery compression. The conventional tests for vascular compression—obliteration of the pulse when the patient, seated and with the arm extended, takes and holds a full breath, tilts the head back, and turns it to the affected side (Adson test) or abducts and externally rotates the arm and braces the shoulders and turns the head to either side (Wright maneuver)—are not entirely reliable. Sometimes these maneuvers fail to obliterate the radial pulse in cases of proved compression; contrariwise, these tests may be positive in normal persons. Nevertheless, a positive test only on the symptomatic side (with reproduction of the patient’s symptoms) is suggestive of the diagnosis of arterial compression and, by implication, some form of thoracic outlet syndrome. Plethysmographic recording of the radial pulse and ultrasound of the vessel add greatly to the accuracy of these positional tests. A primarily neurologic problem may characterize the thoracic outlet syndrome. There is slight wasting and weakness of the hypothenar, interosseous, adductor pollicis, and deep flexor muscles of the fourth and fifth fingers (i.e., the muscles innervated by the lower trunk of the brachial plexus and ulnar nerve). Weakness of the flexor muscles of the forearm may be present in advanced cases. Tendon reflexes are usually preserved.A loss of superficial sensation in these areas is variable.It may be possible to reproduce the sensory symptoms by firm pressure just above the clavicle or by traction on the arm.Vascular features are often absent or minimal in patients with the neurologic form of the syndrome.In patients with neurologic signs, nerve conduction studies disclose reduced amplitude of the ulnar sensory potentials.

This led to the concept of “healthy” start and is congruent with the philosophy that it is better to keep patients feeling well all along rather than allowing them to become ill with uremia before trying to return them to better health with dialysis or transplantation.337) Temporary relief of symptoms and signs of impending uremia, such as anorexia, nausea, vomiting, lassitude, and pruritus, may sometimes be achieved with protein restriction. However, this carries a significant risk of malnutrition, and thus plans for more long-term management should be in place. Maintenance dialysis and kidney transplantation have extended the lives of hundreds of thousands of patients with CKD worldwide. Clear indications for initiation of renal replacement therapy for patients with CKD include uremic pericarditis, encephalopathy, intractable muscle cramping, anorexia, and nausea not attributable to reversible causes such as peptic ulcer disease, evidence of malnutrition, and fluid and electrolyte abnormalities, principally hyperkalemia or ECFV overload, that are refractory to other measures. Recommendations for the Optimal Time for Initiation of Renal Replacement 1821 Therapy Because of the individual variability in the severity of uremic symptoms and renal function, it is ill-advised to assign an arbitrary urea nitrogen or creatinine level to the need to start dialysis. Moreover, patients may become accustomed to chronic uremia and deny symptoms, only to find that they feel better with dialysis and realize in retrospect how poorly they were feeling before its initiation. Previous studies suggested that starting dialysis before the onset of severe symptoms and signs of uremia was associated with prolongation of survival. This led to the concept of “healthy” start and is congruent with the philosophy that it is better to keep patients feeling well all along rather than allowing them to become ill with uremia before trying to return them to better health with dialysis or transplantation.

Several classes of effectors that stimulate intestinal growth include spe-cific nutrients, peptide hormones and growth factors, pancreatic secretions, and some cytokines.The gastrin secretory response to secretin administration forms the basis for the standard test used to establish the diagnosis of Zollinger-Ellison syndrome. Chole-cystokinin is used in evaluations of gallbladder ejection frac-tion, a parameter that may have utility in patients who have symptoms of biliary colic but are not found to have gallstones. Of the peptides listed in Table 28-2, glucagon-like peptide 2 (GLP-2) has been identified as a specific and potent intestino-trophic hormone and is currently under clinical evaluation as an intestinotrophic agent in patients suffering from the short bowel syndrome, as discussed in the “Short Bowel Syndrome” section.Intestinal AdaptationThe small intestine has the capacity to adapt in response to vary-ing demands imposed by physiologic and pathologic conditions. Of relevance to many of the diseases discussed in this chapter is the adaptation that occurs in the remnant intestine following surgical resection of a large portion of the small intestine (mas-sive small bowel resection). Postresection intestinal adaptation has been studied extensively using animal models. Within a few hours after bowel resection, the remnant small intestine displays evidence of epithelial cellular hyperplasia. With additional time, villi lengthen, intestinal absorptive surface area increases, and digestive and absorptive functions improve. Postresection intes-tinal adaptation in human patients is less well studied, but it seems to follow similar steps as that seen in experimental mod-els, and it takes 1 to 2 years to complete.13The mechanisms responsible for inducing postresection intestinal adaptation are under active investigation. Several classes of effectors that stimulate intestinal growth include spe-cific nutrients, peptide hormones and growth factors, pancreatic secretions, and some cytokines.Jejunal resection is generally better tolerated, as ileum shows better capacity to compensate.However, the magnitude of this response is limited.If enough small intestine is resected, a devastating condition known as the short bowel syndrome results.

