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Many public health programs that require INH prophylaxis for a positive tuberculin skin test or Quantiferon test include monthly monitoring of aminotransferase levels, although this practice has been called into question.A clinical picture resembling chronic hepatitis has been observed in a few patients.In 10% of patients treated with INH, elevated serum aminotransferase levels develop during the first few weeks of therapy; however, these elevations in most cases are self-limited, mild (values for ALT <200 IU/L), and resolve despite continued drug use. This adaptive response allows continuation of the agent if symptoms and progressive enzyme elevations do not follow the initial elevations. Acute hepatocellular drug-induced liver injury secondary to INH is evident with a variable latency period up to 6 months and is more frequent in alcoholics and patients taking certain other medications, such as barbiturates, rifampin, and pyrazinamide. If the clinical threshold of encephalopathy is reached, severe hepatic injury is likely to be fatal or to require liver transplantation. Liver biopsy reveals morphologic changes similar to those of viral hepatitis or bridging hepatic necrosis. Substantial liver injury appears to be age-related, increasing substantially after age 35; the highest frequency is in patients over age 50, and the lowest is in patients under the age of 20. Even for patients >50 years of age monitored carefully during therapy, hepatotoxicity occurs in only ~2%, well below the risk estimate derived from earlier experiences. Fever, rash, eosinophilia, and other manifestations of drug allergy are distinctly unusual. Recently, antibodies to INH have been detected in INH recipients, but a link to causality of liver injury remains unclear. A clinical picture resembling chronic hepatitis has been observed in a few patients. Many public health programs that require INH prophylaxis for a positive tuberculin skin test or Quantiferon test include monthly monitoring of aminotransferase levels, although this practice has been called into question.Sodium valproate, an anticonvulsant useful in the treatment of petit mal and other seizure disorders, has been associated with the development of severe hepatic toxicity and, rarely, fatalities, predominantly in children but also in adults.Among children listed as candidates for liver transplantation, valproate is the most common antiepileptic drug implicated.

When nutritional rehabilitation is initiated, calories can be safely started at 20% above the child’s recent intake. If no estimate of the caloric intake is available, 50% to 75% of the normal energy requirement is safe. High-calorie oral solutions or ready-to-use therapeutic foods (a mixture of powdered milk, peanuts, sugar, vitamins, and minerals) are frequently used in developing countries. Nutritional rehabilitation can be complicated by refeeding syndrome, which is characterized by fluid retention, hypophosphatemia, hypomagnesemia, and hypokalemia. Careful monitoring of laboratory values and clinical status with severe malnutrition is essential. When nutritional rehabilitation has begun, caloric intakecan be increased 10% to 20% per day, monitoring for electrolyte imbalances, poor cardiac function, edema, or feedingintolerance. If any of these occurs, further caloric increasesare not made until the child’s status stabilizes. Caloric intake is increased until appropriate regrowth or catch-up growth isinitiated. Catch-up growth refers to gaining weight at greaterthan 50th percentile for age and may require 150% or more ofthe recommended calories for an age-matched, well-nourishedchild. A general rule of thumb for infants and children up to3 years of age is to provide 100 to 120 kcal/kg based on ideal weight for height. Protein needs also are increased as anabolismbegins and are provided in proportion to the caloric intake.Vitamin and mineral intake in excess of the daily recommendedintake is provided to account for the increased requirements;this is frequently accomplished by giving an age-appropriatedaily multiple vitamin, with other individual micronutrientsupplements as warranted by history, physical examination,or laboratory studies.Additional iron may pose an oxidative stress; iron supplementationis associated with higher morbidity and mortality.In most cases, cow’s milk–based formulas are tolerated and provide an appropriate mix of nutrients.Other easily digested foods, appropriate for the age, also may be introduced slowly.If feeding intolerance occurs, lactose-free or semielemental formulas should be considered.

Headache, at times severe, often occurs as a prodrome of a thrombotic stroke or subarachnoid hemorrhage; unless this is appreciated, a diagnosis of migraine may be made.Contrariwise, certain manifestations of stroke may be incorrectly interpreted as evidence of some other neurologic disorder.Finally, the diagnosis of cerebrovascular disease should always be made on positive data, not by exclusion. A few conditions are so often confused with cerebrovascular diseases that they merit further comment. Miscellaneous conditions occasionally taken to be a stroke are migraine; Bell palsy; Stokes-Adams syncopal attacks; a severe attack of labyrinthine vertigo; diabetic ophthalmoplegia; acute ulnar, radial, or peroneal palsy; embolism to a limb; and temporal arteritis associated with blindness all of which are discussed in later parts of this chapter. A brain tumor, especially a rapidly growing glioblastoma or lymphoma, may produce a severe hemiplegia rapidly. Also, the neurologic deficit caused by cancer metastatic to the cerebrum may evolve rapidly, almost at a stroke-like pace. Moreover, in rare cases of brain tumor, a hemiplegia may be preceded by transitory episodes of neurologic deficit, indistinguishable from TIAs. The presence of the tumor and its effects on the cerebrum may make it difficult for the patient to articulate a clear history. A lack of detailed history may also be responsible for the opposite diagnostic error, that is, mistaking a relatively slowly evolving stroke (usually caused by internal carotid artery or basilar occlusion) for a tumor. CT and MRI usually settle the problem. A brain abscess or inflammatory necrotic lesion—for example, herpes encephalitis or toxoplasmosis—may also develop rapidly. Contrariwise, certain manifestations of stroke may be incorrectly interpreted as evidence of some other neurologic disorder. Headache, at times severe, often occurs as a prodrome of a thrombotic stroke or subarachnoid hemorrhage; unless this is appreciated, a diagnosis of migraine may be made.A detailed account of the attack will usually avert this error.A strikingly focal monoplegia of cerebral origin, causing only weakness of the hand or arm or foot-drop, is not infrequently misdiagnosed as a peripheral neuropathy or plexopathy.Epidemiology of Stroke Stroke assumes importance both because of its high rate of mortality and the residual disability that it causes.

Heritability estimates of 50–80% for bone density and size have been derived on the basis of twin studies.Numerous genes control skeletal growth, peak bone mass, and body size, as well as skeletal structure and density.Nutrition and lifestyle also play an important role in growth, although genetic factors primarily determine peak skeletal mass and density.Osteoporotic bone is more likely to fracture than normal bone at any level of trauma, and a fracture in a person over 50 should trigger evaluation for osteoporosis. This often does not occur because postfracture care is not always well coordinated. Osteoporosis results from bone loss due to age-related changes in bone remodeling as well as extrinsic and intrinsic factors that exaggerate this process. These changes may be superimposed on a low peak bone mass. Consequently, understanding the bone remodeling process is fundamental to understanding the pathophysiology of osteoporosis (Chap. 423). During growth, the skeleton increases in size by linear growth and by apposition of new bone tissue on the outer surfaces of the cortex (Fig. 425-4). The latter process is called modeling, a process that also allows the long bones to adapt in shape to the stresses placed on them. Increased sex hormone production at puberty is required for skeletal maturation, which reaches maximum mass and density in early adulthood. It is around puberty that the sexual dimorphism in skeletal size becomes obvious, although true bone density remains similar between the sexes. Nutrition and lifestyle also play an important role in growth, although genetic factors primarily determine peak skeletal mass and density. Numerous genes control skeletal growth, peak bone mass, and body size, as well as skeletal structure and density. Heritability estimates of 50–80% for bone density and size have been derived on the basis of twin studies.Linkage studies suggest that a genetic locus on chromosome 11 is associated with high bone mass.Families with high bone mass and without much apparent age-related bone loss have been shown to have a point mutation in LRP5, a low-density lipoprotein receptor–related protein.

The appearance and behavior of individuals with this disorder are often inappropri- ately sexually provocative or seductive (Criterion 2).This need is often apparent in their behavior with a clinician (e.g., being flattering, bring- ing gifts, providing dramatic descriptions of physical and psychological symptoms that are replaced by new symptoms each visit).Displays rapidly shifting and shallow expression of emotions. Consistently uses physical appearance to draw attention to self. Has a style of speech that is excessively impressionistic and lacking in detail. Shows self-dramatization, theatricality, and exaggerated expression of emotion. Is suggestible (i.e., easily influenced by others or circumstances). Considers relationships to be more intimate than they actually are. The essential feature of histrionic personality disorder is pervasive and excessive emotion- ality and attention-seeking behavior. This pattern begins by early adulthood and is pres- ent in a variety of contexts. Individuals with histrionic personality disorder are uncomfortable or feel unappreci- ated when they are not the center of attention (Criterion 1). Often lively and dramatic, they tend to draw attention to themselves and may initially charm new acquaintances by their enthusiasm, apparent openness, or flirtatiousness. These qualities wear thin, however, as these individuals continually demand to be the center of attention. They commandeer the role of ”the life of the party." If they are not the center of attention, they may do something dramatic (e.g., make up stories, create a scene) to draw the focus of attention to themselves. This need is often apparent in their behavior with a clinician (e.g., being flattering, bring- ing gifts, providing dramatic descriptions of physical and psychological symptoms that are replaced by new symptoms each visit). The appearance and behavior of individuals with this disorder are often inappropri- ately sexually provocative or seductive (Criterion 2).Emotional expression may be shallow and rapidly shifting (Criterion 3).Individuals with this disorder consistently use physical appearance to draw attention to themselves (Criterion 4).They are overly concerned with impressing others by their appearance and expend an excessive amount of time, energy, and money on clothes and grooming.

Ensure hemostasis of the transected liver edge with an argon beam coagulator and suture ligation.21.Examine the transected liver edge for bleeding; place a figure-of-eight ligating vascular suture if bleeding is encountered.20.Divide the RHV between vascular clamps and suture ligate the RHV.19.Mobilize the liver from the anterior aspect of the IVC in “piggyback” fashion; ligate the short hepatic veins up to the right hepatic vein (RHV).9. Perform a right hilar dissection—gently lower the hilar plate, then doubly ligate and divide the right hepatic artery (RHA), superior to the right side of the common bile duct.10. Doubly ligate and divide a replaced or accessory RHA if present.11. Expose the portal vein, identifying its right and left branches. There is a small lateral portal vein branch off the right portal vein (RPV) to the caudate lobe that should be controlled and ligated to allow the exposure of additional length on the RPV. Divide the RPV either with a vascular stapler or between vascular clamps.12. Dissect the avascular tissue along the suprahepatic vena cava between the right and middle hepatic veins. Pass a silastic tube of a Jackson-Pratt drain through this gap.13. Notch or divide the caudate process crossing to the right hepatic lobe, and bring the drain up and through this notch.14. Hang the liver over the drain by pulling up as you divide through the liver parenchyma.15. Repeat ultrasound and confirm the transection plane, staying just to the right of the middle hepatic vein (MHV) unless the tumor extends over it.16. Cauterize approximately 1 cm into the liver parenchyma, then switch to a hydro-jet dissection device in combination with Bovie electrocautery and suture ligation.17. Continue parenchymal division until the RHV is encoun-tered. During this division, identification, control, ligation, and transection of the right hepatic duct (RHD) are obtained late in the parenchymal transection process.18. Divide the RHV between vascular clamps and suture ligate the RHV.19. Examine the transected liver edge for bleeding; place a figure-of-eight ligating vascular suture if bleeding is encountered.20. Ensure hemostasis of the transected liver edge with an argon beam coagulator and suture ligation.21.These should be clipped or suture ligated.Applying a dilute solution of hydro-gen peroxide can facilitate the visualization of bile leaks.22.Inspect the IVC and right retroperitoneal space for hemostasis.23.Perform completion ultrasound to confirm left portal vein (LPV) inflow and outflow in the remaining hepatic veins.24.

Retransplantation is a consideration if clinical circumstances and other comorbidities are not prohibitive, but survival rates have been inferior to those with primary transplantation.Although therapy may stabilize lung function, the overall results of treatment have been disappointing; the median survival period after onset has been ~3–4 years.Transbronchial biopsies are relatively insensitive for detecting bronchiolitis obliterans, and pathologic confirmation is not required for diagnosis. Thus, after other causes of graft dysfunction have been excluded, the diagnosis of BOS is based primarily on a sustained decrement (≥20%) in forced expiratory volume in 1 s (FEV1), although smaller declines in FEV1 (≥10%) or in midexpiratory flow rate (FEF ) may presage BOS. Spirometric cri teria for diagnosis and staging of BOS have been standardized. The prevalence of BOS approaches 50% by 5 years after transplantation. Antecedent ACR is the main risk factor, but PGD, CMV pneumonitis, other community-acquired respiratory viral infections, and gastroesophageal reflux have been implicated as well. BOS can present acutely and imitate infectious bronchitis, or it can manifest as an insidious decline in lung function. The chest radiograph is typically unchanged; CT may reveal mosaic perfusion, air trapping, ground-glass opacities, or bronchiolectasis. Bronchoscopy is indicated to rule out other processes, but transbronchial biopsies identify bronchiolitis obliterans in a minority of cases. BOS usually is treated with augmented immunosuppression, but there is no consensus about therapy. Strategies include changes in the maintenance drug regimen, including the addition of azithromycin, antilymphocyte globulin, photopheresis, and total lymphoid irradiation. Although therapy may stabilize lung function, the overall results of treatment have been disappointing; the median survival period after onset has been ~3–4 years. Retransplantation is a consideration if clinical circumstances and other comorbidities are not prohibitive, but survival rates have been inferior to those with primary transplantation.Hyperacute rejection is caused by preformed HLA antibodies in the recipient, but it is minimized by pretransplantation antibody screening coupled with virtual or direct cross-matching with any potential donor.

Potential mechanisms for extraesophageal Erosive esophagitis Esophageal stricture with chronic GERD manifestations are either regurgitation with direct contact between the refluxate and supraesophageal structures or via a vagovagal reflex wherein reflux activation of esophageal afferent nerves triggers efferent vagal reflexes such as bronchospasm, cough, or arrhythmias.Jackhammer to disrupted peristalsis or superimposed esophagus is defined by the extraordinarily vigorous and repetitive contractions with normal reflux associated with a hiatal hernia. With peristaltic onset and normal latency of the contraction. Diffuse esophageal spasm is similar but superimposed reflux, fluid retained within primarily defined by a short latency (premature) contraction. a sliding hiatal hernia refluxes back into the FIGURE 347-7 Diffuse esophageal spasm. The characteristic “cork-screw” esophagus results from spastic contraction of the circular muscle in the esophageal wall; more precisely, this is actually a helical array of muscle. These findings are also seen with spastic achalasia. Latency= 3.5 s a peptic stricture or adenocarcinoma, each of which 1907 benefits from early detection and/or specific therapy. Extraesophageal syndromes with an established association to GERD include chronic cough, laryngitis, asthma, and dental erosions. A multitude of other conditions including pharyngitis, chronic bronchitis, pulmonary fibrosis, chronic sinusitis, cardiac arrhythmias, sleep apnea, and recurrent aspiration pneumonia have proposed associations with GERD. However, in both cases, it is important to emphasize the word association as opposed to causation. In many instances, the disorders likely coexist because of shared pathogenetic mechanisms rather than strict causality. Potential mechanisms for extraesophageal Erosive esophagitis Esophageal stricture with chronic GERD manifestations are either regurgitation with direct contact between the refluxate and supraesophageal structures or via a vagovagal reflex wherein reflux activation of esophageal afferent nerves triggers efferent vagal reflexes such as bronchospasm, cough, or arrhythmias.It is especially important that coronary artery disease be given early consideration because of its potentially lethal implications.The remaining elements of the CD differential diagnosis can be addressed by endoscopy, upper gastrointestinal series, or biliary tract ultraso-FIGURE 347-9 Endoscopic appearance of (A) peptic esophagitis, (B) a peptic stricture, nography as appropriate.

Injected subcutaneously.Incretins (exenatide): GLP-1 agonists.Insulin (alone or in conjunction with oral agents).DDP-4 inhibitors (sitagliptin): Inhibit the degradation of the endogenous enzyme that breaks down glucagon-like peptide 1 (GLP-1).Rarely used owing to the side effect of fl atulence.α-glucosidase inhibitors: ↓ intestinal absorption of carbohydrates.Onset is more insidious than that of type 1 DM, and patients often present with complications. Nonketotic hyperglycemia may be seen in the setting of poor glycemic control. Usually occurs in older adults with obesity (often truncal); has a strong genetic predisposition. Diagnostic criteria are the same as those for type 1 DM. Follow-up testing: Patients with no risk factors: Test at 45 years of age; retest every three years. Patients with impaired fasting glucose (> 110 mg/dL but < 126 mg/ dL): Follow up with frequent retesting. The goal of treatment is tight glucose control—i.e., blood glucose levels ranging from 80 to 120 mg/dL and HbA1c levels < 7. Treatment measures include the following: Diet, weight loss, and exercise. Oral agents (monotherapy or combination if uncontrolled): Sulfonylureas (glipizide, glyburide, and glimepiride): Insulin secretagogues. Hypoglycemia and weight gain are side effects. Meglitinides (repaglinide and nateglinide): Short-acting agents whose mechanism of action is similar to that of sulfonylureas. Metformin: Inhibits hepatic gluconeogenesis; ↑ peripheral sensitivity to insulin. Side effects include weight loss, GI upset, and, rarely, lactic acidosis. Contraindicated in the elderly (those > 80 years of age) and in patients with renal disease. Thiazolidinediones (the “glitazones”): ↑ insulin sensitivity. Side effects include weight gain, edema, and potential hepatotoxicity. α-glucosidase inhibitors: ↓ intestinal absorption of carbohydrates. Rarely used owing to the side effect of fl atulence. DDP-4 inhibitors (sitagliptin): Inhibit the degradation of the endogenous enzyme that breaks down glucagon-like peptide 1 (GLP-1). Insulin (alone or in conjunction with oral agents). Incretins (exenatide): GLP-1 agonists. Injected subcutaneously.Side effects include nausea and (rarely) pancreatitis.Statins for hypercholesterolemia (goal LDL < 100); glucose control and fibric acid derivatives for hypertriglyceridemia.Strict BP control to < 130/80; ACEIs/ARBs are usually first-line agents.Antiplatelet agents (ASA) for patients at risk of cardiovascular disease or for those > 40 years of age.

There is a normative age-related decline in sexual desire.There is a requirement that low desire persist for approximately 6 months or more; thus, short-term changes in sexual desire should not be diagnosed as male hypoactive sexual desire disorder.In such situations, the man’s lack of receptivity to a partner’s initiation should be considered when evaluating low desire. In addition to the subtypes ”lifelong /acquired" and "generalized / situational,” the fol- lowing five factors must be considered during assessment and diagnosis of male hypo- active sexual desire disorder given that they may be relevant to etiology and / or treatment: 1) partner factors (e.g., partner’s sexual problems, partner’s health status); 2) relationship factors (e.g., poor communication, discrepancies in desire for sexual activity); 3) individ- ual vulnerability factors (e.g., poor body image, history of sexual or emotional abuse), psy- chiatric comorbidity (e.g., depression, anxiety), or stressors (e.g., job loss, bereavement); 4) cultural/ religious factors (e.g., inhibitions related to prohibitions against sexual activity; attitudes toward sexuality); and 5) medical factors relevant to prognosis, course, or treat- ment. Each of these factors may contribute differently to the presenting symptoms of dif- ferent men with this disorder. The prevalence of male hypoactive sexual desire disorder varies depending on country of origin and method of assessment. Approximately 6% of younger men (ages 18—24 years) and 41% of older men (ages 66—74 years) have problems with sexual desire. However, a persistent lack of interest in sex, lasting 6 months or more, affects only a small proportion of men ages 16—44 (1.8%). By definition, lifelong male hypoactive sexual desire disorder indicates that low or no sex- ual desire has always been present, whereas the acquired subtype would be assigned if the man’s low desire developed after a period of normal sexual desire. There is a requirement that low desire persist for approximately 6 months or more; thus, short-term changes in sexual desire should not be diagnosed as male hypoactive sexual desire disorder. There is a normative age-related decline in sexual desire.Although erotic visual cues may be more potent elicitors of desire in younger men, the potency of sexual cues may decrease with age and must be considered when evaluating men for hypoactive sexual desire disorder.Temperamental.Mood and anxiety symptoms appear to be strong predictors of low de- sire in men.

A second population of intercalated cells secretes HCO3 − rather than H+ into the tubular fluid (also called B-or dHere and in the remainder of the chapter we focus on the function of intercalated cells.HCO3 − exits the cell across the basolateral membrane in exchange for Cl− (via a Cl−/HCO3 − antiporter, AE-1) and enters the peritubular capillary blood.The brush border enzyme catalyzes dehydration of H2CO3 in the luminal fluid, whereas the enzyme localized to basolateral membrane facilitates HCO3 − exit from the cell. The movement of CO2 into and out of the cell occurs via AQP1, which is localized to both the luminal and basolateral membranes. The cellular mechanism for HCO3 − reabsorption by the thick ascending limb (TAL) of the loop of Henle is very similar to that in the proximal tubule. H+ is secreted by a Na+/H+ antiporter and H+-ATPase. Like in the proximal tubule, the Na+/H+ antiporter (NHE3) is the predominant pathway for H+ secretion. HCO3 − exit from the cell involves both a Na+/HCO3 − symporter (NBC1) and a Cl−/HCO3 − antiporter (anion exchanger, AE-2). Some HCO3 − may also exit the cell through Cl− channels present in the basolateral membrane. The distal tubule and collecting duct reabsorb the small amount of HCO3 − that escapes reabsorption by the proximal tubule and loop of Henle. Fig. 37.4 shows the cellular mechanism of H+/HCO3 − transport by the intercalated cells located within these segments (see also One type of intercalated cell secretes H+ (reabsorbs HCO3 −) and is called the A-or α-intercalated cell. Within this cell, H+ and HCO3 − are produced by hydration of CO2; this reaction is catalyzed by carbonic anhydrase (CA-II). H+ is secreted into the tubular fluid via two mechanisms. The first involves an apical membrane H+-ATPase (V-type). The second couples secretion of H+ with reabsorption of via an H+-K+-ATPase similar to those found in the stomach and colon (HKα1 and HKα2). HCO3 − exits the cell across the basolateral membrane in exchange for Cl− (via a Cl−/HCO3 − antiporter, AE-1) and enters the peritubular capillary blood. A second population of intercalated cells secretes HCO3 − rather than H+ into the tubular fluid (also called B-or dHere and in the remainder of the chapter we focus on the function of intercalated cells.The cellular mechanism appears to involve an apical membrane Na+/H+ antiporter (NHE2) and a basolateral Cl−/HCO3 − antiporter (AE2).β-intercalated cells).In these cells the H+-ATPase (V-type) is located in the basolateral membrane and the Cl−/HCO3 − antiporter is located in the apical membrane (see Fig.37.4).

Between 1953 and 1956, a large number of villagers living near Minamata Bay in Kyushu Island, Japan, were afflicted with a syndrome of chronic mercurialism, traced to the ingestion of fish that had been contaminated with industrial wastes containing methylmercury (Harada et al).So-called Minamata disease is a case in point.Nitrate of mercury, used formerly in the manufacture of felt hats (“mad hatters”), and phenyl mercury, used in the paper, pulp, and electrochemical industries, are other sources of intoxication. Paresthesias, lassitude, confusion, incoordination, and intention tremor are characteristic, and, with continued exposure, a delirious state occurs. Headache, various bodily pains, visual and hearing disorders, and corticospinal signs may be added, but their pathologic basis is unknown. The term erethism was coined to describe the timidity, memory loss, and insomnia that were said to be characteristic of chronic intoxication. If the exposure is more than a minimal degree over a long period, gastrointestinal disturbances are prone to occur (anorexia, weight loss), as well as stomatitis and gingivitis with loosening of the teeth. Acute exposure to inorganic mercury in larger amounts is even more corrosive to the gastrointestinal system and produces nausea, vomiting, hematemesis, abdominal pain, and bloody diarrhea, as well as renal tubular necrosis. Isolated instances of polyneuropathy associated with exposure to mercury have also been reported (Albers et al; Agocs et al) and may be responsible for the paresthesias that accompany most cases, as well as the acrodynic syndrome described below. The polyneuropathy associated with mercury poisoning is discussed in Chap. 43. The presence of mercury in industrial waste has contaminated many sources of water supply and fish, which are ingested by humans and cause mercurial poisoning. So-called Minamata disease is a case in point. Between 1953 and 1956, a large number of villagers living near Minamata Bay in Kyushu Island, Japan, were afflicted with a syndrome of chronic mercurialism, traced to the ingestion of fish that had been contaminated with industrial wastes containing methylmercury (Harada et al).The syndrome evolved over a few weeks.Pathologically there was diffuse neuronal loss in both cerebral and cerebellar cortices, most marked in the anterior parts of the calcarine cortex and granule cell layer of the cerebellum.

