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Transposition and conservative site-specific recombination are largely dedicated to moving a wide variety of specialized segments of DNA—collectively termed mobile genetic elements—from one position in a genome to another.DNA SYNTHESIS FILLS GAP, CREATING AN EXTRA COPY OF THE RED ALLELE OF When used as a repair mechanism, homologous recombination occurs between a damaged DNA molecule and its recently duplicated sister molecule, with the undamaged duplex acting as a template to repair the damaged copy flawlessly. In meiosis, homologous recombination is initiated by deliberate, carefully regulated double-strand breaks and occurs preferentially between the homologous chromosomes rather than the newly replicated sister chromatids. The outcome can be either two chromosomes that have crossed over (that is, chromosomes in which the DNA on either side of the site of DNA pairing originates from two different homo-logs) or two non-crossover chromosomes. In the latter case, the two chromosomes that result are identical to the original two homologs, except for relatively minor DNA sequence changes at the site of recombination. We have seen that homologous recombination can result in the exchange of DNA sequences between chromosomes. However, the order of genes on the interacting chromosomes typically remains the same following homologous recombination, inasmuch as the recombining sequences must be very similar for the process to occur. In this section, we describe two very different types of recombination—transposition (also called transpositional recombination) and conservative site-specific recombination—that do not require substantial regions of DNA homology. These two types of recombination reactions can alter gene order along a chromosome and can cause unusual types of mutations that introduce whole blocks of DNA sequence into the genome. Transposition and conservative site-specific recombination are largely dedicated to moving a wide variety of specialized segments of DNA—collectively termed mobile genetic elements—from one position in a genome to another.Often, one of these genes encodes a specialized enzyme that catalyzes the movement of only that element, thereby making this type of recombination possible.Virtually all cells contain mobile genetic elements (known informally as “jumping genes”).As explained in Chapter 4, over evolutionary time scales, they have had a profound effect on the shaping of modern genomes.

No Barr body.Turner’s syndrome (female) 45,XO The most common cause of 1° amenorrhea; due to gonadal dysgenesis.Treat with testosterone (prevents gynecomastia; improves 2° sexual characteristics).Presents with testicular atrophy, a eunuchoid body shape, tall stature, long extremities, and gynecomastia.One of the most common causes of hypogonadism in males.Infants with FTT will f rst fall off of the weight curve, then the height curve, and f nally the head circumference curve. Tables 2.13-2 and 2.13-3 outline common genetic diseases and their associated abnormalities. TABLE 2.13-2. Genetic Diseases Down syndrome Trisomy 21 (most common) or robertsonian translocation (higher risk of recurrence) The most common chromosomal disorder and cause of mental retardation. Associated with advanced maternal age. Presents with mental retardation, a fat facial profle, prominent epicanthal folds, and a simian crease. Associated with duodenal atresia, Hirschsprung’s disease, and congenital heart disease (the most common malformation is atrioventricular canal, which includes an ASD and VSD with mitral and tricuspid valve abnormalities due to endocardial cushion defects). Associated with an ↑ risk of acute lymphocytic leukemia (ALL), hypothyroidism, and early-onset Alzheimer’s. Edwards’ syndrome Trisomy 18 Presents with severe mental retardation, rocker-bottom feet, low-set ears, micrognathia, clenched hands, and a prominent occiput. Associated with congenital heart disease. May have horseshoe kidneys. Death usually occurs within one year of birth. Patau’s syndrome Trisomy 13 Presents with severe mental retardation, microphthalmia, microcephaly, cleft lip/palate, abnormal forebrain structures (holoprosencephaly), “punched-out” scalp lesions, and polydactyly. Associated with congenital heart disease. Death usually occurs within one year of birth. Klinefelter’s syndrome (male) 45,XXY Presence of an inactivated X chromosome (Barr body). One of the most common causes of hypogonadism in males. Presents with testicular atrophy, a eunuchoid body shape, tall stature, long extremities, and gynecomastia. Treat with testosterone (prevents gynecomastia; improves 2° sexual characteristics). Turner’s syndrome (female) 45,XO The most common cause of 1° amenorrhea; due to gonadal dysgenesis. No Barr body.May present with lymphedema of the hands and feet in the neonatal period.May have horseshoe kidney.Double Y males 47,XYY Observed with ↑ frequency among inmates of penal institutions.Phenotypically normal; patients are very tall with severe acne and antisocial behavior (seen in 1–2% of XYY males).TABLE 2.13-2.