4.Presents as child with HTN, hypokalemia, and metabolic alkalosis, but with low aldosterone and low renin 3.Decreased degradation of sodium channels in collecting tubules due to genetic mutation; autosomal dominant 2.1.Responds to dexamethasone; confirmed with genetic testing G. Liddle syndrome mimics hyperaldosteronism.3.II. HYPERALDOSTERONISM A. Excess aldosterone B. Classically presents as HTN, hypokalemia, and metabolic alkalosis 1. Aldosterone increases absorption of sodium and secretion of potassium and hydrogen ions in the distal tubule and collecting duct. 2. Increased sodium expands plasma volume leading to HTN. C. Primary hyperaldosteronism is most commonly due to bilateral adrenal hyperplasia (60%, Fig. 15.15) or adrenal adenoma (40%, Conn syndrome, Fig. 15.16); adrenal carcinoma is rare. 1. CT is useful to determine pathology 2. Treatment for bilateral adrenal hyperplasia is mineralocorticoid receptor antagonist (e.g., spironolactone or eplerenone); adenoma and carcinoma are surgically resected. D. Secondary hyperaldosteronism arises with activation of the renin-angiotensin system (e.g., renovascular hypertension or CHF). Fig. 15.14 Steroidogenesis, adrenal cortex. Fig. 15.15 Adrenal hyperplasia. Fig. 15.16 Adrena l adenoma. E. Primary and secondary hyperaldosteronism are distinguished by plasma renin and edema 1. Primary is characterized by low renin and no edema (aldosterone escape). 2. Secondary is characterized by high renin; edema is often present. F. Glucocorticoid-remediable aldosteronism (GRA) leads to familial hyperaldosteron ism 1. Aberrant expression of aldosterone synthase in the fasciculata due to genetic mutation; autosomal dominant 2. Classically presents as child with HTN and hypokalemia; aldosterone is high and renin is low. 3. Responds to dexamethasone; confirmed with genetic testing G. Liddle syndrome mimics hyperaldosteronism. 1. Decreased degradation of sodium channels in collecting tubules due to genetic mutation; autosomal dominant 2. Presents as child with HTN, hypokalemia, and metabolic alkalosis, but with low aldosterone and low renin 3. 4.H. Syndrome of apparent mineralocorticoid excess (SAME) also mimics hyperaldosteronism.1.11~-hydroxysteroid dehydrogenase 2 (ll~-HSD2) deficiency allows cortisol to activate renal aldosterone receptors; autosomal recessive 2.Presents as child with HTN, hypokalemia, and metabolic alkalosis, but with low aldosterone and low renin 3.4.

When the risk of methicillin-resistant S. aureus is considered high, an agent active against these strains (e.g., vancomycin) should be chosen.If a foot ulcer is clinically infected, prompt empirical antimicrobial therapy may prevent progression to osteomyelitis.FIGURE 158-5 Neuropathic joint disease (Charcot foot) compli-cated by chronic foot osteomyelitis in a 78-year old woman with diabetes mellitus complicated by severe neuropathy. In many cases, foot osteomyelitis can be diagnosed clinically, without imaging procedures. Most clinicians rely on the “probe-to-bone” test, which has a positive predictive value of ~90% in populations with a high pretest probability. Thus, in a patient with diabetes who is hospitalized for a chronic deep foot ulcer, the diagnosis of foot osteomyelitis is highly probable if bone can be directly touched with a metal instrument. In a patient with a lower pretest probability, MRI should be performed because of its high degree of sensitivity (80–100%) and specificity (80–90%). Plain radiography has a sensitivity of only 30–90% and a specificity of only 50–90%; it may be considered for follow-up of patients with confirmed diabetic foot osteomyelitis. As mentioned above, correlation between cultures of bone and those of wound swabs or wound punctures is poor. Antibiotic treatment should be based on bone culture. If no bone biopsy is performed, empirical therapy chosen in light of the most common infecting agents and the type of clinical syndrome should be given. Wound debridement combined with a 4to 6-week course of antibiotics has been shown to render amputation unnecessary in about two-thirds of patients. According to the 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections, the following management strategies should be considered. If a foot ulcer is clinically infected, prompt empirical antimicrobial therapy may prevent progression to osteomyelitis. When the risk of methicillin-resistant S. aureus is considered high, an agent active against these strains (e.g., vancomycin) should be chosen.If the patient has received antibiotics within the past month, the spectrum of empirical antibiotics should include gram-negative bacilli (e.g., clindamycin plus a fluoroquinolone).

The signal in the brain is reflective of blood flow.Blood traversing in the neck is labeled by an MR pulse and then imaged in the brain after a short delay.ASL is a quantitative noninvasive MR technique that measures cerebral blood flow.This technique has proved useful to neuroscientists interested in interrogating the localization of certain brain functions.Perfusion MRI imaging can also be used in the assessment of brain tumors to differentiate intraaxial primary tumors, whose BBB is relatively intact, from extraaxial tumors or metastases, which demonstrate a relatively more permeable BBB. Diffusion tensor imaging is derived from diffusion MRI imaging sequences, which assesses the direction of microscopic motion of water along white matter tracts. This technique has great potential in the assessment of brain maturation as well as disease entities that undermine the integrity of the white matter architecture. It has proven valuable in preoperative assessment of subcortical white matter tract anatomy prior to brain tumor surgery (Fig. 440e-6). fMRI of the brain is an EPI technique that localizes regions of activity in the brain following task activation. Neuronal activity elicits a slight increase in the delivery of oxygenated blood flow to a specific region of activated brain. This results in an alteration in the balance of oxyhemoglobin and deoxyhemoglobin, which yields a 2–3% increase in signal intensity within veins and local capillaries. Further studies will determine whether these techniques are cost effective or clinically useful, but currently, preoperative somatosensory and auditory cortex localization is possible. This technique has proved useful to neuroscientists interested in interrogating the localization of certain brain functions. ASL is a quantitative noninvasive MR technique that measures cerebral blood flow. Blood traversing in the neck is labeled by an MR pulse and then imaged in the brain after a short delay. The signal in the brain is reflective of blood flow.Increased cerebral flow is more easily identified than slow flow, which can be sometimes difficult to quantify.This technique has also been shown useful in detecting arterial venous shunting in arteriovenous malformations and arteriovenous fistulas.MRN is a T2W MR technique that shows promise in detecting increased signal in irritated, inflamed, or infiltrated peripheral nerves.