The arrows indicate the site of mesaxons.The individual fibers or axons (A) are engulfed by the cytoplasm of a Schwann cell.The larger areas of exposed FIGURE 12.15 • Electron micrograph of unmyelinated nerve fbers.Finally, the nodes of Ranvier in the CNS are larger than those in the PNS.Thus, where myelin sheaths of adjacent axons touch, they may share an intraperiod line.Because a single oligodendrocyte may myelinate several nearby axons simultaneously, the cell cannot embed multiple axons in its cytoplasm and allow the mesaxon membrane to spiral around each axon. Instead, each tonguelike process appears to spiral around the axon, always staying in proximity to it, until the myelin sheath is formed. The myelin sheath in the CNS differs from that in the PNS. There are several other important differences between the myelin sheaths in the CNS and those in the PNS. Oligodendrocytes in the CNS express different myelin-specific proteins during myelination than those expressed by Schwann cells in the PNS. Instead of P0 and PMP-22, which are expressed only in myelin of the PNS, other proteins, including proteolipid protein (PLP), myelin oligodendrocyte glyco protein (MOG), and oligodendrocyte myelin glycoprotein (OMgp), perform similar functions in CNS myelin. Deficiencies in the expression of these proteins appear to be important in the pathogenesis of several autoimmune demyelinating diseases of the CNS. On the microscopic level, myelin in the CNS exhibits fewer Schmidt-Lanterman clefts because the astrocytes provide metabolic support for CNS neurons. Unlike Schwann cells of the PNS, oligodendrocytes do not have an external lamina. Furthermore, because of the manner in which oligodendrocytes form CNS myelin, little or no cytoplasm may be present in the outermost layer of the myelin sheath, and with the absence of external lamina, the myelin of adjacent axons may come into contact. Thus, where myelin sheaths of adjacent axons touch, they may share an intraperiod line. Finally, the nodes of Ranvier in the CNS are larger than those in the PNS. The larger areas of exposed FIGURE 12.15 • Electron micrograph of unmyelinated nerve fbers. The individual fibers or axons (A) are engulfed by the cytoplasm of a Schwann cell. The arrows indicate the site of mesaxons.Other features evident in the Schwann cell are its nucleus (N), the Golgi apparatus (G), and the surrounding basal (external) lamina (BL).In the upper part of the micrograph, myelin (M) of two myelinated nerves is also evident.27,000.Inset.Schematic diagram showing the relationship of axons engulfed by the Schwann cell.(Reprinted with permission from Barr ML, Kiernan JA.The Human Nervous System.

The pattern of sleeping, which is adjusted to the 24-h day, also varies in the different epochs of life.However, there are wide individual differences in the length and depth of sleep, apparently as a result of genetic factors, early life conditioning, the amount of physical activity, and psychologic states.A gradual decline to about 6.5 h develops in late adult life.Cases requiring the documentation of apneic episodes or those with more complex disorders such as seizures and other motor symptoms during sleep, benefit from attention in sleep laboratories. Sleep represents one of the basic 24-h (circadian) rhythms, traceable through all mammalian, avian, and reptilian species. The neural control of circadian rhythms is thought to reside in the ventral-anterior region of the hypothalamus, more specifically, in the suprachiasmatic nuclei. The intrinsic circadian rhythm of about 25 hours exists independent of light entrainment but is altered to conform to the day by light. Lesions in these nuclei result in a disorganization of the sleep–wake cycles as well as of the rest–activity, temperature, and feeding rhythms. Chapter 26 describes the ancillary role of melatonin and the pineal body in modulating this cyclic activity. There is also an important dimension of a homeostatic drive to sleep as the day wears on. Effects of Age Observations of the human sleep–wake cycle show it to be closely age linked. The newborn baby sleeps from 16 to 20 h a day, and the child, 10 to 12 h. Total sleep time drops to 9 to 10 h by mid-adolescence and to about 7 to 7.5 h during young adulthood. A gradual decline to about 6.5 h develops in late adult life. However, there are wide individual differences in the length and depth of sleep, apparently as a result of genetic factors, early life conditioning, the amount of physical activity, and psychologic states. The pattern of sleeping, which is adjusted to the 24-h day, also varies in the different epochs of life.(Actually, a large part of the world’s population continues to have an afternoon nap, or siesta, as a lifelong sleep–wake pattern.)Fragmentation of the sleep pattern begins in late adult life.Over ensuing years, night awakenings tend to increase in frequency, and the daytime waking period may be interrupted by episodic sleep lasting seconds to minutes (microsleep), as well as by longer naps.

Parents should expect the same orsimilar questions repeatedly, and that during the preschoolperiod the child’s cognitive limitations make it likely thechild will not fully understand the meaning of adoption.Children’s questions shouldbe answered honestly.Parents should use the term adoption around their children during the toddler years andexplain the simplest facts first.The preadoption period is the time that families are most likely to be able to obtain this information. Depending on the preadoption history, there may be risks of infections, in utero substance exposure, poor nutrition, or inadequate infant care that should be discussed with adoptive parents. When the adopted child is first seen, screening for medical disorders beyond the typical age-appropriate screeningtests should be considered. If the child has not had the standard newborn screening tests, the pediatrician may need toobtain these tests. Documented immunizations should be reviewed and, if needed, a plan developed to complete theneeded immunizations (see Chapter 94). Children may be athigh risk for infection based on the biologic mother’s socialhistory or the country from which the child was adopted, including infection with human immunodeficiency virus, hepatitis B, cytomegalovirus, tuberculosis, syphilis, and parasites. A complete blood count may be needed to screen foriron deficiency. A knowledgeable pediatrician also can be a valuable sourceof support and advice about psychosocial issues. The pediatrician should help the adoptive parents think about how theywill raise the child while helping the child to understand thefact that he or she is adopted. Neither denial of nor intense focus on the adoption is healthy. Parents should use the term adoption around their children during the toddler years andexplain the simplest facts first. Children’s questions shouldbe answered honestly. Parents should expect the same orsimilar questions repeatedly, and that during the preschoolperiod the child’s cognitive limitations make it likely thechild will not fully understand the meaning of adoption.Families may want advice about difficulties created by school assignments such as creating a genealogicchart or teasing by peers.During the teenage years, the childmay have questions about his or her identity and a desire tofind his or her biologic parents.

In Western populations, HCC rarely manifests before 60 years of age, and in almost 90% of cases the malignancy emerges after cirrhosis becomes established.It is hoped that new, effective treatments for hepatitis C infection will stem the rising tide of HCC in the United States.Most primary liver cancers arise from hepatocytes and are termed hepatocellular carcinoma (HCC). Much less common are cancers of bile duct origin, cholangiocarcinomas. Other types of primary liver cancers, such as hepatoblastoma (a childhood hepatocellular tumor) and angiosarcoma, are too rare to merit further discussion. Globally, HCC, also erroneously known as hepatoma, accounts for approximately 5.4% of all cancers, but its incidence varies widely in different parts of the world. More than 85% of cases occur in countries with high rates of chronic HBV infection. The incidence of HCC is highest in Asia (southeast China, Korea, Taiwan) and sub-Saharan Africa, areas in which HBV is transmitted vertically and, as already discussed, the carrier state starts in infancy. Moreover, many of these populations are exposed to aflatoxin, which when combined with HBV infection increases the risk for HCC dramatically. The peak incidence of HCC in these areas is between 20 and 40 years of age and, in almost 50% of cases, the tumor appears in the absence of cirrhosis. Fig. 16.35 Livercelladenoma.(A)Resectedspecimenofthelivermass. (B)Microscopicviewshowingcordsofhepatocytes,withanarterialvascularsupply(arrow) andnoportaltracts. In Western counties, the incidence of HCC is rapidly rising, largely owing to the increased prevalence of hepatitis C. The number of new HCC cases tripled in the United States in recent decades, but its incidence is still 8-fold to 30-fold lower than in some Asian countries. It is hoped that new, effective treatments for hepatitis C infection will stem the rising tide of HCC in the United States. In Western populations, HCC rarely manifests before 60 years of age, and in almost 90% of cases the malignancy emerges after cirrhosis becomes established.Chronic liver diseases are the most common setting for emergence of HCC.While usually identified in a background of cirrhosis, cirrhosis is not required for hepatocarcinogenesis.Rather, progression to cirrhosis and to hepatocellular cancer take place in parallel over many years to decades.

Guidelines that synthesize available literature and expert opinion provide recommendations on therapy duration that are based on infecting organism, organ system, and patient factors.Whether empirical or directed, the duration of therapy should be planned in most clinical situations.Allergies Allergies to antibiotics are among the most common allergies reported, and an allergy history should be obtained whenever possible before therapy is chosen. A detailed allergy history can shed light on the type of reaction experienced previously and on whether rechallenge with the same or a related medication is advisable (and, if so, under what circumstances). Allergies to the penicillins are most common. Although as many as 10% of patients may report an allergy to penicillin, studies suggest that up to 90% of these patients could tolerate a penicillin or cephalosporin. Adverse effects (Table 170-3) should be distinguished from true allergies to ensure appropriate selection of antibacterial therapy. Drug–Drug Interactions Patients commonly receive other drugs that may interact with antibacterial agents. A summary of the most common drug–drug interactions, by antibacterial class, is provided in Table 170-4. Exposures Exposures, both occupational and social, may provide clues to likely pathogens. When relevant, inquiries about exposure to ill contacts, animals, insects, and water should be included in the history, along with sites of residence and travel. Other Host Factors Age, renal and hepatic function, and comorbid conditions are all considerations in the choice of and schedule for therapy. Dose adjustments should be made accordingly. In patients with decreased or unreliable oral absorption, IV therapy may be preferred to ensure adequate blood levels of drug and delivery of the antibacterial agent to the site of infection. Whether empirical or directed, the duration of therapy should be planned in most clinical situations. Guidelines that synthesize available literature and expert opinion provide recommendations on therapy duration that are based on infecting organism, organ system, and patient factors.Similar guidelines from the IDSA exist for bacterial meningitis, catheter-associated urinary tract infections, intraabdominal infections, communityand hospital-acquired pneumonia, and other infections.If a patient does not respond to therapy, investigations often should include the collection of additional specimens for microbiologic testing and imaging as indicated.

Ophthalmologic abnormalities of retinal and optic nerve vessels have been described in some cases but are not typical.Patients often attribute these visual symptoms to one eye rather than to parts of both fields.Alcohol, particularly red wine or port, regularly provokes an attack in some persons; in others, headaches are fairly consistently induced by exposure to glare or other strong sensory stimuli, sudden jarring of the head (“footballer’s migraine”), or by rapid changes in barometric pressure. A common trigger is excess caffeine intake or withdrawal of caffeine. Migraine with aura may occur at any time of day, in some individuals, arising frequently after awakening. During the preceding day or so, there may have been mild changes in mood (sometimes a surge of energy or a feeling of well-being), hunger or anorexia, drowsiness, or frequent yawning. Then, abruptly, there is a disturbance of vision consisting usually of unformed flashes of white, or silver, or, rarely, of multicolored lights (photopsia). This may be followed by an enlarging blind spot with a shimmering edge (scintillating scotoma), or formations of dazzling zigzag lines (arranged like the battlements of a castle, hence the term fortification spectra, or teichopsia). Lashley’s description and drawings of his own auras over 10 min are instructive (Fig. 9-1). The expansion and movement across the visual field of the scotoma and the fortification, maintaining a consistent but expanding shape, are notable. Other patients complain instead of blurred or shimmering or cloudy vision, as though they were looking through thick or smoked glass or the wavy distortions produced by heat rising from asphalt. These luminous hallucinations move slowly across the visual field for several minutes and may leave an island of visual loss in their wake (scotoma); the latter is usually homonymous (involving corresponding parts of the field of vision of each eye), pointing to its origin in the visual cortex. Patients often attribute these visual symptoms to one eye rather than to parts of both fields. Ophthalmologic abnormalities of retinal and optic nerve vessels have been described in some cases but are not typical.Only one or a few neurologic phenomena are present in any given patient and they tend to occur in more or less the same combination in each attack.

A newer approach to modulation of the natriuretic peptide system is inhibition of the neutral endopeptidase enzyme, neprilysin, which is responsible for the degradation of BNP and atrial natriuretic peptide (ANP), as well as angiotensin II, bradykinin, and other peptides.Angiotensin AT1 receptor blockers such as losartan (see Chapters 11 and 17) appear to have similar beneficial effects. In combination with sacubitril, valsartan is now approved for HFrEF. Angiotensin receptor blockers should be considered in patients intolerant of ACE inhibitors because of incessant cough. Aliskiren, a renin inhibitor approved for hypertension, was found to have no definitive benefit in clinical trials for heart failure. Vasodilators are effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both. Some evidence suggests that long-term vasodilation by hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart. A synthetic form of the endogenous peptide brain natriuretic peptide (BNP) is approved for use in acute (not chronic) cardiac failure as nesiritide. This recombinant product increases cGMP in smooth muscle cells and reduces venous and arteriolar tone in experimental preparations. It also causes diuresis. However, large trials with this drug have failed to show an improvement in mortality or rehospitalizations. The peptide has a short half-life of about 18 minutes and is administered as a bolus intravenous dose followed by continuous infusion. Excessive hypotension is the most common adverse effect. Reports of significant renal damage and deaths have resulted in extra warnings regarding this agent, and it should be used with great caution. A newer approach to modulation of the natriuretic peptide system is inhibition of the neutral endopeptidase enzyme, neprilysin, which is responsible for the degradation of BNP and atrial natriuretic peptide (ANP), as well as angiotensin II, bradykinin, and other peptides.A combination of valsartan plus sacubitril has recently been approved for use in HFrEF.Plasma concentrations of endogenous BNP rise in most patients with heart failure and are correlated with severity.Measurement of the plasma precursor NT-proBNP is a useful diagnostic or prognostic test and has been used as a surrogate marker in clinical trials.

Hepatic cytochrome P450 can be inhibited by the earlier PPIs (omeprazole, lansoprazole).As with any agent that leads to significant hypochlorhydria, PPIs may interfere with absorption of drugs such as ketoconazole, ampicillin, iron, and digoxin.IF production is also inhibited, but vitamin B12-deficiency anemia is uncommon, probably because of the large stores of the vitamin.Because the pumps need to be activated for these agents to be effective, their efficacy is maximized if they are administered before a meal (except for the immediate-release formulation of omeprazole) (e.g., in the morning before breakfast). Mild to moderate hypergastrinemia has been observed in patients taking these drugs. Carcinoid tumors developed in some animals given the drugs preclinically; however, extensive experience has failed to demonstrate gastric carcinoid tumor development in humans. Serum gastrin levels return to normal levels within 1–2 weeks after drug cessation. Rebound gastric acid hypersecretion has been described in H. pylori–negative individuals after discontinuation of PPIs. It occurs even after relatively short-term usage (2 months) and may last for up to 2 months after the PPI has been discontinued. The mechanism involves gastrininduced hyperplasia and hypertrophy of histamine-secreting ECL cells. The clinical relevance of this observation is that individuals may have worsening symptoms of GERD or dyspepsia upon stopping the PPI. Gradual tapering of the PPI and switching to an H2 receptor antagonist may prevent this from occurring. H. pylori– induced inflammation and concomitant decrease in acid production may explain why this does not occur in H. pylori–positive patients. IF production is also inhibited, but vitamin B12-deficiency anemia is uncommon, probably because of the large stores of the vitamin. As with any agent that leads to significant hypochlorhydria, PPIs may interfere with absorption of drugs such as ketoconazole, ampicillin, iron, and digoxin. Hepatic cytochrome P450 can be inhibited by the earlier PPIs (omeprazole, lansoprazole).The overall clinical significance of this observation is not definitely established.Caution should be taken when using theophylline, warfarin, diazepam, atazanavir, and phenytoin concomitantly with PPIs.

Protein electrophoresis and measurement of serum immunoglobulins and free light chains are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis.Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated.Patients with only one of these three features have a 25% chance of progression to MM in 5 years, whereas patients with high-risk SMM with all three features have a 76% chance of progression. There are two important variants 715 of myeloma—solitary bone plasmacytoma and solitary extramedullary plasmacytoma. These lesions are associated with an M component in <30% of the cases, they may affect younger individuals, and both are associated with median survivals of ≥10 years. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or progress. The clinical evaluation of patients with myeloma includes a careful physical examination searching for tender bones and masses. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia. Magnetic resonance imaging (MRI) offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes. A complete blood count with differential may reveal anemia. Erythrocyte sedimentation rate is elevated. Rare patients (~1%) may have plasma cell leukemia with >2000 plasma cells/μL. This may be seen in disproportionate frequency in IgD (12%) and IgE (25%) myelomas. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Protein electrophoresis and measurement of serum immunoglobulins and free light chains are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis.Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity.It is also important to quantitate serum β2-microglobulin and albumin (see below).The serum M component will be IgG in 53% of patients, IgA in 25%, and IgD in 1%; 20% of patients will have only light chains in serum and urine.

Micturition Micturition is triggered by the peripheral nervous system under the control of the central nervous system.Neuropathology at almost any level of the neurourologic axis can have an adverse effect on lower urinary tract function.The parasympathetic nervous system controls bladder motor function—bladder contraction and bladder emptying. The parasympathetic nervous system originates in the sacral spinal cord, primarily in S2 to S4, as does the somatic innervation of the pelvic floor, urethra, and external anal sphincter. Sensation in the perineum is also controlled by sensory fibers that connect with the spinal cord at this level. For this reason, examination of perineal sensation, pelvic muscle reflexes, and pelvic muscle or anal sphincter tone is relevant to clinical evaluation of the lower urinary tract. The parasympathetic neurons have long preganglionic neurons and short postganglionic neurons, which are located in the end organ. Both the preganglionic and postganglionic synapses use acetylcholine as their neurotransmitter, acting on muscarinic receptors. Because acetylcholine is the main neurotransmitter used in bladder muscle contraction, virtually all drugs used to control detrusor muscle overactivity have anticholinergic properties. Bladder storage and bladder emptying involve the interplay of the sympathetic and parasympathetic nervous systems. The modulation of these activities appears to be influenced by a variety of nonadrenergic, noncholinergic neurotransmitters and neuropeptides, which fine tune the system at various facilitative and inhibitory levels in the spinal cord and higher areas of the central nervous system (5–7). Neuropathology at almost any level of the neurourologic axis can have an adverse effect on lower urinary tract function. Micturition Micturition is triggered by the peripheral nervous system under the control of the central nervous system.The threshold volume is not fixed; rather, it is variable and can be altered depending on the contributions made by sensory afferents from the perineum, bladder, colon, rectum, and input from the higher centers of the nervous system.The micturition threshold is, therefore, a floating threshold that can be altered or reset by various influences.

Weight loss in older persons is associated with a variety of deleterious effects, including hip fracture, pressure ulcers, impaired immune function, and decreased functional status.People with no known cause of weight loss generally have a better prognosis than do those with known causes, particularly when the source is neoplastic.Frequency of defecation is 3–8 per day during the first year, dropping to 1–3 per day from the second year after surgery. Patients who have a combined (evacuation and transit/motility) disorder should pursue pelvic floor retraining (biofeedback and muscle relaxation), psychological counseling, and dietetic advice first. If symptoms are intractable despite biofeedback and optimized medical therapy, colectomy and ileorectostomy could be considered as long as the evacuation disorder is resolved and optimized medical therapy is unsuccessful. In patients with pelvic floor dysfunction alone, biofeedback training has a 70–80% success rate, measured by the acquisition of comfortable stool habits. Attempts to manage pelvic floor dysfunction with operations (internal anal sphincter or puborectalis muscle division) or injections with botulinum toxin have achieved only mediocre success and have been largely abandoned. Russell G. Robertson, J. Larry Jameson Involuntary weight loss (IWL) is frequently insidious and can have important implications, often serving as a harbinger of serious underlying disease. Clinically important weight loss is defined as the loss of 10 pounds (4.5 kg) or >5% of one’s body weight over a period of 6–12 months. IWL is encountered in up to 8% of all adult outpatients and 27% of frail persons age 65 years and older. There is no identifiable cause in up to one-quarter of patients despite extensive investigation. Conversely, up to half of people who claim to have lost weight have no documented evidence of weight loss. People with no known cause of weight loss generally have a better prognosis than do those with known causes, particularly when the source is neoplastic. Weight loss in older persons is associated with a variety of deleterious effects, including hip fracture, pressure ulcers, impaired immune function, and decreased functional status.(See also Chaps.94e and 415e) Among healthy aging people, total body weight peaks in the sixth decade of life and generally remains stable until the ninth decade, after which it gradually falls.In contrast, lean body mass (fat-free mass) begins to decline at a rate of 0.3 kg per year in the third decade, and the rate of decline increases further beginning at age 60 in men and age 65 in women.

A number of acronyms derived from the initial letters of the main clinical features are used to designate the major mitochondrial syndromes: MERRF, MELAS, PEO, NARP, etc., as summarized in Table 36-9.Fortunately for the clinician, the most important of these diseases are expressed in several recognizable core syndromes and in a few variants thereof and they are each monogenic disorders.As with the metabolic disorders of the nervous system, the diseases included under this heading are so varied and may involve so many parts of the nervous system that the clinical entities by which they are identified cannot be easily addressed in any one part of this book. In their overlapping relationships, however, they are unlike the more discrete clinical entities caused by nuclear genetic mutations. Their diversity is evident not only in the details of their clinical presentations but also in the age at which symptoms first become apparent and, what is most intriguing, sometimes in the abrupt onset of their neurologic manifestations. Most of this variability in presentation is understandable from the principles of mitochondrial genetics outlined in the introductory section of this chapter. Of particular importance is the mosaicism of the mitochondria within cells and from cell to cell and the crucial role the organelles play in the oxidative energy metabolism that supports the function of cells in all organs. Although a ubiquitous metabolic derangement would seemingly offer an explanation for the dysfunction of several disparate tissues in the mitochondrial disorders, such clarification is not available. Fortunately for the clinician, the most important of these diseases are expressed in several recognizable core syndromes and in a few variants thereof and they are each monogenic disorders. A number of acronyms derived from the initial letters of the main clinical features are used to designate the major mitochondrial syndromes: MERRF, MELAS, PEO, NARP, etc., as summarized in Table 36-9.These diseases are the result of mutations in the mitochondrial genome, a ringed DNA of 16,569 base pairs and 37 genes contained within the organelle, or of mutations in a few nuclear genes that code for a component of the mitochondrion.To date, more than 100 point mutations and 200 deletions, insertions, and rearrangements have been identified.

Patients may forget instructions regarding the need to complete a fixed duration of therapy when a course of anti-infective drug is being given.Since the prescriptions are often written by several different practitioners, there is usually no attempt to design “integrated” regimens that use drugs with similar dosing intervals for the several conditions being treated.Similarly, their antimuscarinic action may precipitate urinary retention in geriatric men or glaucoma in patients with a narrow anterior chamber angle. If the patient is also taking a metabolism inhibitor such as cimetidine, the probability of an adverse reaction is greatly increased. A patient taking an herbal medication containing gingko is more likely to experience bleeding while taking low doses of aspirin. The quality of life in elderly patients can be greatly improved and life span can be prolonged by the intelligent use of drugs. However, the prescriber must recognize several practical obstacles to compliance. The expense of drugs can be a major disincentive in patients receiving marginal retirement incomes who are not covered or inadequately covered by health insurance. The prescriber must be aware of the cost of the prescription and of cheaper alternative therapies. For example, the monthly cost of arthritis therapy with newer NSAIDs may exceed $100, whereas that for generic ibuprofen and naproxen, two older but equally effective NSAIDs, about $20. Nonadherence may result from forgetfulness or confusion, especially if the patient has several prescriptions and different dosing intervals. A survey carried out in 1986 showed that the population over 65 years of age accounted for 32% of drugs prescribed in the USA, although these patients represented only 11–12% of the population at that time. Since the prescriptions are often written by several different practitioners, there is usually no attempt to design “integrated” regimens that use drugs with similar dosing intervals for the several conditions being treated. Patients may forget instructions regarding the need to complete a fixed duration of therapy when a course of anti-infective drug is being given.Nonadherence may also be deliberate.A decision not to take a drug may be based on prior experience with it.There may be excellent reasons for such “intelligent” noncompliance, and the practitioner should try to elicit them.