used to treat infections in humans, just in time to prevent tens of thousands of deaths from infected battlefield wounds in World War II.1292 Chapter 23: Pathogens and Infection H2N2 H3N?In 2009, a new strain of HIV was discovered that appears to have resulted from SIV passage from a gorilla to a human.Such recombination events allowed the new virus to replicate rapidly and spread through an immunologically naive human population. Generally, within two or three years, the human population develops immunity to a new recombinant strain of virus, and the infection rate drops to a steady-state level. Because the recombination events are unpredictable, it is not possible to know when the next influenza pandemic will occur or how severe it might be. The development of drugs that cure rather than prevent infections has had a major impact on human health. Antibiotics, which are either bactericidal (they kill bacteria) or bacteriostatic (they inhibit bacterial growth without killing), are the most successful class of such drugs. Penicillin was one of the first antibiotics = jumps from monkey and ape to human Figure 23–31 Diversification of HIV-1, HIV-2, and related strains of SIV. HIV comprises different viral families, all descended from SIV (simian immunodeficiency virus). On three separate occasions, SIV was passed from a chimpanzee to a human, resulting in three HIV-1 groups: major (M), outlier (O), and non-M non-O (N). The HIV-1 M group is the most common and is primarily responsible for the global AIDS epidemic. On two separate occasions, SIV was passed from a sooty mangabey monkey to a human, resulting in the two HIV-2 groups. In 2009, a new strain of HIV was discovered that appears to have resulted from SIV passage from a gorilla to a human. 1292 Chapter 23: Pathogens and Infection H2N2 H3N? used to treat infections in humans, just in time to prevent tens of thousands of deaths from infected battlefield wounds in World War II.These differences enable us to develop antibacterial drugs that exhibit selective toxicity, in that they specifically inhibit these processes in bacteria without disrupting them in the host.

Smoking decreases both gastroduodenal prostaglandin production and pancreaticoduodenal bicarbonate production.Smoking increases gastric acid secretion and duodenogastric reflux.Epidemiologic studies suggest that smokers are about twice as likely to develop PUD as nonsmokers.This risk increases to five times in patients more than age 60 years old. In elderly patients taking NSAIDs, the likelihood that they will require an operation related to a GI complication is 10 times that of the control group, and the risk that they will die from a GI cause is about four and one-half times higher. This problem is put into perspective when one realizes that approximately 20 million patients in the United States take NSAIDs on a regular basis; perhaps even more regularly take aspirin. Persons who take NSAIDs also have a higher hospitalization rate for serious GI events than those who do not.Factors that clearly put patients at increased risk for NSAID-induced GI complications include age >60, prior GI event, high NSAID dose, concurrent steroid intake, and con-current anticoagulant intake. Proton pump inhibitors have been shown to significantly decrease upper GI bleeding risk in patients on chronic warfarin, low dose aspirin, and/or antiplate-let agents.101-103 ANY patient taking NSAIDs or aspirin who has one or more of these risk factors should receive concomitant acid suppressive medication,104 preferably PPI (Table 26-7). High-dose H2 blockers have been shown to be somewhat less effective than PPIs in preventing GI complications in these high-risk patients on antiplatelet therapy, but clearly, they are better than no acid suppression.105Smoking, Stress, and Other Factors. Epidemiologic studies suggest that smokers are about twice as likely to develop PUD as nonsmokers. Smoking increases gastric acid secretion and duodenogastric reflux. Smoking decreases both gastroduodenal prostaglandin production and pancreaticoduodenal bicarbonate production.Decades later, Cushing described the appearance of acute peptic ulcer-ation in patients with head trauma (Cushing’s ulcer).Even the ancients recognized the undeniable links between PUD and stress.Patients still present with ulcer complications (bleeding, perforation, and obstruction) that are seemingly exacerbated by stressful life events.