Night eating syndrome.In such cases, substance/medication-induced sleep disorder, parasomnia type, should be diagnosed (see “Substance/Medication- Induced Sleep Disorder” later in this chapter).The underlying pathophysiology appears to be a relatively isolated amnesia.Such behaviors may arise from the sleep period and may be extremely complex.By history, these behaviors may be indistinguishable from those seen in NREM sleep arousal disorders. Dissociative amnesia, with dissociative fugue. Dissociative fugue may be extremely difficult to distinguish from sleepwalking. Unlike all other parasornnias, nocturnal disso- ciative fugue arises from a period of wakefulness during sleep, rather than precipitously from sleep without intervening wakefulness. A history of recurrent childhood physical or sexual abuse is usually present (but may be difficult to obtain). Malingering or other voluntary behavior occurring during wakefulness. As with disso- ciative fugue, malingering or other voluntary behavior occurring during wakefulness arises from wakefulness. Panic disorder. Panic attacks may also cause abrupt awakenings from deep NREM sleep accompanied by fearfulness, but these episodes produce rapid and complete awakening with- out the confusion, amnesia, or motor activity typical of NREM sleep arousal disorders. Medication-induced complex behaviors. Behaviors similar to those in NREM sleep arousal disorders can be induced by use of, or withdrawal from, substances or medica- tions (e.g., benzodiazepines, nonbenzodiazepine sedative-hypnotics, opiates, cocaine, nic- otine, antipsychotics, tricyclic antidepressants, chloral hydrate). Such behaviors may arise from the sleep period and may be extremely complex. The underlying pathophysiology appears to be a relatively isolated amnesia. In such cases, substance/medication-induced sleep disorder, parasomnia type, should be diagnosed (see “Substance/Medication- Induced Sleep Disorder” later in this chapter). Night eating syndrome.In adults, there is an association between sleepwalking and major depressive episodes and obsessive-compulsive disorder.Children or adults with sleep terrors may have elevated scores for depression and anxiety on personality inventories.

The transversalis is then sutured to the inguinal ligament laterally to the internal ring.Desarda Repair The Desarda hernia repair was recently described in 2001, and it consists of a mesh-free repair utilizing a strip of external oblique aponeurosis.An oblique skin incision is made, and dissection is carried down to the external oblique fascia.A 2 to 4 cm relaxing incision is made in the anterior rectus sheath vertically from the Brunicardi_Ch37_p1599-p1624.indd 161029/01/19 2:03 PM 1611INGUINAL HERNIASCHAPTER 37SpermaticcordPoupart'sligament Internal abdominaloblique muscleExternal abdominaloblique aponeurosisPreperitoneal fatTransversalis fasciaABEOTATFILIOFigure 37-15. Bassini repair. A. The transversalis fascia is opened. B. Reconstruction of the posterior wall by suturing the transver-salis fascia (TF), the transversus abdominis muscle (TA), and the internal oblique muscle (IO) medially to the inguinal ligament (IL) laterally. EO = external oblique aponeurosis.ABFigure 37-16. Shouldice repair. A. The iliopubic tract is sutured to the medial flap of the transversalis fascia and the internal oblique and transverse abdominis muscles. B. The second of the four suture lines, reversing toward the pubic tubercle approximating the inter-nal oblique and transversus muscles to the inguinal ligament. Two more suture lines affix the internal oblique and transversus muscles medially.Cooper’s ligamentFigure 37-17. McVay Cooper’s ligament repair.pubic tubercle. This incision is essential to reduce tension on the repair; however, it may result in increased postoperative pain and higher risk of ventral abdominal herniation. Using either interrupted or continuous suture, the superior transversalis flap is then fastened to Cooper’s ligament, and the repair is contin-ued laterally along Cooper’s ligament to occlude the femoral ring. Lateral to the femoral ring, a transition stitch is placed, affixing the transversalis fascia to the inguinal ligament. The transversalis is then sutured to the inguinal ligament laterally to the internal ring.Desarda Repair The Desarda hernia repair was recently described in 2001, and it consists of a mesh-free repair utilizing a strip of external oblique aponeurosis.An oblique skin incision is made, and dissection is carried down to the external oblique fascia.The cremasteric muscle is then incised, and the spermatic cord along with the cremasteric muscle is separated from the inguinal floor.