Inthe absence of fetal testicular secretion of müllerian-inhibitorysubstance, a normal uterus, fallopian tubes, and posterior third of the vagina develop out of the müllerian ducts, and the wolffian ducts degenerate.In the absence of SRY, an ovary spontaneously develops from the bipotential, primitive gonad.The female phenotype develops unless specific male influences alter development.The Leydig cells of the testis secretetestosterone, which has direct effects (stimulating development of the wolffian ducts) but also is locally converted todihydrotestosterone (DHT) by the 5α-reductase enzyme.DHT causes enlargement, rugation, and fusion of the labioscrotal folds into a scrotum; fusion of the ventral surface of the penis to enclose a penile urethra; and enlargement of the 16.8 mm 49.0 mm 45.0 mm Figure 177-1 Differentiation of male and Labia minora female external genitalia as proceeding from a Scrotum common embryonic anlage. Testosterone acts at 9 to 13 weeks of gestation to virilize the bipotential anlage. In the absence of testosterone action, the female phenotype develops. (From Grumbach MM, Conte FA: Disorders of sexual differentiation. In Wilson JD, Foster DW, editors: Textbook of Endocrinology, ed 8, Philadelphia, 1990, WB Saunders, p 873; adapted from Anus Spaulding MH, Contrib Embryol Instit 13:69−88, 1921.) phallus with ultimate development of male external genitalia.Testicular production and secretion of müllerian-inhibitorysubstance by Sertoli cells cause the regression and disappearance of the müllerian ducts and their derivatives, such as the fallopian tubes and uterus. In the presence of testosterone, the wolffian ducts develop into the vas deferens, seminiferoustubules, and prostate. The female phenotype develops unless specific male influences alter development. In the absence of SRY, an ovary spontaneously develops from the bipotential, primitive gonad. Inthe absence of fetal testicular secretion of müllerian-inhibitorysubstance, a normal uterus, fallopian tubes, and posterior third of the vagina develop out of the müllerian ducts, and the wolffian ducts degenerate.The terms intersex, hermaphroditism, and pseudohermaphroditism are not useful.DSDs are categorized under three main subgroups according to karyotype (XX, XY, and sex chromosome for mosaic karyotypes).Figure 177-2 A diagrammatic scheme of male sex determination and differentiation.

At diagnosis, patients with inherited syndromes are a mean of ∼15 years younger than patients with sporadic tumors.About 25–33% of patients with a pheochromocytoma or paragan glioma have an inherited syndrome.Regular screening in families with inherited pheochromocytomas provides an opportunity to identify and remove asymptomatic tumors in women of reproductive age.Thus, the term malignant pheochromocytoma is restricted to tumors with distant metastases, most commonly found by nuclear medicine imaging in lungs, bone, or liver—locations suggesting a vascular pathway of spread. Because hereditary syndromes are associated with multifocal tumor sites, these features should be anticipated in patients with germ-line mutations of 2331 RET, VHL, SDHD, or SDHB. However, distant metastases also occur in these syndromes, especially in carriers of SDHB mutations. Treatment of malignant pheochromocytoma or paraganglioma is challenging. Options include tumor mass reduction, alpha blockers for symptoms, chemotherapy, and nuclear medicine radiotherapy. The first-line choice is nuclear medicine therapy for scintigraphically documented metastases, preferably with 131I-MIBG in 200-mCi doses at monthly intervals over three to six cycles. Averbuch’s chemotherapy protocol includes dacarbazine (600 mg/m2 on days 1 and 2), cyclophosphamide (750 mg/m2 on day 1), and vincristine (1.4 mg/m2 on day 1), all repeated every 21 days for three to six cycles. Palliation (stable disease to shrinkage) is achieved in about one-half of patients. Other chemotherapeutic options are sunitinib and temozolomide/ thalidomide. The prognosis of metastatic pheochromocytoma or paraganglioma is variable, with 5-year survival rates of 30–60%. Pheochromocytomas occasionally are diagnosed in pregnancy. Endoscopic removal, preferably in the fourth to sixth month of gestation, is possible and can be followed by uneventful childbirth. Regular screening in families with inherited pheochromocytomas provides an opportunity to identify and remove asymptomatic tumors in women of reproductive age. About 25–33% of patients with a pheochromocytoma or paragan glioma have an inherited syndrome. At diagnosis, patients with inherited syndromes are a mean of ∼15 years younger than patients with sporadic tumors.118).The NF1 gene functions as a tumor suppressor by regulating the Ras signaling cascade.Classic features of neurofibromatosis include multiple neurofibromas, café au lait spots, axillary freckling of the skin, and Lisch nodules of the iris (Fig.407-2).Pheochromocytomas occur in only ∼1% of these patients FIGURE 407-2 Neurofibromatosis.A. MRI of bilateral adrenal pheochromocytoma.

This study can provide a three-dimensional analysis of vascular structure such as aortic arch branches and carotid and vertebral arteries.overestimate the degree of in-stent stenosis, while heavy calci-fication can limit the diagnostic accuracy of the method by caus-ing a “blooming artifact.”4 The artifacts can be overcome with alteration in image acquisition technique.B. A 53-year-old man with occluded right common iliac artery (double arrows).The extracted images can also be rotated and viewed from sev-eral different directions during postacquisition image process-ing. This technology has been advanced as a consequence of aortic endografting. CTA provides images for postprocessing that can be used to display the aneurysm in a format that demon-strates thrombus, calcium, lumen, and the outer wall, and allows “fitting” of a proposed endograft into the aneurysm (Fig. 23-4). CTA is increasingly being used to image the carotid bifurca-tion, and as computing power increases, the speed of image acquisition and resolution will continue to increase. The major limitations of multidetector CTA are use of contrast and pres-ence of artifacts caused by calcification and stents. CTA can Brunicardi_Ch23_p0897-p0980.indd 90127/02/19 4:13 PM 902SPECIFIC CONSIDERATIONSPART IIFigure 23-4. Three-dimensional computed tomog-raphy angiogram of an abdominal aortic aneurysm that displays various aneurysm components including thrombus, aortic calcification, blood circulation, and aneurysm wall.Figure 23-5. Magnetic resonance angiogram of aortic arch and carotid arteries. This study can provide a three-dimensional analysis of vascular structure such as aortic arch branches and carotid and vertebral arteries.overestimate the degree of in-stent stenosis, while heavy calci-fication can limit the diagnostic accuracy of the method by caus-ing a “blooming artifact.”4 The artifacts can be overcome with alteration in image acquisition technique.Magnetic resonance angiography (MRA) has the advantage of not requiring iodin-ated contrast agents to provide vessel opacification (Fig.23-5).Gadolinium is used as a contrast agent for MRA studies, and because it is generally not nephrotoxic, it can be used in patients with elevated creatinine.

Having discussed the DNA and protein molecules from which the chromatin fiber is made, we now turn to the organization of the chromosome on a more global scale and the way in which its various domains are arranged in space.These modifications include the mono-, di-, and trimethylation of many different lysine side chains, an important reaction that is incompatible with the acetylation that can occur on the same lysines. Specific combinations of the modifications mark many nucleosomes, governing their interactions with other proteins. These marks are read when protein modules that are part of a larger protein complex bind to the modified nucleosomes in a region of chromatin. These reader proteins then attract additional proteins that perform various functions. Some reader protein complexes contain a histone-modifying enzyme, such as a histone lysine methylase, that “writes” the same mark that the reader recognizes. A reader–writer–remodeling complex of this type can spread a specific form of chromatin along a chromosome. In particular, large regions of condensed heterochromatin are thought to be formed in this way. Heterochromatin is commonly found around centromeres and near telomeres, but it is also present at many other positions in chromosomes. The tight packaging of DNA into heterochromatin usually silences the genes within it. The phenomenon of position effect variegation provides strong evidence for the inheritance of condensed states of chromatin from one cell generation to the next. A similar mechanism appears to be responsible for maintaining the specialized chromatin at centromeres. More generally, the ability to propagate specific chromatin structures across cell generations makes possible an epigenetic cell memory process that plays a role in maintaining the set of different cell states required by complex multicellular organisms. Having discussed the DNA and protein molecules from which the chromatin fiber is made, we now turn to the organization of the chromosome on a more global scale and the way in which its various domains are arranged in space.Clearly, there must be a still higher level of folding, even in interphase chromosomes.Although the molecular details are still largely a mystery, this higher-order packaging almost certainly involves the folding of the chromatin into a series of loops and coils.This chromatin packing is fluid, frequently changing in response to the needs of the cell.

The linker in this case is cleavable, which allows diffusion of the drug out of the cell after delivery.The nuclear targets of these processes include transcription factors (e.g., Myc, AP-1, and serum response factor) and the cell cycle machinery (CDKs and cyclins). Inhibitors of many of these pathways have been developed for the treatment of human cancers. Examples of inhibitors that are currently being evaluated in clinical trials are shown in purple type. reactions. Mutation in the BCR-ABL kinase in the ATP-binding pocket (such as the threonine to isoleucine change at codon 315 [T315I]) can prevent imatinib binding. Other resistance mechanisms include altering other signal transduction pathways to bypass the inhibited pathway. As resistance mechanisms become better defined, rational strategies to overcome resistance will emerge. In addition, many kinase inhibitors are less specific for an oncogenic target than was hoped, and toxicities related to off-target inhibition of kinases limit the use of the agent at a dose that would optimally inhibit the cancer-relevant kinase. Targeted agents can also be used to deliver highly toxic compounds. An important component of the technology for developing effective conjugates is the design of the linker between the two, which needs to be stable. Currently approved antibody drug conjugates include brentuximab vedotin, which links the microtubule toxin monomethyl auristatin E (MMAE) to an antibody targeting the cell surface antigen CD30, which is expressed on a number of malignant cells but especially in Hodgkin’s disease and anaplastic lymphoma. The linker in this case is cleavable, which allows diffusion of the drug out of the cell after delivery.In this case, the linker is noncleavable, thus trapping the chemotherapeutic agent within the cells.There are theoretical pluses and minuses to having either cleavable or noncleavable linkers, and it is likely that both will be used in future developments of antibody-drug conjugates.

Rab proteins Monomeric GTPase in the Ras superfamily present in plasma and organelle membranes in its GTP-bound state, and as a soluble cytosolic protein in its GDP-bound state.Rab effectors Molecules that bind activated, membrane-bound Rab proteins and act as downstream mediators of vesicle transport, membrane tethering, and fusion.Hydrogen has a nucleus composed of a single proton (H+). proton-motive force The force exerted by the electrochemical proton gradient that moves protons across a membrane. protozoan parasite Parasitic, nonphotosynthetic, single-celled, motile eukaryotic organism, for example Plasmodium. pseudogene Nucleotide sequence of DNA that has accumulated multiple mutations that have rendered an ancestral gene inactive and nonfunctional. purified cell-free system Fractionated cell homogenate that retains a particular biological function of the intact cell, and in which biochemical reactions and cell processes can be more easily studied. purifying selection Natural selection operating in a population to slow genome changes and reduce divergence by eliminating individuals carrying deleterious mutations. quantitative RT-PCR (reverse transcription–polymerase chain reaction) Technique in which a population of mRNAs is converted into cDNAs via reverse transcription, and the cDNAs are then amplified by PCR. The quantitative part relies on a direct relationship between the rate at which the PCR product is generated and the original concentration of the mRNA species of interest. quaternary structure Three-dimensional relationship of the different polypeptide chains in a multisubunit protein or protein complex. quinone (Q) Small, lipid-soluble, mobile electron carrier molecule found in the respiratory and photosynthetic electron-transport chains. (Figure 14–17) Rab cascade An ordered recruitment of sequentially acting Rab proteins into Rab domains on membranes, which changes the identity of an organelle and reassigns membrane dynamics. Rab effectors Molecules that bind activated, membrane-bound Rab proteins and act as downstream mediators of vesicle transport, membrane tethering, and fusion. Rab proteins Monomeric GTPase in the Ras superfamily present in plasma and organelle membranes in its GTP-bound state, and as a soluble cytosolic protein in its GDP-bound state.(Table 15–5, p. 854) Rac Member of the Rho family of monomeric GTPases that regulate the actin and microtubule cytoskeletons, cell-cycle progression, gene transcription, and membrane transport.Rad51 Eukaryotic protein that catalyzes synapsis of DNA strands during genetic recombination.Called RecA in E. coli.

How can a mother living in a remote rural village and caring for an infant with febrile convulsions find the means to get her child to appropriate care?Why should a poor slum dweller with no income be expected to come up with the money for a bus fare needed to travel to a clinic to learn the results of a sputum test for tuberculosis?% of global burden of disease % of global workforce FIGURE 13e-5 Global burden of disease and health workforce. (Source: World Health Organization: Working Together for Health, 2006.) Critical diagnostics and drugs often do not reach patients in need because of supply-chain failures. Moreover, facilities fail to provide safe care: new evidence suggests much higher rates of adverse events among hospitalized patients in lowand middle-income countries than in high-income countries. Weak government planning, regulatory, monitoring, and evaluation capacities are associated with rampant, unregulated commercialization of health services and chaotic fragmentation of these services as donors “push” their respective priority programs. With such fragile foundations, it is not surprising that low-cost, affordable, validated interventions are not reaching those who need them. Health care delivery systems do not exist in a vacuum but rather are embedded in a complex of social and economic forces that often stratify opportunities for health unfairly. Most worrisome are the pervasive forces of social inequality that serve to marginalize populations with disproportionately large health needs (e.g., the urban poor; illiterate mothers). Why should a poor slum dweller with no income be expected to come up with the money for a bus fare needed to travel to a clinic to learn the results of a sputum test for tuberculosis? How can a mother living in a remote rural village and caring for an infant with febrile convulsions find the means to get her child to appropriate care?While science has yielded enormous breakthroughs in health in high-income countries, with some spillover to lowand middle-income countries, many important health problems continue to affect primarily lowand middle-income countries whose research and development investments are deplorably inadequate.

There is, however, increasing evidence for an interaction between allergens and pollution, particularly in genetically susceptible individuals.Pollution has been blamed for an increase in the prevalence of nonallergic cardiopulmonary diseases such as chronic bronchitis, but an association with allergic disease has been more difficult to demonstrate.A possible explanation for this association is that the human counterpart of the murine Tim-1 protein (see Section 14-3) is the cellular receptor for hepatitis A virus (designated HAVCR1). The infection of T cells by hepatitis A virus could thus directly influence their differentiation and cytokine production, limiting the development of an IgE-generating response. In contrast to these negative associations between childhood infection and the development of atopy and asthma is evidence that children who have had attacks of bronchiolitis associated with respiratory syncytial virus (RSV) infection are more prone to developing asthma later on. Children hospitalized with RSV infection have a skewed ratio of cytokine production away from IFN-γ toward IL-4, presumably increasing their likelihood of developing TH2 responses and increased production of IgE. This effect of RSV appears to depend on age at first infection. Experimental infection of neonatal mice with RSV was followed by lower increases in the production of IFN-γcompared with mice that received experimental RSV infection at 4 or 8 weeks of age. When the mice were rechallenged at 12 weeks of age with RSV infection, animals that had been primarily infected as neonates had more severe lung inflammation than animals first infected at 4 or 8 weeks of age. Other environmental factors that might contribute to the increase in atopic disease are changes in diet, allergen exposure, atmospheric pollution, and tobacco smoke. Pollution has been blamed for an increase in the prevalence of nonallergic cardiopulmonary diseases such as chronic bronchitis, but an association with allergic disease has been more difficult to demonstrate. There is, however, increasing evidence for an interaction between allergens and pollution, particularly in genetically susceptible individuals.Reactive oxidant chemicals such as ozone are generated as a result of such pollution, and individuals less able to deal with this onslaught may be at increased risk of allergic disease.Genes that might be governing this aspect of susceptibility are GSTP1 and GSTM1, members of the glutathione-S-transferase superfamily that are important in preventing oxidant stress.

his translates into approximately three contractions of 40 mm Hg every 10 minutes.According to Caldeyro-Barcia and Poseiro (1960), clinical labor usually commences when uterine activity reaches values between 80 and 120 Montevideo units.21, p. 409).During this phase, the cervix ripens (Chap.Uterine activity is further enhanced during the last weeks of pregnancy.As expected, when both diameters are contracted, dystocia rates are much greater than when only one is contracted. Either of these measures is used to consider a pelvis contracted. he anteroposterior diameter of the inlet, which is the obstetrical conjugate, is commonly approximated by manually measuring the diagonal conjugate, which is approximately 1.5 cm greater. Ascertainment of these measures is described in Chapter 2 (p. 30). herefore, inlet contraction usually is defined as a diagonal conjugate < 11.5 cm. A small woman is likely to have a small pelvis, but she is also likely to have a small neonate. homs (1937) studied 362 nulliparas and found that the mean birthweight of their ofspring was significantly lower-280 g-in women with a small pelvis than in those with a medium or large pelvis. as the rise in this pressure above a resting pressure baseline. hese investigators also introduced the concept of Montevideo units to deine uterine activity (Chap. 23, p. 443). With this deinition, uterine performance is the product of contraction intensity in mm Hg multiplied by the number of contractions in a 10-minute span. For example, three contractions in 10 minutes, each of 50 mm Hg intensity, would equal 150 Montevideo units. During the irst 30 weeks of pregnancy, uterine activity is comparatively quiescent. Contractions are seldom greater than 20 mm Hg, and these have been equated with those irst described by John Braxton Hicks. Uterine activity increases gradually after 30 weeks, and it is noteworthy that these Braxton Hicks contractions also increase in intensity and frequency. Uterine activity is further enhanced during the last weeks of pregnancy. During this phase, the cervix ripens (Chap. 21, p. 409). According to Caldeyro-Barcia and Poseiro (1960), clinical labor usually commences when uterine activity reaches values between 80 and 120 Montevideo units. his translates into approximately three contractions of 40 mm Hg every 10 minutes.In irst-stage labor, uterine contractions progressively grow in intensity from approximately 25 mm Hg at labor commencement to 50 mm Hg at its end.At the same time, the frequency advances from three to ive contractions per 10 minutes, and uterine baseline tone rises from 8 to 12 mm Hg.Uterine activity is further enhanced during second-stage labor, aided by maternal pushing.

The components of the contractile apparatus in smooth muscle cells are the following.Note that vascular smooth muscle contains vimentin filaments in addition to desmin filaments.Intermediate filaments are part of the cytoskeleton of the cell.These structures are distributed throughout the sarcoplasm in a network of intermediate filaments containing the protein desmin.11.20).The remaining sarcoplasm is filled with thin filaments that form a part of the contractile apparatus. Thick myosin filaments are scattered throughout the sarcoplasm of a smooth muscle cell. They are extremely labile and tend to be lost during tissue preparation. Special techniques can be used, however, to retain the structural integrity of the thick filaments and thus demonstrate them with the TEM. The thin FIGURE 11.19 • Electron micrograph of smooth muscle cells. This electron micrograph shows parts of three smooth muscle cells. The nucleus of one cell is in the lower part of the micrograph. The bulk of the cytoplasm is occupied by thin (actin) filaments, which are just recognizable at this magnification. The -actinin–containing cytoplasmic densities, or dense bodies, are visible among the myofilaments (arrows). Elements of the sarcoplasmic reticulum (SR) and the pinocytotic vesicles (PV ) are also indicated. The other two cells in the middle and upper part of the micrograph possess visible gap junctions (GJ) that allow communication between adjacent cells. The small dark particles are glycogen. 25,000. Inset. Enlargement of the gap junction. Note the presence of pinocytotic vesicles. 35,000. filaments in a smooth muscle cell are attached to cytoplasmic densities or dense bodies that are visible among the filaments (Fig. 11.20). These structures are distributed throughout the sarcoplasm in a network of intermediate filaments containing the protein desmin. Intermediate filaments are part of the cytoskeleton of the cell. Note that vascular smooth muscle contains vimentin filaments in addition to desmin filaments. The components of the contractile apparatus in smooth muscle cells are the following.No troponin is associ ated with smooth muscle tropomyosin.Actin is involved in the force-generating interaction with myosin II molecules.Research suggests that the tropomyosin position on the actin filament is regulated by phosphorylation of myosin heads.Caldesmon (120 to 150 kilodaltons) and calponin (34 kilodaltons) are actin-binding proteins that block the myosin-binding site.

Upper motor neurons originatein the cerebral motor cortex; their axons form the corticospinaltract ending in the spinal cord and control voluntary motor activity.Weakness and hypotonia may be due to disorders of upper motor neurons or lower motor neurons.The differential diagnosis for weakness is extensive (Table 182-1).The duration of anticonvulsant treatment varies according to seizure type and epilepsy syndrome. For most children, anticonvulsant medications can be weaned off after 2 years without seizures. There are some exceptions. Forexample, children with juvenile myoclonic epilepsy, progressive myoclonic epilepsy, atypical absence seizures, and Lennox-Gastaut syndrome usually require treatment for life. Children who have other neurological comorbidities, seizures that were initially difficult to control, orpersistently epileptiform EEGs are at highest risk for recurrence when therapy is discontinued. Although cognitively normal children with epilepsy havethe same rates of injury as normal healthy children, thereare important safety considerations for people with epilepsy.The risk of drowning is high, so swimming and bathing mustonly occur under direct adult supervision. Children shoulduse appropriate helmets for sports such as bicycling or iceskating. There is no contraindication to participation in contact sports, but scuba diving, hang gliding, and free climbing are not safe for people with epilepsy. Each country andindividual states have specific laws regarding driving for people with epilepsy. Most require a period of seizure freedombefore issuing a driving permit. Weakness is a decreased ability to voluntarily and actively movemuscles. This may be generalized or localized to one aspectof the body. Hypotonia is a state of low muscle resistance to movement. Hypotonia can be associated with weakness, but insome cases is present with normal motor strength. The differential diagnosis for weakness is extensive (Table 182-1). Weakness and hypotonia may be due to disorders of upper motor neurons or lower motor neurons. Upper motor neurons originatein the cerebral motor cortex; their axons form the corticospinaltract ending in the spinal cord and control voluntary motor activity.Maintenance of normal strength, tone, and coordination requires integrated communication throughout this complex system, including the cerebral cortex,cerebellum, brainstem, thalamus, basal ganglia, and spinal cord.Available @ StudentConsult.com Weakness caused by upper motor neuron disease differs fromweakness produced by lower motor units (Table 182-2).

In addition, 44% of the patients acquired a culture-proven infection.Diagnosis and Clinical ManagementWhen the medical history is obtained, it is important to address the possibility of exposure to viral infections, medications, and other possible toxins.In contrast, 65% of cases of ALF in the West are thought to be due to drugs and toxins, with acetaminophen (paracetamol) being the most common etiologic agent in the United States, Australia, United Kingdom, and most of Europe. In France and Spain, where acetaminophen sales are restricted, the rate of acetaminophen-induced ALF is quite low.32 Acetaminophen-induced ALF is also uncommon in South America. The U.S. Acute Liver Failure Study Group identified several other causes of ALF, including autoimmune hepatitis, hypoperfusion of the liver (in cardiomyopathy or cardiogenic shock), pregnancy-related conditions, and Wilson’s disease.33 Even with exhaustive efforts to identify a cause, approximately 20% of all cases of ALF remain indeterminate in origin.Clinical PresentationIn a multicenter study involving 17 tertiary care centers and 308 patients in the United States, 73% of all patients with ALF were female, with a median age of 38 years.34 The most common ethnic group affected was whites (74%), followed by Hispanics (9%) and African Americans (3%). Patients were ill for a median of 6 days before the onset of encephalopathy and had a median of 2 days between the onset of jaundice and the development of encephalopathy. Hepatic coma grade at presentation was approximately equally distributed across grades I to IV. Eighty-four percent of the patients in the study were referred from outside hospitals, 40% had a serum creatinine level exceeding 2.0 mg/dL, and 14% had an arterial pH of <7.30. In addition, 44% of the patients acquired a culture-proven infection.Diagnosis and Clinical ManagementWhen the medical history is obtained, it is important to address the possibility of exposure to viral infections, medications, and other possible toxins.The physical examination must assess and document the patient’s mental status as well as attempt to identify findings of chronic liver disease.The initial laboratory examination must evaluate the severity of the ALF as well as attempt to identify the cause (Table 31-1).A liver biopsy should be performed if certain disease entities such as autoimmune hepatitis or lymphoma are a possibility.

First panel: neutrophils are highly specialized for the uptake and killing of pathogens, and contain several different kinds of cytoplasmic granules, such as the primary and secondary granules shown in the first panel.3.5 The microbicidal respiratory burst in phagocytes is initiated by activation-induced assembly of the phagocyte NADPH oxidase.The most common form of CGD is an X-linked heritable disease that arises from inactivating mutations in the gene encoding the gp91 subunit of cytochrome b558. People with this defect are unusually susceptible to bacterial and fungal infections, especially in infancy, though they remain susceptible for life. One autosomal recessive form of NADPH oxidase deficiency, p47phox deficiency, has very low but detectable activity and causes a milder form of CGD. Fig. 3.4 Bactericidal agents produced or released by phagocytes after uptake of microorganisms. Most of the agents listed are directly toxic to microbes and can act directly in the phagolysosome. They can also be secreted into the extracellular environment, and many of these substances are toxic to host cells. Other phagocyte products sequester essential nutrients in the extracellular environment, rendering them inaccessible to microbes and hindering microbial growth. Besides being directly bacteriostatic or bactericidal, acidification of lysosomes also activates the many acid hydrolases that degrade the contents of the vacuole. O2–OCl–H2O2phagosomeprimarygranuleNADPHoxidasesecondarygranulegp91p22Rac2fMLFlysosomeBacterial fMet-Leu-Phe peptides activate Rac2, and bacteria are taken up into phagosomes Phagosomes fuse with primary and secondary granules. Rac2 induces assembly of a functional NADPH oxidase in the phagolysosome membrane, leading to generation of O2 – . Acidifcation as a result of ion infux releases granule proteases from granule matrix p67p47p40Neutrophils engulf and kill the microbes to which they bind primarygranulesecondarygranulemicrobelysosomeK+K+K+SOD Fig. 3.5 The microbicidal respiratory burst in phagocytes is initiated by activation-induced assembly of the phagocyte NADPH oxidase. First panel: neutrophils are highly specialized for the uptake and killing of pathogens, and contain several different kinds of cytoplasmic granules, such as the primary and secondary granules shown in the first panel.Second panel: in resting neutrophils, the cytochrome b558 subunits (gp91 and p22) of the NADPH oxidase are localized in the plasma membrane; the other oxidase components (p40, p47, and p67) are located in the cytosol.