It also appears that the incidence of hepatic adenomas is increased in women taking oral contraceptives.This is probably the result of the alterations responsible for jaundice and bile acid changes described above.These agents have also been found to increase the incidence of symptomatic gallbladder disease, including cholecystitis and cholangitis.It is increased in current users of oral contraceptives but not in past users. However, subarachnoid hemorrhages have been found to be increased among both current and past users and may increase with time. The risk of thrombotic or hemorrhagic stroke attributable to oral contraceptives (based on older, higher-dose preparations) has been estimated at about 37 cases per 100,000 users per year. In summary, available data indicate that oral contraceptives increase the risk of various cardiovascular disorders at all ages and among both smokers and nonsmokers. However, this risk appears to be concentrated in women 35 years of age or older who are heavy smokers. It is clear that these risk factors must be considered in each individual patient for whom oral contraceptives are being considered. Some experts have suggested that screening for coagulopathy should be performed before starting oral contraception. 2. Gastrointestinal disorders—Many cases of cholestatic jaundice have been reported in patients taking progestin-containing drugs. The differences in incidence of these disorders from one population to another suggest that genetic factors may be involved. The jaundice caused by these agents is similar to that produced by other 17-alkyl-substituted steroids. It is most often observed in the first three cycles and is particularly common in women with a history of cholestatic jaundice during pregnancy. Jaundice and pruritus disappear 1–8 weeks after the drug is discontinued. These agents have also been found to increase the incidence of symptomatic gallbladder disease, including cholecystitis and cholangitis. This is probably the result of the alterations responsible for jaundice and bile acid changes described above. It also appears that the incidence of hepatic adenomas is increased in women taking oral contraceptives.3.Depression—Depression of sufficient degree to require cessation of therapy occurs in about 6% of patients treated with some preparations.4.Cancer—The occurrence of malignant tumors in patients taking oral contraceptives has been studied extensively.It is now clear that these compounds reduce the risk of endometrial and ovarian cancer.

Serologic studies should be ordered to identify latent infection with viruses such as herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), Kaposi’s sarcoma–associated herpes-virus (KSHV); acute infection with hepatitis A virus; and infection with the common parasite Toxoplasma gondii.Two central issues are of paramount importance: (1) infectious agents (particularly viruses, but also bacteria, fungi, and parasites) can be introduced into the recipient by the donor; and (2) treatment of the recipient with medicine to prevent rejection can suppress normal immune responses, greatly increasing susceptibility to infection. Thus, what might have been a latent or asymptomatic infection in an immunocompetent donor or in the recipient prior to therapy can become a life-threatening problem when the recipient becomes immunosuppressed. The pretransplantation evaluation of each patient should be guided by an analysis of both (1) what infections the recipient is currently harboring, since organisms that exist in a state of latency or dormancy before the procedure may cause fatal disease when the patient receives immunosuppressive treatment; and (2) what organisms are likely to be transmitted by the donor, particularly those to which the recipient may be naïve. PRETRANSPLANTATION EVALUATION The Donor A variety of organisms have been transmitted by organ transplantation. Transmission of infections that may have been latent or not clinically apparent in the donor has resulted in the development of specific donor-screening protocols. Results from routine blood bank studies, including those for antibodies to Treponema pallidum (syphilis), Trypanosoma cruzi, hepatitis B and C viruses, HIV-1 and -2, human T-lymphotropic virus types 1 and 2 (HTLV-1 and -2), and West Nile virus (WNV), should be documented. Serologic studies should be ordered to identify latent infection with viruses such as herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), Kaposi’s sarcoma–associated herpes-virus (KSHV); acute infection with hepatitis A virus; and infection with the common parasite Toxoplasma gondii.Clinicians caring for prospective organ donors should examine chest radiographs for evidence of granulomatous disease (e.g., caused by mycobacteria or fungi) and should perform skin testing or obtain blood for immune cell–based assays that detect active or latent Mycobacterium tuberculosis infection.

Fundic gland polyps occur sporadically and in individuals with familial adenomatous polyposis (FAP) Polyps associated with FAP (but not sporadic) may show dysplasia, but they almost never progress to become malignant.Intestinal metaplasia developsinbothformsofchronicgastritisandisariskfactorfordevelopmentofgastricdysplasiaandadenocarcinoma. PepticulcerdiseasecanbecausedbyH. pylori chronicgastritisandtheresultanthyperchlorhydriaorNSAIDuse.Ulcerscandevelopinthestomachorduodenumandusuallyhealaftersuppressionofgastricacidproduction,discontinuationofNSAIDuse,or,ifpresent,H. pylori eradication. Polyps are nodules or masses that project above the level of the surrounding mucosa. They are identified in up to 5% of upper gastrointestinal tract endoscopies. Polyps may develop as a result of epithelial or stromal cell hyperplasia, inflammation, ectopia, or neoplasia. Although many different types of polyps can occur in the stomach, only hyper-plastic and inflammatory polyps, fundic gland polyps, and adenomas are considered here. Up to 75% of all gastric polyps are inflammatory or hyperplastic polyps. In the stomach, inflammatory and hyperplastic polyps represent opposite ends of the morphologic spectrum of a single entity; the distinction is based solely on the degree of inflammation. They most commonly affect individuals between 50 and 60 years of age, usually arising in a background of chronic gastritis that initiates the injury and reactive hyperplasia that cause polyp growth. If associated with H. pylori gastritis, polyps may regress after bacterial eradication. The frequency with which dysplasia, a precancerous in situ lesion, develops in these polyps correlates with size; there is a significant increase in risk with polyps larger than 1.5 cm. Fundic gland polyps occur sporadically and in individuals with familial adenomatous polyposis (FAP) Polyps associated with FAP (but not sporadic) may show dysplasia, but they almost never progress to become malignant.This likely results from increased gastrin secretion, in response to reduced acidity, and glandular hyperplasia driven by gastrin.Fundic gland polyps are nearly always asymptomatic, and are usually an incidental finding.

In contrast to response-driven feedback, the physiological responses to the peripherally produced hormone play only a minor role in regulation of feedback within endocrine axis–driven feedback loops.In the response-driven configuration, secretion of a hormone is stimulated or inhibited by a change in the level of a specific extracellular parameter (e.g., an increase in blood glucose level stimulates insulin secretion). Alterations in hormone levels lead to changes in the physiological characteristics of target organs (e.g., decreased hepatic gluconeogenesis, increased uptake of glucose by muscle) that directly regulate the parameter (in this case, blood glucose level) in question. The change in the parameter (decreased blood glucose level) then inhibits further secretion of the hormone (i.e., insulin secretion drops as blood glucose level falls). Much of the endocrine system is organized into endocrine axes; each axis consists of the hypothalamus, the pituitary gland, and the peripheral endocrine glands (see Fig. 38.2 ). Thus the endocrine axis–driven feedback loop involves a three-tiered configuration. The first tier is represented by hypothalamic neuroendocrine neurons that secrete releasing hormones. Releasing hormones stimulate (or, in a few cases, inhibit) the production and secretion of tropic hormones from the pituitary gland (second tier). Tropic hormones stimulate the production and secretion of hormones from peripheral endocrine glands (third tier). The peripherally produced hormones—namely, thyroid hormone, cortisol, sex steroids, and IGF-1—typically have pleiotropic actions (e.g., multiple phenotypic effects) on numerous cell types. However, in endocrine axis–driven feedback, the primary feedback loop involves feedback inhibition of pituitary tropic hormones and hypothalamic releasing hormones by the peripherally produced hormone. In contrast to response-driven feedback, the physiological responses to the peripherally produced hormone play only a minor role in regulation of feedback within endocrine axis–driven feedback loops.Primary disease is a lesion in the peripheral endocrine gland; secondary disease is a lesion in the anterior pituitary gland; and tertiary disease is a lesion in the hypothalamus.An important aspect of the endocrine axes is the ability of descending and ascending neuronal signals to modulate release of the hypothalamic releasing hormones and thereby control the activity of the axis.

Paravertebral ganglia are linked together and form two sympathetic trunks (yellow columns on each side of the spinal cord).These presynaptic fibers communicate with postsynaptic neurons in two locations, the paravertebral and prevertebral ganglia.The sympathetic (thoracolumbar) outflow leaves the CNS from the thoracic and upper lumbar segments (T1–L2 or L3) of the spinal cord.(Redrawn with permission from Reith EJ, Breidenbach B, Lorenc M. Textbook of Anatomy and Physiology. St. Louis: CV Mosby, 1978.) blood vessels of visceral structures, blood vessels, sweat glands, and arrector muscles of hairs eye (iris) cephalic arterial ramus carotid periarterial plexus cardiopulmonary splanchnic nerves heart larynx trachea bronchi lungs diaphragm stomach pancreas spleen liver gallbladder bladder penis (clitoris) gonad inferior mesenteric ganglion superior mesenteric ganglion aorticorenal ganglion celiac ganglion abdominopelvic splanchnic nerves large intestine small intestine kidney suprarenal (adrenal) gland rectum internal anal sphincter presynaptic postsynaptic sympathetic fibers lacrimal gland nasal, palatine, and pharyngeal glands eye (iris, ciliary mm.) sacral parasympathetic outflow (via pelvic splanchnic nerves) parotid gland sublingual and submandibular glands heart larynx trachea bronchi lungs liver gallbladder left colic (splenic) flexure dividing sacral para-sympathetic supply from cranial supply large intestine small intestine rectum innervation via sacral outflow innervation via cranial outflow ciliary ganglion bladder penis (clitoris) stomach pancreas pterygopalatine ganglion otic ganglion submandibular ganglion cranial parasympathetic outflow (via 4 cranial nerves) III VII IX X S2 S3 S4 FIGURE 12.25 • Schematic diagram showing the general arrangement of sympathetic and parasympathetic neurons of the ANS. The sympathetic outflow is shown on the right; the parasympathetic, on the left. The sympathetic (thoracolumbar) outflow leaves the CNS from the thoracic and upper lumbar segments (T1–L2 or L3) of the spinal cord. These presynaptic fibers communicate with postsynaptic neurons in two locations, the paravertebral and prevertebral ganglia. Paravertebral ganglia are linked together and form two sympathetic trunks (yellow columns on each side of the spinal cord).Note the distribution of postsynaptic sympathetic nerve fibers to the viscera.The parasympathetic (craniosacral) outflow leaves the CNS from the gray matter of the brain stem within cranial nerves III, VII, IX, and X and the gray matter of sacral segments (S2–S4) of the spinal cord and is distributed to the viscera.