However, the efficacy and utility of this technology remains unproven.Scintigraphy to Assess Gastrointestinal Bleeding.PET/CT increasingly is used to diagnose recurrent and/or meta-static colorectal cancer.By combining PET and CT technology (PET/CT), anatomic correlation between regions of high isotope accumulation (“hot spots”) on PET and abnormalities on CT can be determined.Experience with this technol-ogy has shown a sensitivity and specificity for detecting 1 cm or larger polyps of 85% to 90% in most studies, making it compa-rable to traditional colonoscopy. Although this technology has yet to be widely adopted, it remains an alternative to traditional colonoscopy for select patients.2Magnetic Resonance Imaging. The main use of magnetic resonance imaging (MRI) in colorectal disorders is in evaluation of pelvic lesions. MRI is more sensitive than CT for detecting bony involvement or pelvic sidewall extension of rectal tumors. MRI accurately determines the extent of spread of rectal cancer into the adjacent mesorectum and can reliably predict diffi-culty achieving radial margin clearance of a rectal cancer by surgery alone. When the radial margin is threatened, neoadju-vant chemoradiation is indicated. MRI also can be helpful in the detection and delineation of complex fistulas in ano. The use of an endorectal coil may increase sensitivity.Positron Emission Tomography. Positron emission tomog-raphy (PET) is used for imaging tissues with high levels of anaerobic glycolysis, such as malignant tumors. 13F-fluorode-oxyglucose (FDG) is injected as a tracer; metabolism of this molecule then results in positron emission. PET has been used as an adjunct to CT in the staging of colorectal cancer and may prove useful in discriminating recurrent cancer from fibrosis. By combining PET and CT technology (PET/CT), anatomic correlation between regions of high isotope accumulation (“hot spots”) on PET and abnormalities on CT can be determined. PET/CT increasingly is used to diagnose recurrent and/or meta-static colorectal cancer. However, the efficacy and utility of this technology remains unproven.Scintigraphy to Assess Gastrointestinal Bleeding.Patients must be actively bleeding at the time of imaging, and a normal distribution of 99mTc-erythrocytes in vasculature, liver, spleen, penile circula-tion with mild uptake in kidneys and bladder can interfere with localization in bowel segments near those structures.

KEY: Figure 13–4 Electron micrographs of clathrin-coated, COPI-coated, and COPII-coated vesicles.In this way, the adaptor proteins select a specific set of transmembrane proteins, together with the soluble proteins that interact with them, and package them into each newly formed clathrin-coated transport vesicle (Figure 13–8).COPI-coated vesicles and COPII-coated vesicles transport material early in the secretory pathway: COPI-coated vesicles bud from Golgi compartments, and COPII-coated vesicles bud from the ER (see Figure 13–5). We discuss clathrin-coated vesicles first, as they provide a good example of how vesicles form. The major protein component of clathrin-coated vesicles is clathrin itself, which forms the outer layer of the coat. Each clathrin subunit consists of three large and three small polypeptide chains that together form a three-legged structure called a triskelion (Figure 13–6A,B). Clathrin triskelions assemble into a basketlike framework of hexagons and pentagons to form coated pits (buds) on the cytosolic surface of membranes (Figure 13–7). Under appropriate conditions, isolated triskelions spontaneously self-assemble into typical polyhedral cages in a test tube, even in the absence of the membrane vesicles that these baskets normally enclose (Figure 13–6C,D). Thus, the clathrin triskelions determine the geometry of the clathrin cage (Figure 13–6E). Adaptor proteins, another major coat component in clathrin-coated vesicles, form a discrete inner layer of the coat, positioned between the clathrin cage and the membrane. They bind the clathrin coat to the membrane and trap various transmembrane proteins, including transmembrane receptors that capture soluble cargo molecules inside the vesicle—so-called cargo receptors. In this way, the adaptor proteins select a specific set of transmembrane proteins, together with the soluble proteins that interact with them, and package them into each newly formed clathrin-coated transport vesicle (Figure 13–8). KEY: Figure 13–4 Electron micrographs of clathrin-coated, COPI-coated, and COPII-coated vesicles.(a clathrin-coated vesicles.(b) copIcoated vesicles and golgi cisternae (red arrows) from a cell-free system in which copI-coated vesicles bud in the test tube.copII-coated vesicles.(a and b, from l. orci, b. glick and J. rothman, Cell 46:171–184, 1986. with permission from elsevier; c, courtesy of charles barlowe and lelio orci.)

The involvement of clinical psychologists and psychiatrists is invaluable in providing guidance and coping techniques to lessen the significant psychological burden of burn injury.PREVENTIONDespite many areas of progress in prevention over the past cen-tury, burns continue to be a common source of injury.A risk scoring system has been developed to pre-dict which burn patients are at risk of developing HO based on admission criteria; however, further validation is warranted.200PSYCHOLOGICAL RECOVERYPsychological rehabilitation is equally important in the burn patient. Depression, posttraumatic stress disorder (PTSD), concerns about image, and anxiety about returning to society constitute predictable barriers to progress in both the inpa-tient and outpatient setting. Psychological distress occurs in as many as 38% of burn patients and persists in severity long after discharge.201 Rates of depression vary between 4% and 54% following injury, although these numbers vary dramatically based on the methodology used to diagnose depression.202 Still, depressive symptoms have been documented in up to 43% of patients 2 years following injury and have been associated with the female gender. Factors such as gender, extraversion, capac-ity for forgiveness, the event as a disaster or nondisaster, alcohol use, and peritraumatic emotional response have been identified as contributing factors to PTSD.203 Despite the psychological impact of burn injury, many patients will be able to quickly return to work or school, and goals should be set accordingly. The involvement of clinical psychologists and psychiatrists is invaluable in providing guidance and coping techniques to lessen the significant psychological burden of burn injury.PREVENTIONDespite many areas of progress in prevention over the past cen-tury, burns continue to be a common source of injury.A 6-year study of second-graders demonstrated both shortand long-term retainment of information related to burn, fire, and life safety following multiple educational sessions.Smoke alarms are known to decrease mortality from structural fires, but not all homes are equipped with proper smoke alarms, particularly in low-income households.

Not all sur-geons choose to undertake a Collis procedure, however, as there is controversy about the actual incidence of the shortened esophagus and widely divergent views are held about how often this prob-lem is encountered.Following gastroplasty a fundoplica-tion is constructed, with the highest suture is placed on the native esophagus when constructing a Nissen fundoplication.25-38).25-37) provides a more robust fundoplication and achieves an excellent longer-term outcome in approximately 90% of patients at follow-up of at least 10 years. With this procedure, the fundus and esophagus are sutured to the right side of the hiatal rim to create a flap valve at the gastroesophageal junction and to stabilize a 3 to 4 cm length of intra-abdominal esophagus.Collis Gastroplasty. When a shortened esophagus is encoun-tered, many surgeons choose to add an esophageal lengthening procedure before fundoplication, to reduce the tension on the gastroesophageal junction, believing this will minimize the risk of failure due to postoperative hiatus hernia. The commonest approach to this is the Collis gastroplasty. This entails using a stapler to divide the cardia and upper stomach, parallel to the lesser curvature of Figure 25-37. Completed laparoscopic anterior 180° partial fun-doplication. The fundoplication fully covers the anterior surface of the esophagus, and it is stabilized by suturing the fundus to the right side of the esophagus, and to the right hiatal pillar. Unlike the Nissen procedure, the fundus is not pulled behind the esophagus.the stomach, thereby creating a gastric tube in continuity with the esophagus, and effectively lengthening the esophagus by several centimeters. Laparoscopic techniques for Collis gastroplasty have been described (Fig. 25-38). Following gastroplasty a fundoplica-tion is constructed, with the highest suture is placed on the native esophagus when constructing a Nissen fundoplication. Not all sur-geons choose to undertake a Collis procedure, however, as there is controversy about the actual incidence of the shortened esophagus and widely divergent views are held about how often this prob-lem is encountered.Studies of long-term outcome following both open and laparoscopic fundoplication document the ability of laparoscopic fundoplication to relieve typical reflux symptoms (heartburn, regurgitation, and dysphagia) in more than Figure 25-35.(Continued )Brunicardi_Ch25_p1009-p1098.indd 104201/03/19 6:03 PM 1043ESOPHAGUS AND DIAPHRAGMATIC HERNIACHAPTER 25Figure 25-38.A.

In contrast to the other organisms discussed in this chapter, B. mallei is not an environmental organism and does not persist outside its equine hosts.The last case seen in the United States occurred in 2001 in a laboratory worker; before that, B. mallei had last been seen in this country in 1949.The organism was eradicated from Europe and North America decades ago.B. pseudomallei causes a wide spectrum of disease, ranging from asymptomatic infection to abscesses, pneumonia, and disseminated disease. It is a significant cause of fatal community-acquired pneumonia and septicemia in endemic areas, with mortality rates as high as 44% reported in Thailand. Acute pulmonary infection is the most commonly diagnosed form of melioidosis. Pneumonia may be asymptomatic (with routine chest radiographs showing mainly upper-lobe infiltrates) or may present as severe necrotizing disease. B. pseudomallei also causes chronic pulmonary infections with systemic manifestations that mimic those of tuberculosis, including chronic cough, fever, hemoptysis, night sweats, and cavitary lung disease. Besides pneumonia, the other principal form of B. pseudomallei disease is skin ulceration with associated lymphangitis and regional lymphadenopathy. Spread from the lungs or skin, which is most often documented in debilitated individuals, gives rise to septicemic forms of melioidosis that carry a high mortality rate. TREATMEnT b. pseUdomallei infections B. pseudomallei is susceptible to advanced penicillins and cephalosporins and to carbapenems (Table 189-2). Treatment is divided into two stages: an intensive 2-week phase of therapy with ceftazidime or a carbapenem followed by at least 12 weeks of oral TMP-SMX to eradicate the organism and prevent relapse. The recognition of this bacterium as a potential agent of biologic warfare has stimulated interest in the development of a vaccine. B. mallei causes the equine disease glanders in Africa, Asia, and South America. The organism was eradicated from Europe and North America decades ago. The last case seen in the United States occurred in 2001 in a laboratory worker; before that, B. mallei had last been seen in this country in 1949. In contrast to the other organisms discussed in this chapter, B. mallei is not an environmental organism and does not persist outside its equine hosts.The polysaccharide capsule is a critical virulence determinant; diabetics are thought to be especially susceptible to infection by this organism.The organism is transmitted from animals to humans by inoculation into the skin, where it causes local infection with nodules and lymphadenitis.Regional lymphadenopathy is common.Respiratory secretions from infected horses are extremely infectious.

In a patient with multisys-tem trauma, enteral access via gastrostomy or jejunostomy tube should be considered.After injuries are identified, whether to use damage control techniques or per-form primary repair of injuries is based on the patient’s intraop-erative physiologic status (see “Damage Control Surgery” and “Treatment of Specific Injuries”).If hemostasis is not adequate to expose the vessel proximal and distal to the injury, sponge sticks can be strategi-cally placed on either side of the injury and carefully adjusted to improve hemostasis. Alternatively, complete pelvic vascular isolation (Fig. 7-42) may be required to control hemorrhage for adequate visualization of the injuries. The right common iliac artery obscures the bifurcation of the vena cava and the right iliac vein; the iliac artery may require division to expose venous injuries in this area (Fig. 7-43). The artery must be repaired after the venous injury is treated, however, because of limb-threatening ischemia.Once overt hemorrhage is controlled, sources of enteric contamination are identified by serially running along the small and large bowel, looking at all surfaces. Associated hematomas should be unroofed to rule out adjacent bowel injury. The ante-rior and posterior aspects of the stomach should be inspected, which requires opening the lesser sac for complete visualiza-tion. Duodenal injuries should be evaluated with a wide Kocher maneuver. During exploration of the lesser sac, visualization and palpation of the pancreas is done to exclude injury. Palpat-ing the anterior surface is not sufficient because the investing Brunicardi_Ch07_p0183-p0250.indd 21210/12/18 6:19 PM 213TRAUMACHAPTER 7fascia may mask a pancreatic injury; mobilization, including evaluation of the posterior aspect, is critical. After injuries are identified, whether to use damage control techniques or per-form primary repair of injuries is based on the patient’s intraop-erative physiologic status (see “Damage Control Surgery” and “Treatment of Specific Injuries”). In a patient with multisys-tem trauma, enteral access via gastrostomy or jejunostomy tube should be considered.The skin is closed selectively based on the amount of intra-abdominal contamination.Figure 7-42.Pelvic vascular isolation.A.Initially, clamps are placed on the aorta, inferior vena cava, and bilateral external iliac vessels.B.With continued dissection, the clamps can be moved progressively closer to the vascular injury to limit unwarranted ischemia.Figure 7-43.

Speciically, each gram of hemoglobin carries 1.25 mL of oxygen when 90-percent saturated.Oxygen delivery can be greatly improved by correction of anemia.Because sepsis is commonplace in lung injury, vigorous antimicrobial therapy is given for infection, and any necrotic tissues are debrided.When shunting exceeds 30 percent, severe refractory hypoxemia develops along with metabolic and respiratory acidosis that can result in myocardial irritability, dysfunction, and cardiac arrest. Reduced ARDS mortality rates have resulted from advances in care of the critically ill (Levy, 2015). his requires close attention to: (1) recognizing and treating underlying medical and surgical disorders, (2) minimizing procedures and their complications, (3) administering prophylaxis against venous thromboembolism, gastrointestinal bleeding, aspiration, and central venous catheter infection, (4) promptly diagnosing nosocomial infections, and (5) providing adequate nutrition. FIGURE 47-1 Anteroposterior chest radiograph of a secondtrimester pregnant woman with marked bilateral parenchymal and pleural opacification secondary to acute respiratory distress syndrome (ARDS) due to pyelonephritis. In cases of severe acute lung injury, providing adequate oxygenation of peripheral tissues is balanced against maneuvers that further aggravate lung injury. At least intuitively, increasing oxygen delivery should produce a corresponding increase in tissue uptake, but this is diicult to measure. Support of systemic perfusion with intravenous crystalloid and blood is imperative. As discussed earlier, the trial conducted by the National Heart, Lung, and Blood Institute (2006) showed that pulmonary artery catheter use did not improve outcomes. Because sepsis is commonplace in lung injury, vigorous antimicrobial therapy is given for infection, and any necrotic tissues are debrided. Oxygen delivery can be greatly improved by correction of anemia. Speciically, each gram of hemoglobin carries 1.25 mL of oxygen when 90-percent saturated.Reasonable goals in caring for the woman with severe lung injury are to attain a Pao2 of 60 mm Hg or 90-percent oxygen saturation using an inspired oxygen content < 50 percent and positive end-expiratory pressures < 15 mm Hg.With regard to the pregnancy, it remains controversial whether delivery of the fetus improves maternal oxygenation (Mallampalli, 2010).

VI.[Note: Changes in the carbohydrate portion of glycosphingolipids (and glycoproteins) are characteristic of transformed cells (cells with dysregulated growth).]Genetic disorders associated with an inability to properly degrade the glycosphingolipids result in lysosomal accumulation of these compounds.Although Niemann-Pick disease occurs in all ethnic groups, type A occurs with greater frequency in the Ashkenazi Jewish population. type A.] V. GLYCOLIPID OVERVIEW Glycolipids are molecules that contain both carbohydrate and lipid components. Like the phospholipid sphingomyelin, glycolipids are derivatives of ceramides in which a LCFA is attached to the amino alcohol sphingosine. Therefore, they are more precisely called glycosphingolipids. [Note: Thus, ceramides are the precursors of both phosphorylated and glycosylated sphingolipids.] Like the phospholipids, glycosphingolipids are essential components of all membranes in the body, but they are found in greatest amounts in nerve tissue. They are located in the outer leaflet of the plasma membrane, where they interact with the extracellular environment. As such, they play a role in the regulation of cellular interactions (for example, adhesion and recognition), growth, and development. Membrane glycosphingolipids associate with cholesterol and GPI-anchored proteins to form lipid rafts, laterally mobile microdomains of the plasma membrane that function to organize and regulate membrane signaling and trafficking functions. Glycosphingolipids are antigenic and are the source of ABO blood group antigens (see p. 165), various embryonic antigens specific for particular stages of fetal development, and some tumor antigens. [Note: The carbohydrate portion of a glycolipid is the antigenic determinant.] They have been coopted for use as cell surface receptors for cholera and tetanus toxins as well as for certain viruses and microbes. Genetic disorders associated with an inability to properly degrade the glycosphingolipids result in lysosomal accumulation of these compounds. [Note: Changes in the carbohydrate portion of glycosphingolipids (and glycoproteins) are characteristic of transformed cells (cells with dysregulated growth).] VI.17.14).The number and type of carbohydrate moieties present determine the type of glycosphingolipid.A.Neutral glycosphingolipids The simplest neutral glycosphingolipids are the cerebrosides.These are ceramide monosaccharides that contain either a molecule of galactose (forming ceramide-galactose or galactocerebroside, the most common cerebroside found in myelin, as shown in Fig.

Redundant regions of the synovial membrane and fibrous membrane allow for large movements at joints.Fat pads usually occur between the synovial membrane and the capsule and move into and out of regions as joint contours change during movement.The synovial membrane attaches to the margins of the joint surfaces at the interface between the cartilage and bone and encloses the articular cavity. The synovial membrane is highly vascular and produces synovial fluid, which percolates into the articular cavity and lubricates the articulating surfaces. Closed sacs of synovial membrane also occur outside joints, where they form synovial bursae or tendon sheaths. Bursae often intervene between structures, such as tendons and bone, tendons and joints, or skin and bone, and reduce the friction of one structure moving over the other. Tendon sheaths surround tendons and also reduce friction. The fibrous membrane is formed by dense connective tissue and surrounds and stabilizes the joint. Parts of the fibrous membrane may thicken to form ligaments, which further stabilize the joint. Ligaments outside the capsule usually provide additional reinforcement. Another common but not universal feature of synovial joints is the presence of additional structures within the area enclosed by the capsule or synovial membrane, such as articular discs (usually composed of fibrocartilage), fat pads, and tendons. Articular discs absorb compression forces, adjust to changes in the contours of joint surfaces during movements, and increase the range of movements that can occur at joints. Fat pads usually occur between the synovial membrane and the capsule and move into and out of regions as joint contours change during movement. Redundant regions of the synovial membrane and fibrous membrane allow for large movements at joints.Hinge joints are uniaxial, whereas ball and socket joints are multiaxial.Specific types of synovial joints (Fig.

The interplay of these various cytokines and their cross-regulation determine the host’s response.TH2 cells produce IL-4, IL-5, IL-10, and IL-13 and may also promote humoral immunity.TH1 cells produce IFN-γ—an activator of macrophages and monocytes—and IL-2.Activated CD4+ T lymphocytes can differentiate into cytokine-producing TH1 or TH2 cells.However, alternatively activated alveolar macrophages may be particularly susceptible to M. tuberculosis growth early on, given their more limited proinflammatory and bactericidal activity, which is related in part to being bathed in surfactant. New monocytes and macrophages attracted to the site are key components of the immune response. Their primary mechanism is probably related to production of oxidants (such as reactive oxygen intermediates or nitric oxide) that have antimycobacterial activity and increase the synthesis of cytokines such as TNF-α and IL-1, which in turn regulate the release of reactive oxygen intermediates and reactive nitrogen intermediates. In addition, macrophages can undergo apoptosis—a defensive mechanism to prevent release of cytokines and bacilli via their sequestration in the apoptotic cell. Recent work also describes the involvement of neutrophils in the host response, although the timing 1107 of their appearance and their effectiveness remain uncertain. Alveolar macrophages, monocytes, and dendritic cells are also critical in processing and presenting antigens to T lymphocytes, primarily CD4+ and CD8+ T cells; the result is the activation and proliferation of CD4+ T lymphocytes, which are crucial to the host’s defense against M. tuberculosis. Qualitative and quantitative defects of CD4+ T cells explain the inability of HIV-infected individuals to contain mycobacterial proliferation. Activated CD4+ T lymphocytes can differentiate into cytokine-producing TH1 or TH2 cells. TH1 cells produce IFN-γ—an activator of macrophages and monocytes—and IL-2. TH2 cells produce IL-4, IL-5, IL-10, and IL-13 and may also promote humoral immunity. The interplay of these various cytokines and their cross-regulation determine the host’s response.IFN-γ may induce the generation of reactive nitrogen intermediates and regulate genes involved in bactericidal effects.TNF-α also seems to be important.Observations made originally in transgenic knockout mice and more recently in humans suggest that other T cell subsets, especially CD8+ T cells, may play an important role.

It has numerous branches, which perforate the interosseous membrane to supply deep muscles of the posterior compartment; it also has a small branch, which contributes to the vascular network around the carpal bones and joints.7.88) and anastomoses with the superficial palmar arch formed by the ulnar artery. The ulnar artery is larger than the radial artery and passes down the medial side of the forearm (Fig. 7.88). It leaves the cubital fossa by passing deep to the pronator teres muscle, and then passes through the forearm in the fascial plane between the flexor carpi ulnaris and flexor digitorum profundus muscles. In the distal forearm, the ulnar artery often remains tucked under the anterolateral lip of the flexor carpi ulnaris tendon, and is therefore not easily palpable. In distal regions of the forearm, the ulnar nerve is immediately medial to the ulnar artery. The ulnar artery leaves the forearm, enters the hand by passing lateral to the pisiform bone and superficial to the flexor retinaculum of the wrist, and arches over the palm (Fig. 7.88). It is often the major blood supply to the medial three and one-half digits. Branches of the ulnar artery that arise in the forearm include: the ulnar recurrent artery with anterior and posterior branches, which contribute to an anastomotic network of vessels around the elbow joint (see Fig. 7.66B); numerous muscular arteries, which supply surrounding muscles; the common interosseous artery, which divides into anterior and posterior interosseous arteries (Fig. 7.88); and two small carpal arteries (dorsal carpal branch and palmar carpal branch), which supply the wrist. The posterior interosseous artery passes dorsally over the proximal margin of the interosseous membrane into the posterior compartment of the forearm. The anterior interosseous artery passes distally along the anterior aspect of the interosseous membrane and supplies muscles of the deep compartment of the forearm and the radius and ulna. It has numerous branches, which perforate the interosseous membrane to supply deep muscles of the posterior compartment; it also has a small branch, which contributes to the vascular network around the carpal bones and joints.Deep veins of the anterior compartment generally accompany the arteries and ultimately drain into brachial veins associated with the brachial artery in the cubital fossa.Nerves in the anterior compartment of the forearm are the median and ulnar nerves and the superficial branch of the radial nerve (Fig.7.89).

Meanwhile, the rest of the cancer cell genome remained in darkness: it was a mystery how many other mutations might lurk there, of what types, in which varieties of cancer, at what frequencies, with what variations from patient to patient, and with what consequences.the chromosome carrying the remaining normal copy may be lost from the cell through errors in chromosome segregation; or the normal gene, along with neighboring genetic material, may be replaced by a mutant version through either a mitotic recombination event or a gene conversion that accompanies it (see p. 286). Figure 20–21 summarizes the range of ways in which the remaining good copy of a tumor suppressor gene can be lost through a DNA sequence change, using the Rb gene as an example. It is important to note that, except for the point mutation mechanism illustrated at the far right, these pathways all produce cells that carry only a single type of DNA sequence in the chromosomal region containing their Rb genes—a sequence that is identical to the sequence in the original mutant chromosome. Epigenetic changes provide another important way to permanently inactivate a tumor suppressor gene. Most commonly, the gene may become packaged into heterochromatin and/or the C nucleotides in CG sequences in its promoter may become methylated in a heritable manner (see pp. 404–405). These mechanisms can irreversibly silence the gene in a cell and in all of its progeny. Analysis of methylation patterns in cancer genomes shows that epigenetic gene silencing is a frequent event in tumor progression, and epigenetic mechanisms are now thought to help inactivate several different tumor suppressor genes in most human cancers (Figure 20–22). Systematic Sequencing of Cancer Cell Genomes has Transformed Our Understanding of the Disease Methods such as those we have described above shone a spotlight on a set of can-cer-critical genes that were identified in a piecemeal fashion. Meanwhile, the rest of the cancer cell genome remained in darkness: it was a mystery how many other mutations might lurk there, of what types, in which varieties of cancer, at what frequencies, with what variations from patient to patient, and with what consequences.478–481), it has become possible to see the whole picture—to view cancer cell genomes in their entirety.This transforms our understanding of the disease.Cancer cell genomes can be scanned systematically in several different ways.At one extreme—the most costly, but no longer prohibitively so—one can determine a tumor’s complete genome sequence.