For treatment of athlete’s foot, apply product to spaces between toes and change shoes and socks daily.Adverse effects include: confusion, excitement, irritability, nervousness, and serotonin syndrome (uncommon).Use with caution in patients with a chronic cough that occurs with smoking, asthma, and emphysema and in patients with cough with production of mucus.(Continued) Miconazole (Desenex, Lotrimin AF) Miconazole (Monistat-1, Monistat-3, Monistat-7, Vagistat-3) Tioconazole (Monistat-1 1-Day, Vagistat-1) Dextromethorphan (Delsym, Robitussin Cough, Vicks 44) Relieves itching, burning, scaling, chafing, and discomfort associated with tinea pedis (athlete’s foot), tinea cruris (jock itch), and tinea corporis (ringworm). Treatment of vaginal yeast (candidiasis) infections and for the relief of external vulvar itching and irritation associated with vaginal yeast infections. Temporary relief of cough due to minor throat and bronchial irritation with the common cold or inhaled irritants. For external use only. Avoid contact with eyes, nose, mouth, or other mucous membranes. Avoid use: in children <2 years of age (clotrimazole, miconazole, tolnaftate) or children <12 years of age (butenafine, terbinafine). Adverse effects include: erythema, irritation, itching, and burning. For vaginal use only. Avoid use: in children <12 years of age; if patient has lower abdominal, back, or shoulder pain, or fever, chills, nausea, vomiting, or foul-smelling vaginal discharge; in combination with tampons, douches, spermicides, or other vaginal products. Adverse effects include: vaginal itching, burning, vaginal soreness, and swelling. Avoid use: in patients taking a monoamine oxidase inhibitor (MAOI), or for 2 weeks after discontinuation of an MAOI. Use with caution in patients with a chronic cough that occurs with smoking, asthma, and emphysema and in patients with cough with production of mucus. Adverse effects include: confusion, excitement, irritability, nervousness, and serotonin syndrome (uncommon). For treatment of athlete’s foot, apply product to spaces between toes and change shoes and socks daily.Therapy should be discontinued if symptoms do not improve within 3 days or if symptoms persist after 7 days of treatment.Vaginal products (7-day therapy preferred) can be used for treatment in pregnant women.Products with similar brand names may contain different antifungal products; read labels and instructions for use carefully.

Syringomyelia (see also Chap.Removal of the fibrous-bony spicule and untethering of the spinal cord have been beneficial in some cases.With body growth, the restriction created by the bone spicule leads to a traction myelopathy, presenting with pain and progressive sensory, motor, and bladder symptoms, sometimes as late as adult life.Complex disturbances of bladder function that produce urgency and incontinence beginning in the second or third decade may be the only manifestation, or the bladder symptoms may be combined with impotence (in the male) and numbness of the feet and legs or foot-drop (Pang and Wilberger). Several of our adult patients have had unusual visceral reflex reactions, such as involuntary defecation or priapism with stimulation of the abdomen or perineum. According to most surgeons, it is not the myelolipoma but the tethering of the cord that gives rise to symptoms; removal of the tumor is of little benefit unless the cord is detached from the sacrum at the same time. This may be difficult, for the lipoma may be fused with the dorsal surface of the spinal cord. Diastematomyelia is another unusual abnormality of the spinal cord often associated with spina bifida. Here a bony spicule or fibrous band protrudes into the spinal canal from the body of one of the thoracic or upper lumbar vertebrae and divides the spinal cord into halves for a variable vertical extent. In extreme examples, the division of the cord may be complete, each half with its own dural sac and complete set of nerve roots. This longitudinal fissuring and doubling of the cord are spoken of as diplomyelia. With body growth, the restriction created by the bone spicule leads to a traction myelopathy, presenting with pain and progressive sensory, motor, and bladder symptoms, sometimes as late as adult life. Removal of the fibrous-bony spicule and untethering of the spinal cord have been beneficial in some cases. Syringomyelia (see also Chap.There are a variety of other neurodevelopmental spinal abnormalities in the high cervical region, such as fusion of atlas and occiput or of cervical vertebrae (Klippel-Feil syndrome), congenital dislocation of the odontoid process and atlas, platybasia, and basilar impression.These abnormalities are discussed in Chap.42, with other diseases of the spinal cord.

Systemic symptoms are uncommon, but cysts may develop into perianal fistulas.Patients present with an abscess at the natal cleft that can be tender, fl uctuant, warm, and indurated and is sometimes associated with purulent drainage or cellulitis.It most commonly occurs between the ages of 20 and 40, affecting men more often than women.Women in their 20s tend to have a variant that flares cyclically with menstruation, featuring fewer comedones and more painful lesions on the chin. Androgenic stimulation may contribute to these lesions. Diagnosed by the clinical picture. Treat comedones with topical tretinoin (Retin-A) and benzoyl peroxide. Inflammatory lesions should be treated with topical antibiotics (e.g., erythromycin, clindamycin) or systemic agents (e.g., tetracycline, erythromycin). Isotretinoin (Accutane) leads to marked improvement in > 90% of acne patients and has greatly improved the treatment of severe acne. Isotretinoin is, however, a teratogen and may cause transient elevations in cholesterol, triglycerides, and LFTs, and it may also be associated with depression. Patients on isotretinoin are thus carefully monitored and are required to get monthly blood tests to check quantitative serum β-hCG (to rule out pregnancy), LFTs, cholesterol, and triglycerides. Monthly refills are contingent on completion of blood testing and evaluation by a dermatologist. Abscesses in the sacrococcygeal region that usually occur near the top of the natal cleft. Their name may not be appropriate, as not all such cysts contain hair, and not all are true cysts. Repetitive trauma to the region plays a role. The condition is thought to start as a folliculitis that becomes an abscess complicated by perineal microbes, especially Bacteroides. It most commonly occurs between the ages of 20 and 40, affecting men more often than women. Patients present with an abscess at the natal cleft that can be tender, fl uctuant, warm, and indurated and is sometimes associated with purulent drainage or cellulitis. Systemic symptoms are uncommon, but cysts may develop into perianal fistulas.Diagnosed by the clinical picture.Rule out perirectal and anal abscess.Treatment consists of incision and drainage of the abscess under local anesthesia followed by sterile packing of the wound.Abscesses should be allowed to heal by 2° intention.Antibiotics are not needed unless cellulitis is present; if they are prescribed, both aerobic and anaerobic coverage is required.