4.These are expressions of damage to basal ganglionic and thalamic structures and are discussed in Chap.In some patients, as they recover from hemiplegia, a variety of movement abnormalities emerge, such as tremor, athetosis, and chorea on the affected side.Mirror movements are also a feature of Parkinson disease and of lesions in the upper cervical spinal cord.This occurs because these muscles are bilaterally innervated; that is, stimulation of either the right or left motor cortex results in contraction of these muscles on both sides of the body. Upper motor neuron paralysis is rarely complete for any long period of time; in this respect it differs from the absolute paralysis that results from destruction of anterior horn cells or interruption of their axons. Upper motor neuron lesions are characterized further by certain peculiarities of retained movement. There is decreased voluntary drive on spinal motor neurons (fewer motor units are recruitable and their firing rates are slower), resulting in a slowness of movement. There is also an increased degree of cocontraction of antagonistic muscles, reflected in a decreased rate of rapid alternating movements. These abnormalities probably account for the greater sense of effort and the manifest fatigability in effecting voluntary movement of the weakened muscles. Another phenomenon is the activation of paralyzed muscles as parts of certain automatisms (synkinesias). For example, the paralyzed arm may move suddenly during yawning and stretching. Attempts by the patient to move the hemiplegic limbs may also result in a variety of associated movements. Thus, flexion of the arm may result in involuntary pronation and flexion of the leg or in dorsiflexion and eversion of the foot. Also, volitional movements of the paretic limb often evoke imitative (mirror) movements in the normal one or vice versa. Mirror movements are also a feature of Parkinson disease and of lesions in the upper cervical spinal cord. In some patients, as they recover from hemiplegia, a variety of movement abnormalities emerge, such as tremor, athetosis, and chorea on the affected side. These are expressions of damage to basal ganglionic and thalamic structures and are discussed in Chap. 4.3-5).Because Broadbent was the first to call attention to this distribution of facial paralysis that relatively spares the forehead muscles, it has been referred to as “Broadbent’s law.” The precise course taken by fibers that innervate the facial nucleus is still somewhat uncertain; however, the majority crosses in the mid-pons to innervate the contralateral facial nerve nucleus.

However, massive hemorrhage that includes bleeding from the rectum may necessitate proctectomy and creation of either a permanent ileostomy or an ileal pouch–anal anastomosis.Elective Operation Elective resection for ulcerative colitis usually is performed for refractory inflammation and/or the risk of malignancy (dysplasia).Although low-grade dysplasia was long thought to represent minimal risk, more recent studies show that invasive cancer may be present in up to 20% of patients with low-grade dysplasia. For this rea-son, any patient with dysplasia should be advised to undergo proctocolectomy. Controversy exists over whether prophylac-tic proctocolectomy should be recommended for patients who have had chronic ulcerative colitis for greater than 10 years in the absence of dysplasia. Proponents of this approach note that surveillance colonoscopy with multiple biopsies samples only a small fraction of the colonic mucosa, and dysplasia and carci-noma are often missed. Opponents cite the relatively low risk of progression to carcinoma (approximately 2.4%) if all biopsies lack dysplasia. Neither approach has been shown definitively to decrease mortality from colorectal cancer.Operative ManagementEmergent Operation In a patient with fulminant colitis or toxic megacolon, total abdominal colectomy with end ileostomy (with or without a mucus fistula), rather than total proctocolectomy, is recommended. Although the rectum is invariably diseased, most patients improve dramatically after an abdominal colectomy, and this operation avoids a difficult and time-consuming pelvic dissection in a critically ill patient. Rarely, a loop ileostomy and decompressing colostomy may be necessary if the patient is too unstable to withstand colectomy. Definitive surgery may then be undertaken at a later date once the patient has recovered. Complex techniques, such as an ileal pouch–anal reconstruction, generally are contraindicated in the emergent setting. However, massive hemorrhage that includes bleeding from the rectum may necessitate proctectomy and creation of either a permanent ileostomy or an ileal pouch–anal anastomosis.Elective Operation Elective resection for ulcerative colitis usually is performed for refractory inflammation and/or the risk of malignancy (dysplasia).Total procto-colectomy with end ileostomy has been the “gold standard” for treating patients with chronic ulcerative colitis.This operation removes the entire affected intestine and avoids the functional disturbances associated with ileal pouch–anal reconstruction.Most patients function well physically and psychologically after this operation.

The idiopathic granulomatous painful condition of the cavernous sinus has been termed Tolosa-Hunt syndrome; a similar process affecting structures of the orbit is known as orbital pseudotumor.A dural arteriovenous fistula is another rare cause.12 and 33).Cavernous Sinus Syndrome, Tolosa-Hunt syndrome, and Orbital Pseudotumor Some of the diseases discussed previously are associated with a degree of pain, often over the site of an affected nerve or muscle or in the immediately surrounding area. But the development over days or longer of a painful unilateral ophthalmoplegia should raise suspicion for other conditions such as aneurysm, tumor, or inflammatory and granulomatous process in the anterior portion of the cavernous sinus or the adjacent superior orbital fissure (Table 13-4). In the cavernous sinus syndrome, involvement of the ocular motor nerves on one or both sides is accompanied by periorbital pain and chemosis (Fig. 13-5B). In a series of 151 such cases reported by Keane, the third nerve (typically with pupillary abnormalities) and sixth nerve were affected in almost all and the fourth nerve in one-third; complete ophthalmoplegia, usually unilateral, was present in 28 percent. Sensory loss in the distribution of the ophthalmic division of the trigeminal nerve was often added, a finding that is helpful in the differentiation of cavernous sinus disease from other causes of orbital edema and ocular muscle weakness. Trauma and neoplastic invasion are the most frequent causes of the cavernous sinus syndrome. Thrombophlebitis, intracavernous carotid aneurysm or fistula, fungal infection, meningioma, and pituitary tumor or hemorrhage account for a smaller proportion (see “Septic Cavernous Sinus Thrombophlebitis” and “Cavernous Sinus Thrombosis” in Chaps. 12 and 33). A dural arteriovenous fistula is another rare cause. The idiopathic granulomatous painful condition of the cavernous sinus has been termed Tolosa-Hunt syndrome; a similar process affecting structures of the orbit is known as orbital pseudotumor.13-8).It is often accompanied by injection of the conjunctiva and lid and slight proptosis.One or more muscles may be involved and there is a tendency to relapse and later to involve the opposite globe.Visual loss from compression of the optic nerve is a rare complication.

It functions as an MTOC consisting of nine short microtubule triplets arranged in a ring.The basal body is a modified centriole.The 9 2 microtubule array courses from the tip of the cilium to its base, whereas the outer paired microtubules join the basal body.Basal bodies and basal body–associated structures firmly anchor cilia in the apical cell cytoplasm.The A microtubule is composed of 13 tubulin protoflaments, arranged in side-by-side configuration, whereas the B micro-tubule is composed of 10 tubulin protoflaments. Tubulin molecules incorporated into ciliary microtubules are tightly bound together and post-translationally modified in the process of acetylation and polyglutamylation. Such modifications ensure that microtubules of ciliary axoneme are highly stable and resist depolymerization. When seen in cross-section at high resolution, each doublet exhibits a pair of “arms” that contain ciliary dynein, a microtubule-associated motor protein. This motor protein uses the energy of adenosine triphosphate (ATP) hydrolysis to move along the surface of the adjacent microtubule (see Fig. 5.7). The dynein arms occur at 24-nm intervals along the length of the A microtubule and extend out to form temporary cross-bridges with the B microtubule of the adjacent doublet. A passive elastic component formed by nexin (165 kilodaltons) permanently links the A microtubule with the B microtubule of adjacent doublets at 86-nm intervals. The two central microtubules are separate but partially enclosed by a central sheath projection at 14-nm intervals along the length of the cilium (see Fig. 5.7). Radial spokes extend from each of the nine doublets toward the two central microtubules at 29-nm intervals. The proteins forming the radial spokes and the nexin connections between the outer doublets make large-amplitude oscillations of the cilia possible. Basal bodies and basal body–associated structures firmly anchor cilia in the apical cell cytoplasm. The 9 2 microtubule array courses from the tip of the cilium to its base, whereas the outer paired microtubules join the basal body. The basal body is a modified centriole. It functions as an MTOC consisting of nine short microtubule triplets arranged in a ring.The third incomplete C microtubule in the triplet extends from the bottom to the transitional zone at the top of the basal body near the transition between the basal body and the axoneme.The two central micro-tubules of the cilium originate at the transitional zone and extend to the top of axoneme (see Fig.5.7b).

19.16 ApproximatedistributionofcardiacoutputatrestandatdifferentlevelsofexerciseuptothemaximalO2consumption(V˜O2)in 0 0 5 10 15 800 1600 0.006 0.010 0.014 60 100 140 180 5 10 15 90 100 110 60 100 140 180 Mean Systolic pressure Diastolic pressure anormalyoungman.•Fig.Reflexes are activated intramuscularly by stimulation of mechanoreceptors (by stretch, tension) and chemoreceptors (by metabolic products) in response to muscle contraction. Impulses from these receptors travel centrally via small myelinated (group III) and unmyelinated (group IV) afferent nerve fibers. Group IV unmyelinated fibers may represent the muscle chemoreceptors, inasmuch as no morphological chemoreceptor has been identified. The central connections of this reflex are unknown, but the efferent limb consists of sympathetic nerve fibers to the heart and peripheral blood vessels. The baroreceptor reflex is described in , and local factors that influence skeletal muscle blood flow (metabolic vasodilators) are described in . Vascular chemoreceptors are important in regulation of the cardiovascular system during exercise. Evidence for this assertion comes from the observations that the PaCO2, the PaO2, and the pH of arterial blood remain normal during exercise. Mild to Moderate Exercise In humans or trained animals, anticipation of physical activity inhibits vagal nerve impulses to the heart and increases sympathetic discharge. The result is an increase in heart rate and myocardial contractility. The tachycardia and enhanced contractility increase cardiac output. When cardiac stimulation occurs, the sympathetic nervous system also changes vascular resistance in the periphery. Sympathetic nervous system–mediated vasoconstriction increases vascular resistance and thereby diverts blood away from the skin, kidneys, splanchnic regions, and inactive Cardiac output (L/min) 22 18 14 10 6 2 0.25 1 2 3 4 O2 uptake (L/min) Skin Heart and brain Viscera Muscle Maximum Vo2 . •Fig. 19.16 ApproximatedistributionofcardiacoutputatrestandatdifferentlevelsofexerciseuptothemaximalO2consumption(V˜O2)in 0 0 5 10 15 800 1600 0.006 0.010 0.014 60 100 140 180 5 10 15 90 100 110 60 100 140 180 Mean Systolic pressure Diastolic pressure anormalyoungman.12thed.Philadelphia:Saunders;1974.)Fig.19.16 ).This increase in vascular resistance persists throughout the period of exercise.Cardiac output and blood flow to active muscles increase as the intensity of exercise increases.Blood flow to the myocardium increases, whereas flow to the brain is unchanged.

Temperamental.Long—term course is not yet described beyond 7—12 years.It appears that the diagnosis is best applied to individuals ages 15—35 years.In some cases, the syndrome may transition to a depres- sive or bipolar disorder with psychotic features, but development to a schizophrenia spec- trum disorder is more frequent.In help-seeking cohorts, criteria for a psychotic disorder.The individual must experience distress and/ or impaired performance in social or role functioning (Criterion D), and the individual or responsible others must note the changes and express concern, such that clinical care is sought (Criterion A). The individual may experience magical thinking, perceptual aberrations, difficulty in con- centration, some disorganization in thought or behavior, excessive suspiciousness, anxi- ety, social withdrawal, and disruption in sleep-wake cycle. Impaired cognitive function and negative symptoms are often observed. Neuroimaging variables distinguish cohorts with attenuated psychosis syndrome from normal control cohorts with patterns similar to, but less severe than, that observed in schizophrenia. However, neuroimaging data is not diagnostic at the individual level. The prevalence of attenuated psychosis syndrome is unknown. Symptoms in Criterion A are not uncommon in the non-help-seeking population, ranging from 23%—13% for hallu- cinatory experiences and delusional thinking. There appears to be a slight male prepon- derance for attenuated psychosis syndrome. Onset of attenuated psychosis syndrome is usually in mid-to-late adolescence or early adulthood. It may be preceded by normal development or evidence for impaired cogni- tion, negative symptoms, and/ or impaired social development. In help-seeking cohorts, criteria for a psychotic disorder. In some cases, the syndrome may transition to a depres- sive or bipolar disorder with psychotic features, but development to a schizophrenia spec- trum disorder is more frequent. It appears that the diagnosis is best applied to individuals ages 15—35 years. Long—term course is not yet described beyond 7—12 years. Temperamental.Genetic and physiological.A family history of psychosis places the individual with at- tenuated psychosis syndrome at increased risk for developing a full psychotic disorder.Structural, functional, and neurochemical imaging data are associated with increased risk of transition to psychosis.Many individuals may experience functional impairments.

For antibody production against the same antigen, active antigen is bound to sIg within the B cell receptor complex and drives B cell maturation into plasma cells that secrete Ig.CD8+ T cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T cell generation, as well as induction of cytokine-producing CD8+ cytotoxic T cells.This is a particularly important host defense mechanism against parasitic diseases. Basophils express high-affinity surface receptors for IgE (FcεRII) (CD23) and, upon cross-linking of basophil-bound IgE by antigen, can release histamine, eosinophil chemotactic factor of anaphylaxis, and neutral protease— all mediators of allergic immediate (anaphylaxis) hypersensitivity responses (Table 372e-11). In addition, basophils express surface receptors for activated complement components (C3a, C5a), through IL-12 antigen presentation Myeloid dendritic cell IL-1,IL-6 phagocytosis of microbes CD8+ cytotoxic T cell CD4+, CD8+ regulatory cells TH1 TH2 TH0 TR IL-12 IL-4 IFN-°intracellular microbes IL-4,IL-5 extracellular microbes Phagocytosis of microbes; secretion of inflammatory products Neutrophilic granulocyte FIGUrE 372e-2 Schematic model of intercellular interactions of adaptive immune system cells. In this figure, the arrows denote that cells develop from precursor cells or produce cytokines or antibodies; lines ending with bars indicate suppressive intercellular interactions. Stem cells differentiate into either T cells, antigen-presenting dendritic cells, natural killer cells, macrophages, granulocytes, or B cells. Foreign antigen is processed by dendritic cells, and peptide fragments of foreign antigen are presented to CD4+ and/or CD8+ T cells. CD8+ T cell activation leads to induction of cytotoxic T lymphocyte (CTL) or killer T cell generation, as well as induction of cytokine-producing CD8+ cytotoxic T cells. For antibody production against the same antigen, active antigen is bound to sIg within the B cell receptor complex and drives B cell maturation into plasma cells that secrete Ig.TH17 cells secrete IL-17, IL-22, IL-26, which contribute to host defense against extracellular bacteria and fungi, particularly at mucosal surfaces.CD4+, CD25+ T regulatory cells produce IL-10 and downregulate T and B cell responses once the microbe has been eliminated.GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF, tumor necrosis factor.

The age of onset was in childhood or adolescence, and the disability progressed to the point where the patient was chairbound by early adult life.Hereditary spastic paraplegia with polyneuropathy Our colleagues had observed several patients in whom a sensorimotor polyneuropathy was combined with unmistakable signs of corticospinal disease.6.The syndrome is transmitted as an autosomal recessive trait, with onset in infancy and slow progression. The mutation is in OPA3. There may be a relationship to decreased excretion of 3-methylglutaconic aciduria of an optic atrophy and cataract syndrome (Costeff syndrome). 4. Hereditary spastic paraplegia with macular degeneration (Kjellin syndrome, SPG11 and SPG15 mutations) Spastic paraplegia with amyotrophy, oligophrenia, and central retinal degeneration constitutes the syndrome described in 1959 by Kjellin. Although the developmental delay is stationary, the spastic weakness and retinal changes are of late onset and progressive. Mutations have been found in SPG11 and SPG15. 5. Hereditary spastic paraplegia with developmental delay or dementia Many of the children with progressive spastic paraplegia either have been developmentally delayed since early life or have appeared to regress mentally as other neurologic symptoms developed. Examples of this syndrome and its variants are too numerous to be considered here but are contained in the review by Gilman and Romanul. The autosomal recessive syndrome of Sjögren-Larsson, with the onset in infancy of spastic weakness of the legs in association with developmental delay, stands somewhat apart from the others in this large group because of the associated ichthyosis. The mutation for the latter is in ALDH3A2 that codes for fatty aldehyde dehydrogenase. This relates to both dry skin, itchy and discolored skin, and the myelinopathy that characterize Sjögren-Larsson syndrome. 6. Hereditary spastic paraplegia with polyneuropathy Our colleagues had observed several patients in whom a sensorimotor polyneuropathy was combined with unmistakable signs of corticospinal disease. The age of onset was in childhood or adolescence, and the disability progressed to the point where the patient was chairbound by early adult life.The syndrome resembles the myeloneuropathy of adrenoleukodystrophy.7.Spastic paraparesis with distal muscle wasting (Troyer syndrome, SPG20 mutation) This disorder is transmitted as an autosomal recessive trait in the Amish population.Onset is in childhood with amyotrophy of the hands, followed by spasticity and contractures of the lower limbs.

315.8 (F88) This diagnosis is reserved for individuals under the age of 5 years when the clinical severity level cannot be reliably assessed during early childhood.Rather than listing specifiers as is done in DSM-5, the AAIDD emphasizes a profile of supports based on severity.The AAIDD’s classification is multidimensional rather than categorical and is based on the disability construct.The most common co-occurring mental and neurodevelopmental disorders are atten- behavior); impulse-control disorders; and major neurocognitive disorder. Major depres- sive disorder may occur throughout the range of severity of intellectual disability. Self- agnosis of stereotypic movement disorder. Individuals with intellectual disability, partic- ularly those with more severe intellectual disability, may also exhibit aggression and disruptive behaviors, including harm of others or property destruction. Relationship to Other Classifications ICD-ll (in development at the time of this publication) uses the term intellectual develop- mental disorders to indicate that these are disorders that involve impaired brain functioning early in life. These disorders are described in ICD-11 as a metasyndrome occurring in the developmental period analogous to dementia or neurocognitive disorder in later life. There are four subtypes in ICD-ll: mild, moderate, severe, and profound. The American Association on Intellectual and Developmental Disabilities (AAIDD) also uses the term intellectual disability with a similar meaning to the term as used in this manual. The AAIDD’s classification is multidimensional rather than categorical and is based on the disability construct. Rather than listing specifiers as is done in DSM-5, the AAIDD emphasizes a profile of supports based on severity. 315.8 (F88) This diagnosis is reserved for individuals under the age of 5 years when the clinical severity level cannot be reliably assessed during early childhood.This category requires reassessment after a period of time.

5.Margin status is a useful clinical predictor of residual disease as is endocervical sampling at the time of excision.The overall failure rate of excision is less than 10%.If future fertility is desired, conservative excisional management is acceptable.4.Negative margins in an excisional specimen do not mean the lesion is completely excised.3.Treatment is recommended for a histologic diagnosis of CIN 3 or if colposcopy is unsatisfactory. Although invasive cervical cancer is very rare in this age group, prospective follow-up of a histological diagnosis of CIN 2 or 3, not otherwise specified, in young women should be limited to those women likely to be compliant with the recommendations. 3. After 2 consecutive negative for intraepithelial lesion or malignancy results, implying negative cytology and colposcopy with satisfactory colposcopic examinations, adolescents and young women can return to routine cytologic screening. An annual screening interval should be recommended. 4. Treatment is recommended if CIN 3 is diagnosed histologically or if CIN 2 or 3 persists for 24 months. 1. Hysterectomy remains the preferred management recommendation for women with a histological diagnosis of AIS on a specimen from a diagnostic excisional procedure (Fig 19.16F). 2. A histologic diagnosis of AIS from a punch biopsy or a cytological diagnosis of AIS is not sufficient to justify hysterectomy without a diagnostic excisional procedure. The difficulty in defining colposcopic limits of AIS lesions, the frequent extension of disease within the endocervical canal and the presence of multifocal, “skip-lesions” (i.e., lesions that are not contiguous) compromise conservative excisional procedures. 3. Negative margins in an excisional specimen do not mean the lesion is completely excised. 4. If future fertility is desired, conservative excisional management is acceptable. The overall failure rate of excision is less than 10%. Margin status is a useful clinical predictor of residual disease as is endocervical sampling at the time of excision. 5.6.A reassessment at 6 months using a combination of cytology, colposcopy, HPV DNA testing, and endocervical sampling is acceptable.Long-term follow-up is recommended for women who do not undergo hysterectomy for AIS.Cryotherapy Cryotherapy destroys the surface epithelium of the cervix by crystallizing the intracellular water, resulting in the eventual destruction of the cell.

The theoreti-cal disadvantages of neoadjuvant chemotherapy are related to myelosuppression and potential postoperative wound healing complications.A recent randomized study comparing three preoperative cycles of full-dose anthracycline-ifosfamide–based chemother-apy with three preoperative plus two postoperative cycles of the same regimen in high-risk extremity and trunk wall soft tissue sarcomas showed equivalence between the two approaches, sug-gesting the possibility of limiting chemotherapy administration to the three preoperative courses, improving the ratio between toxicity and expected benefit.151A subanalysis on response showed how tumor attenuation on CT scan and MRI obtained by the administration of such preoperative treatment was associated with a higher percentage of pathologic necrosis152 and better outcome.153Eilber and colleagues examined treatment-induced patho-logic necrosis in patients who received neoadjuvant therapy for high-grade extremity sarcomas.154 The addition of ifosfamide to other agents (doxorubicin alone or doxorubicin and cisplatin) increased the rate of pathologic necrosis to 48% compared to 13% with other combinations. The 5and 10-year local recur-rence rates were significantly lower for patients with 95% or greater pathologic necrosis (6% and 11%, respectively) than for patients with less than 95% pathologic necrosis (17% and 23%, respectively).Concurrent Chemoradiation TherapyTreatment approaches that combine systemic chemotherapy with radiosensitizers and concurrent external-beam radiation therapy may improve disease-free survival by treating micro-scopic disease and enhancing the treatment of macroscopic disease.

The di- agnosis of pyromania should also not be given when fire setting results from impaired judgment associated with major neurocognitive disorder, intellectual disability, or sub- stance intoxication.In individuals with pyromania, fire-setting incidents are episodic and may wax and wane in frequency. Longitudinal course is unknown. Although fire setting is a major problem in children and adolescents (over 40% of those arrested for arson offenses in the United States are younger than 18 years), pyromania in childhood appears to be rare. Ju- venile fire setting is usually associated with conduct disorder, attention—deficit/hyperac- tivity disorder, or an adjustment disorder. Pyromania occurs much more often in males, especially those with poorer social skills and learning difficulties. Other causes of intentional fire setting. It is important to rule out other causes of fire setting before giving the diagnosis of pyromania. Intentional fire setting may occur for profit, sabotage, or revenge; to conceal a crime; to make a political statement (e.g., an act of terrorism or protest); or to attract attention or recognition (e.g., setting a fire in order to dis- cover it and save the day). Fire setting may also occur as part of developmental experi- mentation in childhood (e.g., playing with matches, lighters, or fire). Other mental disorders. A separate diagnosis of pyromania is not given when fire set— ting occurs as part of conduct disorder, a manic episode, or antisocial personality disorder, or if it occurs in response to a delusion or a hallucination (e.g., in schizophrenia) or is at- tributable to the physiological effects of another medical condition (e.g., epilepsy). The di- agnosis of pyromania should also not be given when fire setting results from impaired judgment associated with major neurocognitive disorder, intellectual disability, or sub- stance intoxication.478 Disruptive, Impulse-Control, and Conduct Disorders Diagnostic Criteria 312.32 (F63.3) A. Recurrent failure to resist impulses to steal objects that are not needed for personal use or for their monetary value.B.Increasing sense of tension immediately before committing the theft.C. Pleasure, gratification, or relief at the time of committing the theft.

Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels.Gene-dosage effects are causative in some cases of Parkinson’s disease (α-synuclein), Alzheimer’s disease (amyloid precursor protein), spinal muscular atrophy (survival motor neuron 2), the dysmyelinating disorder Pelizaeus-Merzbacher syndrome (proteolipid protein 1), late-onset leukodystrophy (lamin B1), and a variety of developmental neurologic disorders. It is likely that copy-number variations contribute substantially to normal human genomic variation for numerous genes involved in neurologic function, regulation of cell growth, and regulation of metabolism. It is also already clear that gene-dosage effects will influence many behavioral phenotypes, learning disorders, and autism spectrum disorders. Deletions at ch444eq and ch15q have been associated with schizophrenia, and deletions at 15q and 16p with autism. Interestingly, the 16p deletion is also associated with epilepsy. Duplications of the X-linked MeCP2 gene cause autism in males and psychiatric disorders with anxiety in females, whereas point mutations in this gene produce the neurodevelopmental disorder Rett’s syndrome. The understanding of the role of copy number variation in human disease is still in its infancy. The role of splicing variation as a contributor to neurologic disease is another area of active investigation. Alternative splicing refers to the inclusion of different combinations of exons in mature mRNA, resulting in the potential for many different protein products encoded by a single gene. Alternative splicing represents a powerful mechanism for generation of complexity and variation, and this mechanism appears to be highly prevalent in the nervous system, affecting key processes such as neurotransmitter receptors and ion channels.Increased inclusion of exon 10–containing transcripts of MAPT can cause frontotemporal dementia.Aberrant splicing also contributes to the pathogenesis of Duchenne’s, myotonic, and facioscapulohumeral muscular dystrophies; ataxia telangiectasia; neurofibromatosis; some inherited ataxias; and fragile X syndrome, among other disorders.

These arteries dilate during erection (see Folder 22.5) to increase the blood flow to the penis.3. blood, principally derived from the helicine arteries.Note the arrangement of the corpora cavernosa and corpus spongiosum; the latter contains the urethra.This photomicrograph shows an H&E–stained specimen of a cross section of the penis near the base of the organ.This photomicrograph shows an H&E–stained section of the compound tubuloalveolar bulbourethral gland. The epithelium consists of columnar mucus-secreting cells. The nuclei are displaced to the base of the cells by the accumulated secretory material that they contain. The cytoplasm has an appearance similar to typical mucus-secreting cells. Note several ducts (D) lined by a simple columnar epithelium. The ducts will merge to form a single excretory duct. In some sites the ducts contain mucus-secreting cells (arrows). 40. tissue, the corpus spongiosum, in which the spongy part of the urethra is embedded. A dense, fibroelastic layer, the tunica albuginea, binds the three together and forms a capsule around each (Fig. 22.30). The corpora cavernosa contain numerous wide, irregularly shaped vascular spaces lined with vascular endothelium. These spaces are surrounded by a thin layer of smooth muscle that forms trabeculae within the tunica albuginea interconnecting and criss-crossing the corpus cavernosum. Irregular smooth muscle bundles are observed frequently as “subendothelial cushions” surrounding irregular vascular spaces (Fig. 22.31). The interstitial connective tissue contains many nerve endings and lymphatic vessels. The vascular spaces increase in size and rigidity by filling with FIGURE 22.30 • Photomicrograph of a histologic section of the penis. This photomicrograph shows an H&E–stained specimen of a cross section of the penis near the base of the organ. Note the arrangement of the corpora cavernosa and corpus spongiosum; the latter contains the urethra. 3. blood, principally derived from the helicine arteries. These arteries dilate during erection (see Folder 22.5) to increase the blood flow to the penis.The skin of the penis is thin and loosely attached to the underlying loose connective tissue except at the glans penis, where it is very thin and tightly attached.The skin of the glans is so thin that blood within its large, muscular anastomosing veins that drain the corpus spongiosum may give it a bluish color.There is no adipose tissue in the subcutaneous tissue.

As a more chronic affliction, we have observed numerous cases in which cranial nerves were affected sequentially over a period of many years (polyneuritis cranialis multiplex).Others probably are examples of the entity described by Juncos and Beal, possibly reflecting a granulomatous process in the pachymeninges.Juncos and Beal reported on 14 cases of this type, incorporating 6 well-documented cases of the Tolosa-Hunt orbitocavernous sinus syndrome with oculomotor palsies. In the group that was not attributable to Tolosa-Hunt, the onset was with facial pain and headache (temporofrontal), followed within days by abducens palsy (12 of 14), oculomotor palsy (6 of 14), trigeminal palsy (5 of 14), and facial weakness (4 of 14), and less often by involvement of the eighth, ninth, and tenth cranial nerves (unilaterally in most instances). Increased CSF protein and pleocytosis occurred in several. The prompt relief of pain upon administration of steroids was similar to that obtained in the Tolosa-Hunt syndrome. The mode of recovery, which usually occurred within a few months, was also much the same in the 2 groups of patients. Juncos and Beal concluded that the clinical features of the 2 groups overlapped and that their separation into 2 syndromes was arbitrary. We have seen a relapsing form of this illness in young adults, responsive on each occasion to steroids and stabilizing after several years. Numerous tests of the CSF by polymerase chain reaction revealed no viruses. Conceivably, some of these cases represent variant forms of GBS, in as much as they may be preceded by a nonspecific infection and may at times be accompanied by areflexia or evanescent paresthesias and elevated CSF protein without pleocytosis. Others probably are examples of the entity described by Juncos and Beal, possibly reflecting a granulomatous process in the pachymeninges. As a more chronic affliction, we have observed numerous cases in which cranial nerves were affected sequentially over a period of many years (polyneuritis cranialis multiplex).No cause was determined in the rest.Symonds had similar experience.It is usually worth obtaining a biopsy of an enlarged cervical lymph node in these circumstances.The cavernous sinus syndrome, discussed in Chaps.

Although these peptides are generally considered individually, many belong to families, the members of which have similarities in structure and function and act on the same or related receptors.If consumed in suf-ficient amount, enough histamine can be absorbed to cause the clinical picture described. This syndrome is Ian A. Reid, PhD During a routine check and on two follow-up visits, a 45-year-old man was found to have high blood pressure (160–165/95–100 mm Hg). His physician initially prescribed hydrochlorothiazide, a diuretic commonly used to treat hyper-tension. His blood pressure was reduced by hydrochloro-thiazide but remained at a hypertensive level (145/95 mm Hg), and he was referred to the university hypertension clinic. Because the patient had elevated plasma renin activity and aldosterone concentration, hydrochlorothiazide was replaced with enalapril, an angiotensin-converting enzyme inhibitor. Enalapril lowered his blood pressure to almost normotensive levels. However, after several weeks on enalapril, the patient returned complaining of a persistent cough. In addition, some signs of angioedema were detected. How does enalapril lower blood pressure? Why does it occasionally cause coughing and angioedema? What other drugs could be used to inhibit the renin-angiotensin system and decrease blood pressure, without the adverse effects of enalapril? Peptides are used by most tissues for cell-to-cell communication. As noted in Chapters 6 and 21, they play important roles as transmitters in the autonomic and central nervous systems. Several peptides exert important direct effects on vascular and other smooth muscles. These peptides include vasoconstrictors (angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin) and vasodilators (bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide, and adrenomedullin). Although these peptides are generally considered individually, many belong to families, the members of which have similarities in structure and function and act on the same or related receptors.Many of these peptides were initially regarded as physiologic curiosities, but subsequent investigation showed that they play important roles not only in physiologic regulation, but also in a variety of disease states.Moreover, many drugs that alter the biosynthesis or actions of the peptides have been synthesized.

One presumes that the main clinical features are due to dysfunction of the frontal lobes and their connections with the striatum, from mechanical pressure or distortion, but this is conjecture.In those cases, the difficulty with walking and stability is ostensibly a result of frontal lobe disease, either degenerative or infarctive, as discussed in Chap. 6. Unfortunately, beyond the above-noted defects that are elicitable by routine testing, we have not found neuropsychologic tests of great value in the diagnosis of NPH. Urinary symptoms appear relatively later in the illness. Initially, they consist of urinary urgency and frequency. Later, the urgency is associated with incontinence, and ultimately there is frontal lobe incontinence,” in which the patient is indifferent to his lapses of continence, and bowel control becomes similarly disordered. The cause of the syndrome of NPH in most cases cannot be established and on weak grounds, asymptomatic fibrosing meningitis is often presumed to have been present. An uncertain proportion of cases can be traced to congenital aqueductal stenosis that has allowed normal brain function into adulthood and, for unknown reasons, decompensates; a few of our patients have become symptomatic after mild head trauma. This is probably the most common imputed cause of the syndrome but again, on uncertain grounds. An identical syndrome may follow subarachnoid hemorrhage from ruptured aneurysm, resolved acute meningitis or a chronic meningitis (tubercular, fungal, syphilitic, or other), Paget disease of the base of the skull, mucopolysaccharidosis of the meninges, and achondroplasia. That the mechanical effect of ventricular enlargement on the adjacent brain is responsible for the syndrome is supported by Fisher’s observations (2002) that a reduction in ventricular size caused by extrinsic compression from subdural collections has been associated with clinical improvement. One presumes that the main clinical features are due to dysfunction of the frontal lobes and their connections with the striatum, from mechanical pressure or distortion, but this is conjecture.The CT scan, as shown in Fig.29-4, displays enlarged ventricles without convolutional atrophy.This disproportionate enlargement of the ventricular system in comparison to the degree of cortical atrophy is judged by the CT and MRI appearance, but there is no broadly agreed upon method for its determination.Various unwieldy formulas have been designed to assess this ratio.

Regardless of the many roles of dopamine under physi-ologic conditions, all addictive drugs significantly increase its concentration in target structures of the mesolimbic projection.These recent findings suggest that in parallel to the reward system, a system for aversion-learning originates in the VTA, which may be at the origin of the negative affective state seen during drug withdrawal.However, in DAT –/– mice, in which basal synaptic dopamine levels are high, cocaine still leads to increased dopamine release, presumably because other cocaine-sensitive monoamine transporters (NET, SERT) are able to clear some dopamine. When cocaine is given, these transporters are also inhibited and dopamine is again increased. As a conse-quence of this substitution among monoamine transporters, fluoxetine (a selective serotonin reuptake inhibitor, see Chapter 30) becomes addictive in DAT –/– mice. This concept is supported by newer evidence showing that deletion of the cocaine-binding site on DAT leaves basal dopamine levels unchanged but abol-ishes the rewarding effect of cocaine. The dopamine hypothesis of addiction has also been chal-lenged by the observation that salient stimuli that are not rewarding (they may actually even be aversive and therefore nega-tive reinforcers) also activate a subpopulation of dopamine neu-rons in the VTA. The neurons that are activated by aversive stimuli preferentially project to the prefrontal cortex, while the dopamine neurons inhibited by aversive stimuli are those that mostly tar-get the nucleus accumbens. These recent findings suggest that in parallel to the reward system, a system for aversion-learning originates in the VTA, which may be at the origin of the negative affective state seen during drug withdrawal. Regardless of the many roles of dopamine under physi-ologic conditions, all addictive drugs significantly increase its concentration in target structures of the mesolimbic projection.In fact manipulations that drive sustained activity of VTA dopamine neurons cause the same cellular adaptations and behavioral changes typically observed with addictive drug exposure, including late-stage symptoms such as persistence of self-stimulation during punishment.

Large-vessel renal artery occlusive disease can result from extrinsic compression of the vessel, fibromuscular dysplasia, or, most commonly, atherosclerotic disease.299-1).Experimental studies demonstrate functional changes and rarefaction of renal microvessels under conditions of accelerated atherosclerosis and/or compromise of proximal perfusion pressures with large-vessel disease (Fig.Treatment of hypertension in patients with acute aortic dissection is discussed in Chap. 301, and treatment of hypertension in pregnancy is discussed in Chap. 8. Stephen C. Textor The renal vasculature is unusually complex with rich arteriolar flow to the cortex in excess of metabolic requirements, consistent with its primary function as a filtering organ. After delivering blood to cortical glomeruli, the postglomerular circulation supplies deeper medullary segments that support energy-dependent solute transport at multiple levels of the renal tubule. These postglomerular vessels carry less blood, and high oxygen consumption leaves the deeper medullary regions at the margin of hypoxemia. Vascular disorders that commonly threaten the blood supply of the kidney include large-vessel atherosclerosis, fibromuscular diseases, and embolic disorders. Microvascular injury, including inflammatory and primary hematologic disorders, is described in Chap. 341. The glomerular capillary endothelium shares susceptibility to oxidative stress, pressure injury, and inflammation with other vascular territories. Rates of urinary albumin excretion (UAE) are predictive of systemic atherosclerotic disease events. Increased UAE may develop years before cardiovascular events. UAE and the risk of cardiovascular events are both reduced with pharmacologic therapy such as statins. Experimental studies demonstrate functional changes and rarefaction of renal microvessels under conditions of accelerated atherosclerosis and/or compromise of proximal perfusion pressures with large-vessel disease (Fig. 299-1). Large-vessel renal artery occlusive disease can result from extrinsic compression of the vessel, fibromuscular dysplasia, or, most commonly, atherosclerotic disease.Because restoration of perfusion pressures can reverse these pathways, renal artery stenosis is considered a specifically treatable “secondary” cause of hypertension.Renal artery stenosis is common and often has only minor hemodynamic effects.Fibromuscular dysplasia (FMD) is reported in 3–5% of normal subjects presenting as potential kidney donors without hypertension.

It may seem that air pollution is a modern phenomenon.Together, some of these agents produce the well-known smog that sometimes stifles major cities such as Cairo, Los Angeles, Houston, Mexico City, and São Paulo.The cytochrome P-450 system also participates in the metabolism of a large number of common therapeutic drugs such as acetaminophen, barbiturates, and anti-convulsants, and in alcohol metabolism (discussed later). • P-450 enzymes vary widely in activity among different people, owing to both polymorphisms in the genes encoding the enzymes and interactions with drugs that are metabolized through the system. The activity of the enzymes also may be decreased by fasting or starvation, and increased by alcohol consumption and smoking. Air pollution is a significant cause of morbidity and mortality worldwide, particularly among at-risk individuals with preexisting pulmonary or cardiac disease. The life-giving air that we breathe is also often laden with many potential causes of disease. Airborne microorganisms have long been major causes of morbidity and death. More widespread are the chemical and particulate pollutants found in the air, both in so-called “developed” and “underdeveloped” countries. Specific hazards have been recognized for both outdoor and indoor air. The ambient air in industrialized nations is contaminated with an unsavory mixture of gaseous and particulate pollutants, more so in cities and in proximity to heavy industry. In the United States, the Environmental Protection Agency (EPA) monitors and sets allowable upper limits for six pollutants: sulfur dioxide, CO, ozone, nitrogen dioxide, lead, and particulate matter. Together, some of these agents produce the well-known smog that sometimes stifles major cities such as Cairo, Los Angeles, Houston, Mexico City, and São Paulo. It may seem that air pollution is a modern phenomenon.It could be argued that modern man has lost his head to drown himself in pollution!The lungs bear the brunt of the adverse consequences of air pollution, but air pollutants affect many organ systems (as with the effects of lead poisoning and CO, discussed later).More detailed discussion of pollutant-caused lung diseases is found in Chapter 13.

Even where malaria is rare, there appears to be no survival benefit.However, some studies suggest that in areas where malaria rates are high, this approach may increase the incidence of severe illness and death.Prophylactic folic acid has been used to reduce homocysteine levels to prevent cardiovascular disease and for cognitive function in the elderly, but there are no firm data to show any benefit. Pregnancy In over 70 countries (but none in Europe), food is fortified with folic acid (in grain or flour) to reduce the risk of NTDs. Nevertheless, folic acid, 400 μg daily, should be given as a supplement before and throughout pregnancy to prevent megaloblastic anemia and reduce the incidence of NTDs, even in countries with fortification of the diet. The levels of fortification provide up to 400 μg daily on average in Chile, but in most countries, it is nearer to 200 μg, so periconceptual folic acid is still needed. Studies in early pregnancy show significant lack of compliance with the folic acid supplements, emphasizing the benefit of food fortification. Supplemental folic acid reduces the incidence of birth defects in babies born to diabetic mothers. In women who have had a previous fetus with an NTD, 5 mg daily is recommended when pregnancy is contemplated and throughout the subsequent pregnancy. Infancy and Childhood The incidence of folate deficiency is so high in the smallest premature babies during the first 6 weeks of life that folic acid (e.g., 1 mg daily) should be given routinely to those weighing <1500 g at birth and to larger premature babies who require exchange transfusions or develop feeding difficulties, infections, or vomiting and diarrhea. The World Health Organization currently recommends routine supplementation with iron and folic acid in children in countries where iron deficiency is common and child mortality, largely due to infectious diseases, is high. However, some studies suggest that in areas where malaria rates are high, this approach may increase the incidence of severe illness and death. Even where malaria is rare, there appears to be no survival benefit.Antiviral nucleoside analogues used in treatment of HIV infection may also cause macrocytosis and megaloblastic marrow changes.In the rare disease orotic aciduria, two consecutive enzymes in purine synthesis are defective.The condition responds to therapy with uridine, which bypasses the block.

18.6) the liver acinus occupies parts of adjacent classic lobules.Therefore, in a two-dimensional view (Fig.The long axis of the acinus is a line drawn between the two central veins closest to the short axis.The short axis of the acinus is defined by the terminal branches of the portal triad that lie along the border between two classic lobules.At the edges of the portal canal, between the connective tissue stroma and the hepatocytes, is a small space called the periportal space (space of Mall). This space is thought to be one of the sites where lymph originates in the liver. In some species (e.g., the pig; Fig. 18.4a), the classic lobule is easily recognized because the portal areas are connected by relatively thick layers of connective tissue. In humans, however, there is normally very little interlobular connective tissue, and it is necessary, when examining histologic sections of liver, to draw imaginary lines between portal areas surrounding a central vein to get some sense of the size of the classic lobule (Fig. 18.4b). The portal lobule emphasizes the exocrine functions of the liver. The major exocrine function of the liver is bile secretion. Thus, the morphologic axis of the portal lobule is the interlobular bile duct of the portal triad of the classic lobule. Its outer margins are imaginary lines drawn between the three central veins that are closest to that portal triad (Fig. 18.5). These lines define a roughly triangular block of tissue that includes those portions of three classic lobules that secrete the bile that drains into its axial bile duct. This concept allows a description of hepatic parenchymal structure comparable to that of other exocrine glands. The liver acinus is the structural unit that provides the best correlation between blood perfusion, metabolic activity, and liver pathology. The liver acinus is lozenge shaped and represents the smallest functional unit of the hepatic parenchyma. The short axis of the acinus is defined by the terminal branches of the portal triad that lie along the border between two classic lobules. The long axis of the acinus is a line drawn between the two central veins closest to the short axis. Therefore, in a two-dimensional view (Fig. 18.6) the liver acinus occupies parts of adjacent classic lobules.The hepatocytes in each liver acinus are described as being arranged in three concentric elliptical zones surrounding the short axis (see Fig.18.6). Zone 1 is closest to the short axis and the blood supply from penetrating branches of the portal vein and hepatic artery.This zone corresponds to the periphery of the clas sic lobules.

Treatment Most instances of hyponatremia have developed slowly, allowing for maintenance of brain volume by the extrusion from cells of various osmotic substances.Lack of recognition of this state may allow the serum Na to fall to dangerously low levels, 100 mEq/L or lower.Hyponatremia and Syndrome of Inappropriate Antidiuretic Hormone Hyponatremia is defined as a serum sodium level below 135 mEq/L. The hyponatremic state may be isotonic, hypertonic, or hypotonic, depending on the mechanism of reduced sodium concentration. The hypotonic variety is most common in neurologic practice but one also encounters cases of pseudohyponatremia caused by hyperlipidemia or hyperproteinemia (isotonic), hyperglycemic or mannitol-induced hyponatremia (hypertonic), and also cases of water intoxication. The last of these may be associated with systemic hypovolemic (blood loss, salt wasting), hypervolemic (edematous states such as renal, hepatic or heart failure), or isovolemic states (retention of free water). Hypotonic isovolemic hypernatremia is most often a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This state is of special importance because it complicates neurologic diseases of many types: head trauma, bacterial meningitis and encephalitis, cerebral infarction, subarachnoid hemorrhage, cerebral and systemic neoplasm, Guillain-Barré syndrome and the effects of certain medications. SIADH is the result of excretion of urine that is hypertonic relative to the plasma. As the hyponatremia develops, there is a decrease in alertness, which progresses through stages of confusion to coma, often with convulsions. As with many other metabolic derangements, the severity of the clinical effect is related to the rapidity of decline in serum Na. Lack of recognition of this state may allow the serum Na to fall to dangerously low levels, 100 mEq/L or lower. Treatment Most instances of hyponatremia have developed slowly, allowing for maintenance of brain volume by the extrusion from cells of various osmotic substances.This, in turn, is associated with a special type of central nervous system demyelination (“osmotic demyelination” and central pontine myelinolysis) discussed below.One’s first impulse is to administer NaCl intravenously, but this must be done cautiously to avoid these complications.

All Present-Day Cells Use DNA as Their Hereditary Material If the evolutionary speculations embodied in the RNA world hypothesis are correct, early cells would have differed fundamentally from the cells we know today in having their hereditary information stored in RNA rather than in DNA (Figure 6–93).As attractive as the RNA world idea is for envisioning early life, it does not explain how the modern-day system of protein synthesis arose. Although we can only speculate on the origins of the genetic code, several experimental observations have provided plausible scenarios. In modern cells, some short peptides (such as antibiotics) are synthesized without the ribosome; peptide synthetase enzymes assemble these peptides, with their proper sequence of amino acids, without mRNAs to guide their synthesis. It is plausible that this noncoded, primitive version of protein synthesis first developed in the RNA world, where it would have been catalyzed by RNA molecules. This idea presents no conceptual difficulties because, as we have seen, rRNA catalyzes peptide bond formation in present-day cells. However, it leaves unexplained how the genetic code—which lies at the core of protein synthesis in today’s cells— might have arisen. We know that ribozymes created in the laboratory can perform specific aminoacylation reactions; that is, they can match specific amino acids to specific tRNAs. It is therefore possible that tRNA-like adaptors, each matched to a specific amino acid, could have arisen in the RNA world, marking the beginnings of a genetic code. Once coded protein synthesis evolved, the transition to a protein-dominated world could proceed, with proteins eventually taking over the majority of catalytic and structural tasks because of their greater versatility, with 20 rather than 4 different subunits. Although these ideas are highly speculative, they are consistent with the known properties of RNA and protein molecules. All Present-Day Cells Use DNA as Their Hereditary Material If the evolutionary speculations embodied in the RNA world hypothesis are correct, early cells would have differed fundamentally from the cells we know today in having their hereditary information stored in RNA rather than in DNA (Figure 6–93).This hypothetical process would require catalysis both of the production of a second RNA strand of complementary nucleotide sequence (not shown) and the use of this second RNA molecule as a template to form many molecules of RNA with the original sequence.The red rays represent the active site of this hypothetical RNA enzyme.

One must remember that radionuclide contamination of the skin commonly is not an acute life-threatening situation for the patient or for the personnel who care for the patient.CBC, complete blood count.FIGURE 263e-1 General guidelines for treatment of radiation casualties.Less severely injured victims should undergo preliminary decontamination before or during evacuation to a hospital.One of the goals of terrorist attackers is to overwhelm medical facilities and minimize the salvage of casualties. Initial management consists of primary triage and transportation of the wounded to medical facilities for treatment. The rationale behind triage is to sort patients into classes according to the severity of injury for the purpose of expediting clinical care and maximizing the use of the available clinical services and facilities. Triage requires determination of the level of emergency care needed. The higher the number and broader the range of casualties, the more complex and difficult triage becomes. The mildly wounded and victims of contamination only can be sent to evacuation, registration (with disaster response teams), and decontamination/treatment centers. Figure 263e-2 illustrates an evacuation scheme after a radiologic event causing multiple casualties. The goal of such an algorithm is to treat all possible victims of exposure and minor injury outside of the hospital setting. This approach prevents hospitals from being directly overwhelmed and enhances treatment for persons who are severely wounded. Emergency treatment should be administered initially for conventional injuries such as wounds, trauma, and thermal or chemical burns. Individuals with such injuries should be stabilized, if possible, and immediately transported to a medical facility. Removing clothing and wrapping the victim in clean blankets or nylon sheets reduce both the exposure of the patient and the contamination risk to the staff. Less severely injured victims should undergo preliminary decontamination before or during evacuation to a hospital. FIGURE 263e-1 General guidelines for treatment of radiation casualties. CBC, complete blood count. One must remember that radionuclide contamination of the skin commonly is not an acute life-threatening situation for the patient or for the personnel who care for the patient.It is important to emphasize that exposure to a radiation field alone does not necessarily create any contamination.The exposed person, if not contaminated, is not radioactive and does not directly emit any radiation.To protect the staff, protective gear (gowns, gloves, masks, and caps) should be used.