These include the seven transmembrane receptor family, which is the main agoniststimulated receptor family.Many families and subfamilies of receptors are found on platelets that regulate a variety of platelet functions.Stimulation of nonthrombotic receptors results in platelet adhesion or interaction with other vascular cells including endothelial cells, neutrophils, and mononuclear cells.The GPIb-IX-V comtion of the platelet, shape change, and the synthesis and release of thromboxane (TxA2), serotonin plex binds to the exposed von Willebrand (5-HT), and adenosine diphosphate (ADP). Platelet stimuli cause conformational change in the factor, causing platelets to adhere (Fig. platelet integrin glycoprotein (GP) IIb/IIIa receptor, leading to the high-affinity binding of fibrino-142-1). In addition, the engagement of the gen and the formation of a stable platelet thrombus. GPIb-IX-V complex with ligand induces 742 signaling pathways that lead to platelet activation. von Willebrand factor–bound GPIb-IX-V promotes a calcium-dependent conformational change in the GPIIb/IIIa receptor, transforming it from an inactive low-affinity state to an active high-affinity receptor for fibrinogen. Platelet Activation The activation of platelets is controlled by a variety of surface receptors that regulate various functions in the activation process. Platelet receptors control many distinct processes and are stimulated by a wide variety of agonists and adhesive proteins that result in variable degrees of activation. In general terms, the stimulation of platelet receptors triggers two specific processes: (1) activation of internal signaling pathways that lead to further platelet activation and granule release and (2) the capacity of the platelet to bind to other adhesive proteins/platelets. Both of these processes contribute to the formation of a thrombus. Stimulation of nonthrombotic receptors results in platelet adhesion or interaction with other vascular cells including endothelial cells, neutrophils, and mononuclear cells. Many families and subfamilies of receptors are found on platelets that regulate a variety of platelet functions. These include the seven transmembrane receptor family, which is the main agoniststimulated receptor family.Receptors for thrombin comprise the major seven transmembrane receptors found on platelets.Among this last group, the first identified was the protease activation receptor 1 (PAR1).The PAR class of receptors has a distinct mechanism of activation that involves specific cleavage of the N-terminus of thrombin, which, in turn, acts as a ligand for the receptor.

Herpesviruses often enter latency.It does, however, make neurons attractive as cellular reservoirs for persistent infections.The low level of MHC class I expression is beneficial because it reduces the risk that neurons, which have a limited capacity for regeneration, will be targeted inappropriately by cytotoxic T cells.An example is herpes simplex virus (HSV), the cause of cold sores, which infects epithelial cells and then spreads to sensory neurons serving the infected area. An effective immune response controls the epithelial infection, but the virus persists in a latent state in the sensory neurons. Factors such as sunlight, bacterial infection, or hormonal changes reactivate the virus, which then travels down the axons of the sensory neuron and reinfects the epithelial tissues (Fig. 13.26). At this point, the immune response again becomes active and controls the local infection by killing the epithelial cells, producing a new sore. This cycle can be repeated many times. Fig. 13.26 Persistence and reactivation of herpes simplex virus infection. the initial infection in the skin is cleared by an effective immune response, but residual infection persists in sensory neurons such as those of the trigeminal ganglion, whose axons innervate the lips. When the virus is reactivated, usually by some environmental stress and/or alteration in immune status, the skin in the area served by the nerve is reinfected from virus in the ganglion and a new cold sore results. this process can be repeated many times. There are two reasons why the sensory neuron remains infected: first, the virus is quiescent and generates few virusderived peptides to present on MHC class I molecules; second, neurons carry very low levels of MHC class I molecules, which makes it harder for CD8 cytotoxic T cells to recognize infected neurons and attack them. The low level of MHC class I expression is beneficial because it reduces the risk that neurons, which have a limited capacity for regeneration, will be targeted inappropriately by cytotoxic T cells. It does, however, make neurons attractive as cellular reservoirs for persistent infections. Herpesviruses often enter latency.It then spreads down the nerve and reinfects the skin to cause the disease herpes zoster, or shingles, which is marked by the reappearance of the classic varicella rash in the area of skin served by the infected dorsal root.Unlike herpes simplex, which reactivates frequently, herpes zoster usually reactivates only once in a lifetime in an immunocompetent host.