The severity of fetal disease varies inversely with the gestational age at which maternal infection occurs.Transmission rates and the timing of fetal infection correlate directly with placental blood flow; the risk of infection increases throughout gestation to 90% or greater near term, and the time interval between maternal and fetal infection decreases.Many of the clinical manifestations of congenital infections aresimilar, including intrauterine growth restriction, nonimmunehydrops, anemia, thrombocytopenia, jaundice, hepatosplenomegaly, chorioretinitis, and congenital malformations. Some unique manifestations and epidemiologic characteristics of theseinfections are listed in Table 66-1. Evaluation of patients thoughtto have a congenital infection should include attempts to isolatethe organism by culture (for rubella, CMV, HSV, gonorrhea, and M. tuberculosis), to identify the antigen of the pathogen (for hepatitis B and Chlamydia trachomatis), to identify the pathogen’sgenome with polymerase chain reaction (PCR), and to identifyspecific fetal production of antibodies (IgM or increasing titer ofIgG for Toxoplasma, syphilis, parvovirus, HIV, or Borrelia). Treatment is not always available, specific, or effective. Nonetheless, some encouraging results have been reported for preventing the disease and for specifically treating the infant when the correct diagnosis is made (see Table 66-1). Available @ StudentConsult.com Abnormal Head Size, Shape, and Fontanels Visual Impairment and Leukocoria Petechiae/Purpura Vertical transmission of Toxoplasma gondii occurs by trans-placental transfer of the organism from the mother to the fetus after an acute maternal infection. Fetal infection rarely can occur after reactivation of disease in an immunocompromised pregnant mother. Transmission from an acutely infected mother to her fetus occurs in about 30% to 40% of cases, but the rate varies directly with gestational age. Transmission rates and the timing of fetal infection correlate directly with placental blood flow; the risk of infection increases throughout gestation to 90% or greater near term, and the time interval between maternal and fetal infection decreases. The severity of fetal disease varies inversely with the gestational age at which maternal infection occurs.The classic findings of hydrocephalus, chorioretinitis, and intracerebral calcifications suggest the diagnosis of congenital toxoplasmosis.Affected infants tend to be small for gestational age, develop early-onset jaundice, have hepatosplenomegaly, and present with a generalized maculopapular rash.

Typically, a patient will have a history of cervical dysplasia and a prior hysterectomy.Vaginal intraepithelial neoplasia, or VaIN, is similar to VIN and is classified based on the degree of epithelial involvement as mild (I), moderate (II), severe (III), or carcinoma in situ.26 Upwards of 65% to 80% of VaIN or vaginal cancers are associated with HPV infection.Initial treatment is usually a 7-day course of metronidazole.Vulvovaginal Candidiasis Vulvovaginal candidiasis (VVC) is the most common cause of vulvar pruritus. It is generally caused by C albicans and occasionally by other Candida species. It is common in pregnancy, diabetics, patients taking antibiotics, and in immunocompromised hosts. Initial treatment is usually with topical antifungals, although one dose oral antifungal treatments is also effective.Trichomonas Vaginalis Trichomoniasis is a sexually transmit-ted infection of a flagellated protozoan and can present with malodorous, purulent discharge. It is typically diagnosed with visualization of the trichomonads during saline wet mount microscopy. Initial treatment is usually a 7-day course of metronidazole.Gartner’s Duct Cyst. A Gartner’s duct cyst is a remnant of the Wolffian tract; it is typically found on the lateral vaginal walls. Patients can be asymptomatic or present with complaints of dyspareunia or difficulty inserting a tampon. If symptom-atic, these cysts may be surgically excised or marsupialized. If surgery is planned, preoperative magnetic resonance imaging (MRI) should be obtained to determine the extent of the cyst and verify the diagnosis.Vaginal Condyloma. The etiology and treatment of vaginal condyloma is similar to vulvar condyloma (see earlier section, “Vulvar Condyloma”).Vaginal Intraepithelial Neoplasia. Vaginal intraepithelial neoplasia, or VaIN, is similar to VIN and is classified based on the degree of epithelial involvement as mild (I), moderate (II), severe (III), or carcinoma in situ.26 Upwards of 65% to 80% of VaIN or vaginal cancers are associated with HPV infection. Typically, a patient will have a history of cervical dysplasia and a prior hysterectomy.Lesions are usually asymptomatic and found incidentally on cytological screening.Biopsy at the time of colposcopy is diagnostic and rules out invasive disease.VaIN is treated with laser ablation, surgical excision, or topical 5-FU therapy.4Brunicardi_Ch41_p1783-p1826.indd 179318/02/19 4:34 PM 1794SPECIFIC CONSIDERATIONSPART IICervical LesionsBenign Cervical Lesions.

After an overnight incubation, you crush the oocytes, prepare an extract, and determine the state of MAP kinase phosphorylation (hence, activation) by SDS polyacrylamide-gel electrophoresis (Figure Q15–3A).To determine the dose–response curve for pro-gesterone-induced activation of MAP kinase, you place 16 oocytes in each of six plastic dishes and add various concentrations of progesterone.15–10 How is it that different cells can respond in different ways to exactly the same signaling molecule even when they have identical receptors? 15–11 Why do you suppose that phosphorylation/ dephosphorylation, as opposed to allosteric binding of small molecules, for example, has evolved to play such a prominent role in switching proteins on and off in signaling pathways? 15–12 Consider a signaling pathway that proceeds through three protein kinases that are sequentially activated by phosphorylation. In one case, the kinases are held in a signaling complex by a scaffolding protein; in the other, the kinases are freely diffusible (Figure Q15–1). Discuss the properties of these two types of organization in terms of signal amplification, speed, and potential for cross-talk between signaling pathways. Figure Q15–1 A kinase cascade organized by a scaffolding protein or composed of freely diffusing components (Problem 15–12). 15–13 Describe three ways in which a gradual increase in an extracellular signal can be sharpened by the target cell to produce an abrupt or nearly all-or-none response. 15–14 Activation (“maturation”) of frog oocytes is signaled through a MAP kinase signaling module. An increase in the hormone progesterone triggers the module by stimulating the translation of Mos mRNA, which is the frog’s MAP kinase kinase kinase (Figure Q15–2). Maturation is easy to score visually by the presence of a white spot in the middle of the brown surface of the oocyte (see Figure Q15–2). To determine the dose–response curve for pro-gesterone-induced activation of MAP kinase, you place 16 oocytes in each of six plastic dishes and add various concentrations of progesterone. After an overnight incubation, you crush the oocytes, prepare an extract, and determine the state of MAP kinase phosphorylation (hence, activation) by SDS polyacrylamide-gel electrophoresis (Figure Q15–3A).progesterone Figure Q15–2 Progesterone-induced MAP kinase activation, leading to oocyte Mos maturation (Problem 15–14).(Courtesy of Helfrid Hochegger.)(A) POOLED OOCYTES –+ of frog oocytes (Problem 15–14).pooled oocytes.(B) Phosphorylation of MAP kinase in individual oocytes.MAP kinase 0.001 0.01 0.1 1 10 immunoblotting using progesterone (µM) a MAP-kinase-specific antibody.

FIGURE 7.4 • Photomicrograph of a typical hyaline cartilage specimen stained with H&E.Thus, the basophilia and metachromasia seen in stained sections of cartilage provide information about the distribution and relative concentration of sulfated proteoglycans.They also secrete metalloproteinases, enzymes that degrade cartilage matrix, allowing the cells to expand and reposition themselves within the growing isogenous group. The appearance of chondrocyte cytoplasm varies according to chondrocyte activity. Chondrocytes that are active in matrix production display areas of cytoplasmic basophilia, which are indicative of protein synthesis, and clear areas, which indicate their large Golgi apparatus (Fig. 7.5). Chondrocytes not only secrete the collagen present in the matrix but also all of the glycosaminoglycans and proteoglycans. In older, less active cells, the Golgi apparatus is smaller; clear areas of cytoplasm, when evident, usually indicate sites of extracted lipid droplets and glycogen stores. In such specimens, chondrocytes also display considerable distortion resulting from shrinkage after the glycogen and lipid are lost during preparation of the tissue. In the transmission electron microscope (TEM), the active chondrocyte displays numerous profiles of rough-surfaced endoplasmic reticulum (rER), a large Golgi apparatus, secretory granules, vesicles, intermediate filaments, microtubules, and actin microfilaments (Fig. 7.6). Components of the hyaline cartilage matrix are not uniformly distributed. Because the proteoglycans of hyaline cartilage contain a high concentration of bound sulfate groups, ground substance stains with basic dyes and hematoxylin (Plate 7, page 210). Thus, the basophilia and metachromasia seen in stained sections of cartilage provide information about the distribution and relative concentration of sulfated proteoglycans. FIGURE 7.4 • Photomicrograph of a typical hyaline cartilage specimen stained with H&E.A slightly basophilic layer of growing cartilage (GC) underlying the perichondrium contains chondroblasts and immature chondrocytes that display little more than the nucleus residing in an empty-appearing lacuna.This layer represents deposition of new cartilage (appositional growth) on the surface of the existing hyaline cartilage.

40-12).The two-piece device has the fluid maintained in the lower half of the penile cylinders, whereas, the three-piece device has a fluid reservoir placed in the pelvis or abdominal wall (Fig.The two-piece and three-piece devices are inflatable and dif-fer on the presence of a separate fluid reservoir.There is poor compliance due to difficulty with use and the common reactions of petechia, temporary paresthesia, color changes, and the penis being cold to touch.173,174 Alternatively, ICI uses vasoactive substances (prostaglandin E1 [alprostadil], papaverine, and phentolamine) either alone or in combination to trigger the erection cascade.168 Patients are trained to give themselves a self-injection when they want an erection, and it takes approximately 5 to 15 minutes until they are fully rigid if they respond. With ICI, there is greater concern for prolonged Figure 40-12. A three-piece penile implant for the treatment of erectile dysfunction. The prosthesis is composed of two cylinders placed in the penis, a fluid reservoir placed in the pelvis (upper left), and a pump placed within the scrotum (bottom left).erection or priapism, so dose titration must be closely moni-tored. Intraurethral suppositories are composed of alprostadil in the form of a pellet which is then placed in the urethra and mas-saged for absorption. With suppository use, there are concerns about efficacy (only 46–65%) and compliance due to a burning sensation that limits the interest of some users.175,176Third-line treatment of ED is with surgery placement of a penile prosthesis. There are three main types (malleable, two-piece, and three-piece). The malleable device does not inflate/deflate and merely bends in and out of position for intercourse. The two-piece and three-piece devices are inflatable and dif-fer on the presence of a separate fluid reservoir. The two-piece device has the fluid maintained in the lower half of the penile cylinders, whereas, the three-piece device has a fluid reservoir placed in the pelvis or abdominal wall (Fig. 40-12).The most obvious aspect of hypospadias is a urethral opening that is not at the tip of the glans, and 70% to 80% of affected babies will have a meatus on the mid to distal shaft or proximal glans.A lesser number will have more proximal openings, whether penoscrotal, scrotal, or perineal.In addition to an abnormally located meatus, boys usually have deficient ventral foreskin.

Each is a polymer of glucose.Important polysaccharides include branched glycogen (from animal sources) and starch (plant sources) and unbranched cellulose (plant sources).Important disaccharides include lactose (galactose + glucose), sucrose (glucose + fructose), and maltose (glucose + glucose).For example, glycogen is synthesized from α-D-glucopyranose, whereas cellulose is synthesized from β-D-glucopyranose. The cyclic α and β anomers of a sugar in solution spontaneously (but slowly) form an equilibrium mixture, a process known as mutarotation (see Fig. 7.6). [Note: For glucose, the α form makes up 36% of the mixture.] six-membered ring (5 C + 1 O) is termed a pyranose, whereas one with a five-membered ring (4 C + 1 O) is a furanose. Virtually all glucose in solution is in the pyranose form.] 2. Reducing sugars: If the hydroxyl group on the anomeric carbon of a cyclized sugar is not linked to another compound by a glycosidic bond (see E. below), the ring can open. The sugar can act as a reducing agent and is termed a reducing sugar. Such sugars can react with chromogenic agents (for example, the Benedict reagent) causing the reagent to be reduced and colored as the aldehyde group of the acyclic sugar is oxidized to a carboxyl group. All monosaccharides, but not all disaccharides, are reducing sugars. [Note: Fructose, a ketose, is a reducing sugar because it can be isomerized to an aldose.] A colorimetric test can detect a reducing sugar in urine. A positive result is indicative of an underlying pathology (because sugars are not normally present in urine) and can be followed up by more specific tests to identify the reducing sugar. D. Monosaccharide joining Monosaccharides can be joined to form disaccharides, oligosaccharides, and polysaccharides. Important disaccharides include lactose (galactose + glucose), sucrose (glucose + fructose), and maltose (glucose + glucose). Important polysaccharides include branched glycogen (from animal sources) and starch (plant sources) and unbranched cellulose (plant sources). Each is a polymer of glucose.They are formed by enzymes known as glycosyltransferases that use nucleotide sugars (activated sugars) such as uridine diphosphate glucose as substrates.Glycosidic bonds between sugars are named according to the numbers of the connected carbons and with regard to the position of the anomeric hydroxyl group of the first sugar involved in the bond.

4.Chemoprophylaxis of malaria—Daily treatment with 30 mg (0.5 mg/kg) of primaquine base provided good protection against falciparum and vivax malaria, and the drug is now listed as an alternative chemoprophylactic regimen by the CDC.3.To diminish the likelihood of relapse, some authorities advocate the use of primaquine after the completion of travel to an endemic area.Primaquine is widely distributed to the tissues, but only a small amount is bound there. It is rapidly metabolized and excreted in the urine. Primaquine is active against hepatic stages of all human malaria parasites. It is the only available agent active against the dormant hypnozoite stages of P vivax and P ovale. The drug is also gametocidal against the four human malaria species and it has weak activity against erythrocytic stage parasites. The mechanism of antimalarial action is unknown. Some strains of P vivax in New Guinea, Southeast Asia, Central and South America, and other areas are relatively resistant to primaquine. Liver forms of these strains may not be eradicated by a single standard treatment and may require repeated therapy. 1. Therapy (radical cure) of acute vivax and ovale malaria—Standard therapy for these infections includes chloroquine to eradicate erythrocytic forms and primaquine to eradicate liver hypnozoites and prevent a subsequent relapse. Chloroquine is given acutely, and therapy with primaquine is withheld until the G6PD status of the patient is known. If the G6PD level is normal, a 14-day course of primaquine is given. Prompt evaluation of the G6PD level is helpful, since primaquine appears to be most effective when instituted before completion of dosing with chloroquine. 2. Terminal prophylaxis of vivax and ovale malaria— Standard chemoprophylaxis does not prevent a relapse of vivax or ovale malaria, because the hypnozoite forms of these parasites are not eradicated by available blood schizonticides. To diminish the likelihood of relapse, some authorities advocate the use of primaquine after the completion of travel to an endemic area. 3. Chemoprophylaxis of malaria—Daily treatment with 30 mg (0.5 mg/kg) of primaquine base provided good protection against falciparum and vivax malaria, and the drug is now listed as an alternative chemoprophylactic regimen by the CDC. 4.Including primaquine with treatment for falciparum malaria is used in some areas to decrease transmission, and routine inclusion of single low doses of primaquine (which may be safe without testing for G6PD deficiency) is under study.5.

It is also associated with reactive arthritis (ReA) (Chap.384), both in its idiopathic form and in association with chronic inflammatory bowel disease or psoriasis vulgaris.HLA-B*27:05 is the predominant subtype in whites and most other non-Asian populations, and this subtype is very highly associated with ankylosing spondylitis (AS) (Chap.In each case studied, even in diseases with very strong HLA associations, the concordance of disease in mono-zygotic twins is higher than in HLA-identical dizygotic twins or other sibling pairs, indicating that non-HLA genes contribute to susceptibility and can significantly modify the risk attributable to HLA. Another group of diseases is genetically linked to HLA, not because of the immunologic function of HLA alleles but rather because they are caused by autosomal dominant or recessive abnormal alleles at loci that happen to reside in or near the HLA region. Examples of these are 21-hydroxylase deficiency (Chap. 406), hemochromatosis (Chap. 428), and spinocerebellar ataxia (Chap. 452). Although the associations of human disease with particular HLA alleles or haplotypes predominantly involve the class II region, there are also several prominent disease associations with class I alleles. These include the association of Behçet’s disease (Chap. 387) with HLA-B51, psoriasis vulgaris (Chap. 71) with HLA-Cw6, and, most notably, the spondyloarthritides (Chap. 384) with HLA-B27. Twenty-five HLA-B locus alleles, designated HLA-B*27:01–B*27:25, encode the family of 373e-7 B27 class I molecules. All of the subtypes share a common B pocket in the peptide-binding groove—a deep, negatively charged pocket that shows a strong preference for binding the arginine side chain. In addition, B27 is among the most negatively charged of HLA class I heavy chains, and the overall preference is for positively charged peptides. HLA-B*27:05 is the predominant subtype in whites and most other non-Asian populations, and this subtype is very highly associated with ankylosing spondylitis (AS) (Chap. 384), both in its idiopathic form and in association with chronic inflammatory bowel disease or psoriasis vulgaris. It is also associated with reactive arthritis (ReA) (Chap.B27 is found in 50–90% of individuals with these conditions, compared with a prevalence of ∼7% in North American whites.It can be concluded that the B27 molecule itself is involved in disease pathogenesis, based on strong evidence from clinical epidemiology and on the occurrence of a spondyloarthropathy-like disease in HLA-B27 transgenic rats.

Benzathine penicillin G, 2.4 million units intramuscularly in a single dose, is the recommended treatment for adults with primary, secondary, or early latent syphilis.Parenteral administration of penicillin G is the preferred treatment of all stages of syphilis.One to three extremely painful ulcers, accompanied by tender inguinal lymphadenopathy, are unlikely to be anything except chancroid. This is especially true if the adenopathy is fluctuant. 4. An inguinal bubo accompanied by one or several ulcers is most likely chancroid. If no ulcer is present, the most likely diagnosis is LGV. Recommended regimens for the treatment of chancroid include azithromycin, 1 g orally in a single dose; ceftriaxone, 250 mg intramuscularly in a single dose; ciprofloxacin, 500 mg orally twice a day for 3 days; or erythromycin base, 500 mg orally four times daily for 7 days. Patients should be reexamined 3 to 7 days after initiation of therapy to ensure the gradual resolution of the genital ulcer, which can be expected to heal within 2 weeks unless it is unusually large. A first episode of genital herpes should be treated with acyclovir, 400 mg orally three times a day; or famciclovir, 250 mg orally three times a day; or valacyclovir, 1.0 orally twice a day for 7 to 10 days or until clinical resolution is attained. Although these agents provide partial control of the symptoms and signs of clinical herpes, it neither eradicates latent virus nor affects subsequent risk, frequency, or severity of recurrences after the drug is discontinued. Daily suppressive therapy (acyclovir, 400 mg orally twice daily; or famciclovir, 250 mg twice daily; or valacyclovir, 1.0 g orally once a day) reduces the frequency of HSV recurrences by at least 75% among patients with six or more recurrences of HSV per year. Suppressive treatment partially, but not totally, decreases symptomatic and asymptomatic viral shedding and the potential for transmission (49). Parenteral administration of penicillin G is the preferred treatment of all stages of syphilis. Benzathine penicillin G, 2.4 million units intramuscularly in a single dose, is the recommended treatment for adults with primary, secondary, or early latent syphilis.Table 18.6 Treatment Options for External Genital and Perianal Warts ND, no data.a May be self-applied by patients at home.bExpensive; reserve for patients who have not responded to other regimens.Latent syphilis is defined as those periods after infection with T. pallidum when patients are seroreactive but show no other evidence of disease.

This condition is reminiscent of the fact that other lentiviruses, in particular the caprine arthritis-encephalitis virus, are capable of directly causing arthritis.The cause of this arthropathy is unclear; however, it is thought to result from a direct effect of HIV on the joint.These syndromes occur with increasing frequency as the competency of the immune system declines. This association may be related to an increase in the number of infections with organisms that may trigger a reactive arthritis with progressive immunodeficiency or to a loss of important regulatory T cells. Reactive arthritides in HIV-infected individuals generally respond well to standard treatment; however, therapy with methotrexate has been associated with an increase in the incidence of opportunistic infections and should be used with caution and only in severe cases. HIV-infected individuals also experience a variety of joint problems without obvious cause that are referred to generically as HIVor AIDS-associated arthropathy. This syndrome is characterized by sub-acute oligoarticular arthritis developing over a period of 1–6 weeks and lasting 6 weeks to 6 months. It generally involves the large joints, predominantly the knees and ankles, and is nonerosive with only a mild inflammatory response. X-rays are nonrevealing. Nonsteroidal anti-inflammatory drugs are only marginally helpful; however, relief has been noted with the use of intraarticular glucocorticoids. A second form of arthritis also thought to be secondary to HIV infection is called painful articular syndrome. This condition, reported as occurring in as many as 10% of AIDS patients, presents as an acute, severe, sharp pain in the affected joint. It affects primarily the knees, elbows, and shoulders; lasts 2–24 h; and may be severe enough to require narcotic analgesics. The cause of this arthropathy is unclear; however, it is thought to result from a direct effect of HIV on the joint. This condition is reminiscent of the fact that other lentiviruses, in particular the caprine arthritis-encephalitis virus, are capable of directly causing arthritis.Using the criteria of widespread musculoskeletal pain of at least 3 months’ duration and the presence of at least 11 of 18 possible tender points by digital palpation, 11% of an HIV-infected cohort containing 55% IDUs were diagnosed as having fibromyalgia (Chap.396).

Despite their radically different phenotypes, they retain the same complete genome that was present in the zygote; their differences arise instead from differential gene expression.The pluripotency is lost as gastrulation proceeds: a cell located in the endodermal germ layer, for example, can give rise to the cell types that will line the gut or form gut-derived organs such as the liver or pancreas, but it no longer has the potential to form mesoderm-derived structures such as skeleton, heart, or kidney. Such a cell is said to be determined for an endodermal fate. Thus, cell determination starts early and progressively narrows the options as the cell steps through a programmed series of intermediate states—guided at each step by its genome, its history, and its interactions with neighbors. The process reaches its limit when a cell undergoes terminal differentiation to form one of the highly specialized cell types of the adult body (Figure 21–4). Although there are cell types in the adult that retain some degree of pluripotency, their range of options is generally narrow (discussed in Chapter 22). Underlying the richness and astonishingly complex outcomes of development is cell memory (see p. 404). Both the genes a cell expresses and the way it behaves depend on the cell’s past, as well as on its present circumstances. The cells of our body—the muscle cells, the neurons, the skin cells, the gut cells, and so on—maintain their specialized characters largely because they retain a record of the extracellular signals their ancestors received during development, rather than because they continually receive such instructions from their surroundings. Despite their radically different phenotypes, they retain the same complete genome that was present in the zygote; their differences arise instead from differential gene expression.In this chapter, we shall see how these basic processes are collectively deployed to create an animal.The anatomical features that animals share have undergone many extreme modifications in the course of evolution.As a result, the differences between species are usually more striking to our human eye than the similarities.

The disadvantages are the greater cost and the need for specific materials prepared in a nuclear medicine laboratory.This approach simultaneously assesses gastric, small bowel (which may be important in ∼20% of patients with delayed colonic transit because they reflect a more generalized GI motility disorder), and colonic transit.Clinical and basic laboratory tests Bloods, chest and abd x-ray Exclude mechanical obstruction, e.g., colonoscopy Colonic transit Consider functional bowel disease Known disorder Rx No known underlying disorder Anorectal manometry and balloon expulsion Slow colonic transit Normal Rectoanal angle measurement, defecation proctography? Appropriate Rx: Rehabilitation program, surgery, or other Chronic Constipation Normal Abnormal FIguRE 55-4 Algorithm for the management of constipation. abd, abdominal. Measurement of Colonic Transit Radiopaque marker transit tests are easy, repeatable, generally safe, inexpensive, reliable, and highly applicable in evaluating constipated patients in clinical practice. Several validated methods are very simple. For example, radiopaque markers are ingested; an abdominal flat film taken 5 days later should indicate passage of 80% of the markers out of the colon without the use of laxatives or enemas. This test does not provide useful information about the transit profile of the stomach and small bowel. Radioscintigraphy with a delayed-release capsule containing radio-labeled particles has been used to noninvasively characterize normal, accelerated, or delayed colonic function over 24–48 h with low radiation exposure. This approach simultaneously assesses gastric, small bowel (which may be important in ∼20% of patients with delayed colonic transit because they reflect a more generalized GI motility disorder), and colonic transit. The disadvantages are the greater cost and the need for specific materials prepared in a nuclear medicine laboratory.These significant symptoms should be contrasted with the simple sense of incomplete rectal evacuation, which is common in IBS.

Medial portions of the pons are perfused by paramedian branches off of the basilar artery as it continues rostrally toward the midbrain.9.43A and B).Rostral levels of the lateral pons are perfused by circumferential branches of the basilar artery (eFig.9.43A).Vascular supply to the brainstem, and other structures in the posterior cranial fossa, is provided by branches off of the vertebrobasilar system of arteries. As mentioned in the “Cerebral Vasculature” section, the vertebrobasilar system begins with the vertebral arteries bilaterally, which arise from the subclavian arteries and ascend through the foramen transversaria of cervical vertebrae C6 to C2 in the neck. At the pontomedullary junction, the vertebral arteries fuse to form the single basilar artery. The basilar artery continues rostrally and terminates as the paired posterior cerebral arteries at the pontomesencephalic junction. Before merging and forming the basilar artery, each vertebral artery gives rise to a posterior inferior cerebellar artery (PICA) and posterior spinal artery and contributes to the formation of the anterior spinal artery (eFig. 9.42). The PICA perfuses the lateral aspect of the medulla and the inferior portion of the cerebellum. The medial and anterior portions of the medulla receive vascular supply from the paramedian branches off of the vertebral and anterior spinal arteries. At the level of the caudal pons, the anterior inferior cerebellar artery (AICA) branches off of the basilar artery and perfuses the lateral portion of the caudal pons (eFig. 9.43A). Rostral levels of the lateral pons are perfused by circumferential branches of the basilar artery (eFig. 9.43A and B). Medial portions of the pons are perfused by paramedian branches off of the basilar artery as it continues rostrally toward the midbrain.Paramedian branches from the basilar artery supply the medial aspect of the midbrain (eFig.9.43C).The final branches emerging from the top of the basilar artery are the PCAs, which perfuse the lateral aspect of the midbrain before reaching the thalamus, medial occipital, and inferior temporal lobes (eFig.9.43C and D).

In addition to pregnancy-induced compounds that promote myometrial cell refractoriness, the activity of enzymes that degrade or inactivate endogenously produced uterotonins are strikingly increased in phase 1.All of these factors and their receptors are expressed in the pregnant uterus.Discussed on page 410, CRH plasma levels rise dramatically during the inal 6 to 8 weeks of normal pregnancy and are implicated in mechanisms that control the timing of human parturition (Smith, 2007; Wadhwa, 1998). CRH appears to promote myometrial quiescence during most of pregnancy but then aids myometrial contractions with parturition onset. Studies suggest that these opposing actions are achieved by diferential actions of CRH via its receptor CRHR1. In nonlaboring myometrium at term, the interaction of CRH with its CRHR1 receptor activates the Gs-adenylate cyclasecAMP signaling pathway. his results in inhibition of inositol triphosphate (IP3) and stabilization of (Ca2+)j levels (You, 2012). However, in term laboring myometrium, (Ca2+)j concentrations are augmented by CRH activation of G proteins Gq and Gi and prompts stimulation ofIP3 production and greater contractility. As just described, cAvIP is an important mediator of myometrial relaxation. However, activation of guanylyl cyclase raises Physiology of Labor 407 intracellular cyclic guanosine monophosphate (cGMP) levels. This also promotes smooth muscle relaxation (Word, 1993). Intracellular cGMP levels are increased in the pregnant myometrium and can be stimulated by atrial natriuretic peptide (ANP) , brain natriuretic peptide (BNP) receptors, and nitric oxide (Telfer, 2001). All of these factors and their receptors are expressed in the pregnant uterus. In addition to pregnancy-induced compounds that promote myometrial cell refractoriness, the activity of enzymes that degrade or inactivate endogenously produced uterotonins are strikingly increased in phase 1.Levels of several of these enzymes decrease late in gestation (Germain, 1994).To ensure uterine quiescence, the synthesis in the decidua of prostaglandins, in particular PGF2', is markedly suppressed.Suppression of prostaglandin production here persists through out most of pregnancy, and suppression withdrawal is a prereq uisite for parturition (Norwitz, 2015).

There is no role for antibiotic prophylaxis.No vaccine is available for human use.Anemia may persist for month and reuire additional transfusion.Some cases have been cured with exchange transfusion and clindamycin monotherapy.The recommended treatment is immediate complete blood exchange transfusion and therapy with intravenous clindamycin plus either oral uinine or intravenous uinidine.In such patients, antimicrobial therapy should be administered for at least weeks, including 2 weeks after parasites are no longer observed on blood smear. High-dose azithromycin (00–1000 mgd) plus atovauone have been successfully used in immunocompromised patients. esistance to atovauone plus azithromycin has occurred in a few cases. In patients who are unresponsive to atovauone plus azithromycin or who do not tolerate clindamycin plus uinine, alternative regimens have been used (Table 21). Partial or complete C exchange transfusion is recommended in patients with high-grade parasitemia (0, severe anemia (hemoglobin, 0 gdL), or pulmonary, hepatic, or renal compromise. Parasitemia and hematocrit should be monitored daily until symptoms recede and the parasitemia level is The regimen for B. duncani infections typically consists of intravenous clindamycin (00 mg tidid or 1200 mg bid) plus oral uinine (00–50 mg tid) for 7–10 days. A regimen often used for B. divergens–like infections is intravenous clindamycin (00 mg tidid, 0 mg tid, or 1200 mg bid) plus oral uinine or uinidine (50 mg tid). In Europe, B. divergens infection is considered a medical emergency. The recommended treatment is immediate complete blood exchange transfusion and therapy with intravenous clindamycin plus either oral uinine or intravenous uinidine. Some cases have been cured with exchange transfusion and clindamycin monotherapy. Anemia may persist for month and reuire additional transfusion. No vaccine is available for human use. There is no role for antibiotic prophylaxis.The skin should be thoroughly examined after outdoor activities, and ticks should be removed with tweezers.Individuals with a history of symptomatic babesiosis or with positive Babesia serology are indefinitely deferred from donating blood.Atlas of Blood Smears of Malaria and Babesiosis Nicholas J.White, Joel G. Breman Six species of blood protozoan parasites cause human malaria (Chap.

However, the hypoandro-genic state of Klinefelter’s syndrome (XXY), in which gyneco-mastia is usually evident, is associated with an increased risk of breast cancer.Gynecomastia generally does not predispose the male breast to cancer.Dominant masses or areas of firmness, irregular-ity, and asymmetry suggest the possibility of a breast cancer, particularly in the older male.Common to each of these phases is an excess of circulating estrogens in relation to circulating testosterone. Neonatal gynecomastia is caused by the action of placental estrogens on neonatal breast tissues, whereas in adolescence, there is an excess of estradiol relative to testosterone, and with senescence, the circulating testosterone level falls, which results in relative hyperestrin-ism. In gynecomastia, the ductal structures of the male breast enlarge, elongate, and branch with a concomitant increase in epithelium. During puberty, the condition often is unilateral and typically occurs between ages 12 and 15 years. In contrast, senescent gynecomastia is usually bilateral. In the nonobese male, breast tissue measuring at least 2 cm in diameter must be present before a diagnosis of gynecomastia may be made. Mammography and ultrasonography are used to differentiate breast tissues. Dominant masses or areas of firmness, irregular-ity, and asymmetry suggest the possibility of a breast cancer, particularly in the older male. Gynecomastia generally does not predispose the male breast to cancer. However, the hypoandro-genic state of Klinefelter’s syndrome (XXY), in which gyneco-mastia is usually evident, is associated with an increased risk of breast cancer.Estrogen excess results from an increase in the secretion of estradiol by the testicles or by nontesticular tumors, nutri-tional alterations such as protein and fat deprivation, endocrine disorders (hyperthyroidism, hypothyroidism), and hepatic dis-ease (nonalcoholic and alcoholic cirrhosis).

Naturally acquired immunity did develop but was usually short-lived and correlated with the presence in the stool of secretory IgA antibody to the major adherence lectin galactose N-acetylgalactosamine (Gal/GalNAc).In this respect, E. dispar is dissimilar to other enteric pathogens such as Cryptosporidium and Cystoisospora belli, which can cause self-limited illnesses in immunocompetent hosts but devastating diarrhea in patients with AIDS. These observations indicate that E. dispar is incapable of causing invasive disease. Unlike E. dispar, E. histolytica can cause invasive disease, as demonstrated in recent reports from Korea, China, and India that suggest higher prevalences of amebic seroconversion, invasive amebiasis, and amebic liver abscesses among HIV-positive than HIV-negative patients. In another study, 10% of asymptomatic patients who were colonized with E. histolytica went on to develop amebic colitis, while the rest remained asymptomatic and cleared the infection within 1 year. The potential of E. moshkovskii to cause diarrhea, weight loss, and colitis was recently demonstrated in a mouse model of cecal infection. However, the pathogenic potential of this species is not clear. A prospective evaluation of children from the Mirpur community of Dhaka, Bangladesh, found that most children who had diarrheal diseases associated with E. moshkovskii were simultaneously infected with at least one other enteric pathogen. Areas of highest incidence of Entamoeba infection (due to inadequate sanitation and crowding) include most developing countries in the tropics, particularly Mexico, India, and nations of Central and South America, tropical Asia, and Africa. In a 4-year follow-up study of preschool children in a highly endemic area of Bangladesh, 80% of children had at least one episode of E. histolytica infection and 53% had more than one episode. Naturally acquired immunity did develop but was usually short-lived and correlated with the presence in the stool of secretory IgA antibody to the major adherence lectin galactose N-acetylgalactosamine (Gal/GalNAc).Data from the GeoSentinel Surveillance Network, which come from tropical medicine clinics on six continents, showed that, among long-term travelers (trip duration, >6 months), diarrhea due to E. histolytica was among the most common diagnoses.1364 PATHOGENESIS AND PATHOLOGY Both trophozoites (Fig.247-1) and cysts (Fig.

Joints.Membranous lupus nephritis (classV)ischaracterizedbydiffusethickeningofthecapillarywallsduetodepositionofsubepithelialimmunecomplexes,similartoidiopathicmembranousnephropathy,describedinChapter14.Theimmunecomplexesareusuallyaccompaniedbyincreasedproductionofbasementmembrane-likematerial,resultingin“holes”and“spikes”onsilverstain.Thislesionisusuallyaccompaniedbysevereproteinuriaornephroticsyndrome,andmayoccurconcurrentlywithfocalordiffuselupusnephritis. Advanced sclerosing lupus nephritis (classVI)ischaracterizedbysclerosisofmorethan90%oftheglomeruli,andrepresentsend-stagerenaldisease. Changesintheinterstitium and tubules arefrequentlypresent.Rarely,tubulointerstitiallesionsmaybethedominantabnormality.Discreteimmunecomplexessimilartothoseinglomeruliarepresentinthetubularorperitubularcapillarybasementmembranesinmanylupusnephritispatients.Sometimes,therearewell-organizedB-cellfolliclesintheinterstitium,associatedwithplasmacellsthatmaybesourcesofautoantibodies. Skin. Characteristicerythemaaffectsthefacealongthebridgeofthenoseandcheeks(thebutterfly rash)inapproximately50%ofpatients,butasimilarrashalsomaybeseenontheextremitiesandtrunk.Urticaria,bullae,maculopapularlesions,andulcerationsalsooccur.Exposuretosunlightincitesoraccentuatestheerythema.Histologicallytheinvolvedareasshowvacuolardegenerationofthebasallayeroftheepidermis( Fig.5.25A ).Inthedermis,thereisvariableedemaandperivascularinflammation.Vasculitiswithfibrinoidnecrosismaybeprominent.Immunofluorescencemicroscopyshowsdepositsofimmunoglobulinandcomplementalongthedermoepidermaljunction( Fig.5.25B );thesealsomaybepresentinuninvolvedskin.ThisfindingisnotdiagnosticofSLEandissometimesseeninsclerodermaanddermatomyositis. Joints.Central Nervous System.AlthoughitwassuggestedinthepastthattheneuropsychiatricmanifestationsofSLEmaybeduetoacutevasculitis,inhistologicstudiesofthenervoussysteminsuchpatients,significantvasculitisisrarelypresent.Instead,noninflammatoryocclusionofsmallvesselsbyintimalproliferationissometimesnoted,whichmaybeduetoendothelialdamagecausedbyautoantibodiesorimmunecomplexes.

8.25 Anterior cranial fossa.Frontal boneFrontal crestGroove for superiorsagittal sinusBregmaGranular foveolaeSagittal sutureLambdoid sutureOccipital boneLambdaParietal boneGrooves for middlemeningeal arteryCoronal sutureGroove for anterior branch of middle meningeal artery Fig.8.24 Roof of the cranial cavity.Sphenoparietal sutureCoronal sutureFrontal bonePterionSphenosquamous sutureGreater wing(of sphenoid bone)ZygomaticofacialforamenZygomatic boneMaxillaMental foramenBody of mandibleTemporal process (of zygomatic bone)Alveolar part(of mandible)Condylar processAngleZygomatic process (of temporal bone)Coronoid process Ramus of mandibleStyloid processMastoid processTympanic part (of temporal bone)Mastoid part of temporal boneOccipitomastoidsutureOccipital boneAsterionLambdoidsutureParietomastoidsutureParietal boneSquamous sutureSquamous part (of temporal bone)Nasal boneLacrimal boneZygomaticotemporalforamen(on deep surface ofzygomatic bone) Fig. 8.20 Posterior view of the skull. Fig. 8.21 Superior view of the skull. Fig. 8.22 Calvaria. Fig. 8.23 Inferior view of the skull. Incisive fossaHard palate (maxilla)Hard palate (palatine bone)Greater palatine foramenHamulusLesser palatine foramenLateral plate of pterygoidprocessMedial plate of pterygoidprocessVomerBody of sphenoidArticular tubercleMandibular fossaForamen ovaleForamen spinosumPetrous part oftemporal boneSquamous part oftemporal boneStyloid processStylomastoid foramenJugular foramenCarotid canalInferior nuchal lineOccipital condyleExternal occipital protuberanceSuperior nuchal lineExternal occipital crestForamen magnumPharyngeal tubercleHypoglossal canalMastoid processMastoid notchBasilar part of occipital boneForamen lacerumGroove for auditory tubeOpening of pterygoid canalPterygoid processScaphoid fossaPterygoid fossaGreater wing (of sphenoid bone)Posterior nasal aperture (choana)Pyramidal process of palatine boneAlveolar archPosterior nasal spine Fig. 8.24 Roof of the cranial cavity. Frontal boneFrontal crestGroove for superiorsagittal sinusBregmaGranular foveolaeSagittal sutureLambdoid sutureOccipital boneLambdaParietal boneGrooves for middlemeningeal arteryCoronal sutureGroove for anterior branch of middle meningeal artery Fig. 8.25 Anterior cranial fossa.8.26 Middle cranial fossa.

Because of the case reports of PTU-related liver failure and the increased risk of birth defects associated with methimazole use during embryogenesis, the FDA and the Endocrine Society recommend PTU never be used as first-line medical treatment of hyperthyroidism for nonpregnant patients.TSHRAb status appears to determine, in an inverse relationship, the reduction in thyroid volume after radioactive iodine therapy. Third-generation TSHRAb assays have been developed, and their utility in evaluation and treatment monitoring is being evaluated. Many patients with Graves disease have or will develop antineutrophil cytoplasmic antibodies (ANCA) after treatment, but the significance of this finding is still under study. Smoking appears to be an independent risk factor for relapse after medical therapy and should be considered when planning treatment. Antithyroid Drugs Antithyroid drugs of the thioamide class include propylthiouracil (PTU) and methimazole. Low doses of either agent block the secondary coupling reactions that form T3 and T4 from MIT and DIT. At higher doses, they also block iodination of tyrosyl residues in thyroglobulin. Propylthiouracil additionally blocks the peripheral conversion of T4 to T3. Approximately one-third of patients treated by this approach alone go into remission and become euthyroid (397). In 2009, the FDA published a warning on the use of propylthiouracil because of 32 reported cases of serious liver injury associated with its use (400,401). The average daily dose associated with liver failure was 300 mg, and liver failure was reported to occur anywhere from 6 days to 450 days after initiation of therapy (402). Traditionally PTU was the drug of choice to treat hyperthyroidism for the duration of pregnancy because it less readily crosses the placenta, and methimazole was associated with an increased risk of choanal atresia and aplasia cutis (403– 406). Because of the case reports of PTU-related liver failure and the increased risk of birth defects associated with methimazole use during embryogenesis, the FDA and the Endocrine Society recommend PTU never be used as first-line medical treatment of hyperthyroidism for nonpregnant patients.The FDA recommends monitoring patients closely for signs and symptoms of liver injury while taking PTU.If liver injury is suspected, PTU should be promptly discontinued (400).The American Thyroid Association recommends an initial dose of 100 to 600 mg per day in three divided doses with a goal to maintain T4 in the upper limit of normal using the lowest possible dose.

The technique and indications for cineand videoradiography will be discussed in the section entitled “Videoand Cineradiography,” as they are more useful to evalu-ate function and seldom used to detect structural abnormalities.The radiographic assessment of the esophagus is not com-plete unless the entire stomach and duodenum have been examined.The density of the barium used to study the esophagus can poten-tially affect the accuracy of the examination. Esophageal disorders shown clearly by a full-column technique include circumferential carcinomas, peptic strictures, large esophageal ulcers, and hia-tal hernias. A small hiatal hernia is usually not associated with significant symptoms or illness, and its presence is an irrelevant finding unless the hiatal hernia is large (Fig. 25-18) or the hernia 1Brunicardi_Ch25_p1009-p1098.indd 101801/03/19 6:02 PM 1019ESOPHAGUS AND DIAPHRAGMATIC HERNIACHAPTER 25Figure 25-16. Complications of reflux disease as seen on endoscopy. A. Linear erosions of LA grade B esophagitis. B. Uncomplicated Barrett’s mucosa. C. High-grade dysplasia in Barrett’s mucosa. D. Early adenocarcinoma arising in Barrett’s mucosa.is of the paraesophageal variety. Lesions extrinsic but adjacent to the esophagus can be reliably detected by the full-column tech-nique if they contact the distended esophageal wall. Conversely, a number of important disorders may go undetected if this is the sole technique used to examine the esophagus. These include small esophageal neoplasms, mild esophagitis, and esophageal varices. Thus, the full-column technique should be supplemented with mucosal relief or double-contrast films to enhance detection of these smaller or more subtle lesions.Motion-recording techniques greatly aid in evaluating functional disorders of the pharyngoesophageal and esophageal phases of swallowing. The technique and indications for cineand videoradiography will be discussed in the section entitled “Videoand Cineradiography,” as they are more useful to evalu-ate function and seldom used to detect structural abnormalities.The radiographic assessment of the esophagus is not com-plete unless the entire stomach and duodenum have been examined.This test may bring out a functional disturbance in esopha-geal transport that can be missed when liquid barium is used.Tests to Detect Functional AbnormalitiesIn many patients with symptoms of an esophageal disorder, standard radiographic and endoscopic evaluation fails to dem-onstrate a structural abnormality.

When speech deficits are in excess of those usually associated with these problems, a diagnosis of speech sound disorder may be made.Deficits of speech sound production may be associated with a hearing impairment, other sensory deficit, or a speech-motor deficit.Hearing impairment or deafness may result in abnormalities of speech.Hearing or other sensory impairment.It is not unusual for typically developing children to use developmental processes for shortening words and syllables as they are learning to talk, but their progression in mastering speech sound production should result in mostly intelligible speech by age 3 years. Children with speech sound disorder continue to use immature phonological simplification processes past the age when most children can produce words clearly. accurately according to age and community norms by age 7 years. The most frequently mis- articulated sounds also tend to be learned later, leading them to be called the ”late eight" (I, r, s, 2, th, ch, dzh, and zh). Misarticulation of any of these sounds by itself could be considered within normal limits up to age 8 years. When multiple sounds are involved, it may be appro- priate to target some of those sounds as part of a plan to improve intelligibility prior to the age at which almost all children can produce them accurately. Lisping (i.e., misarticulating sibi- lants) is particularly common and may involve frontal or lateral patterns of airstream direc- tion. It may be associated with an abnormal tongue—thrust swallowing pattern. Most children with speech sound disorder respond well to treatment, and speech dif- ficulties improve over time, and thus the disorder may not be lifelong. However, when a language disorder is also present, the speech disorder has a poorer prognosis and may be associated with specific learning disorders. Normal variations in speech. Regional, social, or cultural/ethnic variations of speech should be considered before making the diagnosis. Hearing or other sensory impairment. Hearing impairment or deafness may result in abnormalities of speech. Deficits of speech sound production may be associated with a hearing impairment, other sensory deficit, or a speech-motor deficit. When speech deficits are in excess of those usually associated with these problems, a diagnosis of speech sound disorder may be made.Speech impairment may be due to structural deficits (e.g., cleft palate).Dysarth ria.Speech impairment may be attributable to a motor disorder, such as cerebral palsy.

There is a long way to go before evidence-based internal medicine is applied effectively among the world’s poor.But global health equity depends on avoiding the false debates of the past: neither public health nor clinical approaches alone are adequate to address the problems of global health.The same barriers that prevent the poor from having reliable access to insulin or ART prevent them from benefiting from antidepressant, antipsychotic, and antiepileptic agents. To alleviate this problem, some authorities are proposing the training of health workers to provide community-based adherence support, counseling services, and referrals for patients in need of mental health services. One such program instituted in Goa, India, used “lay” counselors and resulted in a significant reduction in symptoms of common mental disorders among the target population. World Mental Health: Problems and Priorities in Low-Income Countries still offers a comprehensive analysis of the burden of mental, behavioral, and social problems in low-income countries and relates the mental health consequences of social forces such as violence, dislocation, poverty, and disenfranchisement of women to current economic, political, and environmental concerns. In the years since this report was published, however, a number of pilot projects designed to deliver community-based care to patients with chronic mental illness have been launched in settings as diverse as Goa, India; Banda Aceh, Indonesia; rural China; post-earthquake Haiti; and Fiji. Some of these programs have been school-based and have sought to link prevention to care. CoNCLUSIoN: ToWARd A SCIENCE oF IMPLEMENTATIoN Public health strategies draw largely on quantitative methods— epidemiology, biostatistics, and economics. Clinical practice, including the practice of internal medicine, draws on a rapidly expanding knowledge base but remains focused on individual patient care; clinical interventions are rarely population-based. But global health equity depends on avoiding the false debates of the past: neither public health nor clinical approaches alone are adequate to address the problems of global health. There is a long way to go before evidence-based internal medicine is applied effectively among the world’s poor.Beyond what is usually termed “communicable diseases”—i.e., in the arena of chronic diseases such as cardiovascular disease and mental illness—global health is a nascent endeavor.Efforts to address any one of these problems in settings of great scarcity need to be integrated into broader efforts to strengthen failing health systems and alleviate the growing personnel crisis within these systems.

Antibody defects (e.g., agammaglobulinemia)and T-cell defects (e.g., severe combined immunodeficiency[SCID]) typically present after 3 months of life after maternal antibody levels have waned.Neutrophil defects (e.g., congenital neutropenia, leukocyte adhesion deficiency) typically present in the first severalmonths of life.Failure to thrive, diarrhea,malabsorption, and infections with opportunistic infections (i.e., fungi, Candida sp, Pneumocystis jiroveci [carinii]) suggest T-cell immunodeficiency. Recurrent viral infections can resultfrom T-cell or NK-cell deficiency. Deep-seated abscesses and infections with Staphylococcus aureus, Serratia marcescens, and Aspergillus suggest a disorder of neutrophil function, such as chronic granulomatous disease (CGD). Delayed separation ofthe umbilical cord, especially in the presence of omphalitis andlater onset periodontal disease, in addition to poorly formedabscesses, indicates leukocyte adhesion deficiency. Age of onset of symptoms can be helpful in defining animmune deficiency, although significant variability does occur. Neutrophil defects (e.g., congenital neutropenia, leukocyte adhesion deficiency) typically present in the first severalmonths of life. Antibody defects (e.g., agammaglobulinemia)and T-cell defects (e.g., severe combined immunodeficiency[SCID]) typically present after 3 months of life after maternal antibody levels have waned.

415e-1).Although not a direct measure of adi posity, the most widely used method to gauge obesity is the body mass index (BMI), which is equal to weight/height2 (in kg/m2) (Fig.Obesity is therefore defined by assessing its linkage to morbidity or mortality.130 Body weights are distributed continuously 130 in populations, so that choice of a medi-120 and obese is somewhat arbitrary.The mechanism underlying this association is unknowndepots, are adapted to store excess energy efficiently as triglyceride but may relate to the fact that intraabdominal adipocytes are more lipoand, when needed, to release stored energy as free fatty acids for use at lytically active than those from other depots. Release of free fatty acidsother sites. This physiologic system, orchestrated through endocrine into the portal circulation has adverse metabolic actions, especially onand neural pathways, permits humans to survive starvation for as the liver. Adipokines and cytokines that are differentially secreted by adilong as several months. However, in the presence of nutritional abunpocyte depots may play a role in the systemic complications of obesity. dance and a sedentary lifestyle, and influenced importantly by genetic endowment, this system increases adipose energy stores and produces PREVALENCE adverse health consequences. Data from the National Health and Nutrition Examination Surveys (NHANES) show that the percentage of the American adult population Obesity is a state of excess adipose tissue Weight Height kg lb cm in. mass. Although often viewed as equivalent to increased body weight, this need not be 340 the case—lean but very muscular individu-150 dards without having increased adiposity. 130 Body weights are distributed continuously 130 in populations, so that choice of a medi-120 and obese is somewhat arbitrary. Obesity is therefore defined by assessing its linkage to morbidity or mortality. Although not a direct measure of adi posity, the most widely used method to gauge obesity is the body mass index (BMI), which is equal to weight/height2 (in kg/m2) (Fig. 415e-1).Using data from the Metropolitan Life Tables, BMIs for the mid-55 point of all heights and frames among both men and women range from 19 to 26 kg/m2; at a similar BMI, women have more body fat than men.Based on data of substantial morbidity, a BMI of 30 is most commonly used as a threshold for obesity in both men 40 85 and women.