In patients with no known preexisting morbidity, the case–fatality rate remains <10% until the fourth decade of life, after which it gradually increases to >35% in the very elderly.325-1).Age and prior health status are probably the most important risk factors (Fig.This analysis suggests that if more aggressive early resuscitation improves survival rates among sicker patients, it will become more difficult to obtain additional benefit from other therapies; that is, if an intervention improves patients’ risk status, moving them into a “less severe illness” category, it will be harder to show that adding another agent to the therapeutic regimen is beneficial. An international consortium has advocated “bundling” of multiple therapeutic maneuvers into a unified algorithmic approach that will become the standard of care for severe sepsis. In theory, such a strategy would improve care by mandating measures that seem to bring maximal benefit, such as the rapid administration of appropriate antimicrobial therapy, fluids, and blood pressure support. Caution may be engendered by the fact that three of the key elements of the initial algorithm were eventually withdrawn for lack of evidence; moreover, the benefit of the current sepsis bundles has not been established in randomized controlled clinical trials. Approximately 20–35% of patients with severe sepsis and 40–60% of patients with septic shock die within 30 days. Others die within the ensuing 6 months. Late deaths often result from poorly controlled infection, immunosuppression, complications of intensive care, failure of multiple organs, or the patient’s underlying disease. Case–fatality rates are similar for culture-positive and culture-negative severe sepsis. Prognostic stratification systems such as APACHE II indicate that factoring in the patient’s age, underlying condition, and various physiologic variables can yield useful estimates of the risk of dying of severe sepsis. Age and prior health status are probably the most important risk factors (Fig. 325-1). In patients with no known preexisting morbidity, the case–fatality rate remains <10% until the fourth decade of life, after which it gradually increases to >35% in the very elderly.Septic shock is also a strong predictor of markers, such as IL-6 levels in blood or the expression of HLA-DR on peripheral-blood monocytes, to identify the patients most likely to benefit from certain interventions.

Due to  PTH, classically associated with 1° (but also seen with 2°) hyperparathyroidism.Osteitis fibrosa cystica—cystic bone spaces filled with brown fibrous tissue A (“brown tumor” consisting of osteoclasts and deposited hemosiderin from hemorrhages; causes bone pain).Chvostek sign—tapping of facial nerve (tap the Cheek) Ž contraction of facial muscles. Trousseau sign—occlusion of brachial artery with BP cuff (cuff the Triceps) Ž carpal spasm. Pseudohypoparathyroidism type 1A—autosomal dominant, maternally transmitted mutations (imprinted GNAS gene). GNAS1-inactivating mutation (coupled to PTH receptor) that encodes the Gs protein α subunit Ž inactivation of adenylate cyclase when PTH binds to its receptor Ž end-organ resistance (kidney and bone) to PTH. Physical findings: Albright hereditary osteodystrophy (shortened 4th/5th digits A , short stature, round face, subcutaneous calcifications, developmental delay). Labs:  PTH, • Ca2+,  PO43–. Pseudopseudohypoparathyroidism—autosomal dominant, paternally transmitted mutations (imprinted GNAS gene) but without end-organ resistance to PTH due to normal maternal allele maintaining renal responsiveness to PTH. Physical findings: same as Albright hereditary osteodystrophy. Labs: normal PTH, Ca2+, PO43–. Usually due to parathyroid adenoma or hyperplasia. Hypercalcemia, hypercalciuria (renal stones), polyuria (thrones), hypophosphatemia,  PTH,  ALP,  urinary cAMP. Most often asymptomatic. May present with bone pain, weakness, constipation (“groans”), abdominal/flank pain (kidney stones, acute pancreatitis), neuropsychiatric disturbances (“psychiatric overtones”). Osteitis fibrosa cystica—cystic bone spaces filled with brown fibrous tissue A (“brown tumor” consisting of osteoclasts and deposited hemosiderin from hemorrhages; causes bone pain). Due to  PTH, classically associated with 1° (but also seen with 2°) hyperparathyroidism.Rarely, can be caused by unopposed secretion of GH and epinephrine.Also seen in patients on glucocorticoid therapy (steroid diabetes).chronic comPlicAtions Nonenzymatic glycation: Small vessel disease (diffuse thickening of basement membrane) Ž retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, nephropathy.

Prophylactic acyclovir or valacyclovir may reduce rates of CMV infection and disease in renal transplant recipients, although neither drug is effective in the treatment of active CMV disease.Studies in hematopoietic stem cell transplant recipients have produced conflicting results.With preemptive therapy, patients are monitored weekly for CMV viremia, and antiviral treatment is initiated once viremia is detected. Because of the bone marrow–suppressive effects of universal prophylaxis, preemptive therapy is more commonly employed in hematopoietic stem cell transplant recipients. For patients with advanced HIV infection (CD4+ T cell counts of <50/μL), some experts have advocated prophylaxis with valganciclovir (see below). However, side effects, lack of proven benefit, possible induction of viral resistance, and high cost have precluded the wide acceptance of this practice. Preemptive therapy is under study in HIV-infected patients. Several additional measures are useful for the prevention of CMV transmission to CMV-naïve, high-risk patients. The use of CMVseronegative or leukocyte-depleted blood greatly decreases the rate of transfusion-associated transmission. In a placebo-controlled trial, a CMV glycoprotein B vaccine reduced infection rates among 464 CMV-seronegative women; this outcome raises the possibility that this experimental vaccine will reduce rates of congenital infection, but further studies must validate this approach. A CMV glycoprotein B vaccine with MF59 adjuvant appeared effective in reducing the risk and duration of viremia in both seropositive and seronegative renal transplant recipients at risk for CMV infection. CMV immune globulin has been reported to prevent congenital CMV infection in infants of women with primary infection during pregnancy. Studies in hematopoietic stem cell transplant recipients have produced conflicting results. Prophylactic acyclovir or valacyclovir may reduce rates of CMV infection and disease in renal transplant recipients, although neither drug is effective in the treatment of active CMV disease.After intracellular conversion by a viral phosphotransferase encoded by CMV gene region UL97, ganciclovir triphosphate is a selective inhibitor of CMV DNA polymerase.Several clinical studies have indicated response rates of 70–90% among patients with AIDS who are given ganciclovir for the treatment of CMV retinitis or colitis.