Asymptomatic seropositive persons shed virus on mucosal surfaces almost as frequently as do those with symptomatic disease.Several studies suggest that many cases of “asymptomatic” genital HSV-2 infection are, in fact, simply unrecognized or confined to anatomic regions of the genital tract that are not easily visualized.Antibody prevalence rates average ~5–10% higher among women than among men.Many studies continue to show that both incident and—more important—prevalent HSV-2 infection enhances the acquisition rate of HIV-1. More specifically, HSV-2 infection is associated with a two-to fourfold increase in HIV-1 acquisition. This association has been amply demonstrated in heterosexual men and women in both the developed and the developing worlds. Epidemiologically, regions of the world with high HSV-2 prevalence and selected populations within such regions have a higher population-based incidence of HIV-1. One study indicated that approximately one-quarter of HIV infections in the high-prevalence city of Kisumu, Kenya, were directly attributable to HSV-2. In addition, HSV-2 facilitates the spread of HIV into low-risk populations on a per-coital basis, and prevalent HSV-2 appears to increase the risk of HIV infection by sevento ninefold. Mathematical models suggest that ~33–50% of HIV-1 infections may be attributable to HSV-2 both in men who have sex with men (MSM) and in sub-Saharan Africa. In addition, HSV-2 is more frequently reactivated in and transmitted by persons co-infected with HIV-1 as opposed to persons not co-infected. Thus, most areas of the world with a high HIV-1 prevalence also have a high HSV-2 prevalence. A wide variety of serologic surveys have indicated a similar or even higher seroprevalence of HSV-2 in most parts of Central America, South America, and Africa. In Africa, HSV-2 seroprevalence has ranged from 40% to 70% in obstetric and other sexually experienced populations. Antibody prevalence rates average ~5–10% higher among women than among men. Several studies suggest that many cases of “asymptomatic” genital HSV-2 infection are, in fact, simply unrecognized or confined to anatomic regions of the genital tract that are not easily visualized. Asymptomatic seropositive persons shed virus on mucosal surfaces almost as frequently as do those with symptomatic disease.HSV-2 infection is an independent risk factor for the acquisition and transmission of infection with HIV-1.Among co-infected persons, HIV-1 virions can be shed from herpetic lesions of the genital region.This shedding may facilitate the spread of HIV through sexual contact.

An observation from a recent meta-analysis was that, compared to usual care, more patients assigned to coronary CTA underwent cardiac catheterization (6.3% vs 8.4%, respectively) and revascularization (2.6% vs 4.6%, respectively).These studies showed decreased length of stay with coronary CTA, and most but not all reported cost savings.FIGURE 270e-17 A four-chamber long-axis late gadolinium enhancement (LGE) image of a patient with acute myocarditis. Note that the LGE primarily involved the epicardial aspect of the myocardium (arrows), sparing the endocardium, which is a feature that distinguishes myocarditis from myocardial infarction, which affects the endocardium. Also note the multiple foci of LGE in this case affecting the lateral wall of the left ventricle. Viral myocarditis often presents with this pattern. As discussed above, coronary CTA is a rapid and accurate imaging technique to exclude the presence of CAD and is well suited for the evaluation of patients with acute chest pain (Fig. 270e-18). Several single-center and, more recently, multicenter studies have demonstrated the feasibility, safety, and accuracy of coronary CTA in the ED. There have been four randomized controlled trials evaluating the efficacy of coronary CTA as the initial testing strategy as compared to usual care (which typically includes stress imaging). Patients in these trials had a very low clinical risk. Overall, there were no deaths and very few myocardial infarctions without differences between the groups. Likewise, there were no differences in postdischarge ED visits or rehospitalizations. These studies showed decreased length of stay with coronary CTA, and most but not all reported cost savings. An observation from a recent meta-analysis was that, compared to usual care, more patients assigned to coronary CTA underwent cardiac catheterization (6.3% vs 8.4%, respectively) and revascularization (2.6% vs 4.6%, respectively).Taken together, the available data clearly suggest that not all patients presenting with acute chest pain require specialized imaging testing.Patients with very low clinical risk and negative biomarkers (especially high-sensitivity troponin assays) can be safely triaged.

However, the mutated K-ras oncogene, which is pres-ent in most cases of pancreatic cancer, has been detected in the ductal epithelium of some patients with chronic pancreatitis.Genetics of Pancreatic Cancer.The mechanisms involved in carcinogenesis in patients with preexisting pancreatitis are unknown.As in other GI cancers, diets high in fat and low in fiber, fruits, and vegetables are thought to be associated with an increased risk of pancreatic cancer.Diabetes has been known to be associated with pancreatic cancer for many years. In fact, glucose intolerance is present in 80% of patients with pancreatic cancer, and approximately 20% have overt diabetes, a much greater incidence than would be expected to occur by chance. Preexisting type 2 diabetes increases the risk for development of pancreatic cancer by about twofold.309 The new onset of diabetes also can be an early mani-festation of otherwise occult pancreatic cancer. Thus, the new onset of diabetes, or a sudden increase in insulin requirement in an older adult patient with preexisting diabetes, should provoke concern for the presence of pancreatic cancer.Recent epidemiologic studies have confirmed the fact that patients with chronic pancreatitis, especially familial pan-creatitis, have an increased risk of developing pancreatic can-cer.124,196-198 Large, retrospective cohort studies of patients with pancreatitis have revealed up to a 20-fold increase in risk for pancreatic cancer. This increased risk seems to be independent of the type of pancreatitis, a finding consistent with the fact that most studies have shown little effect of alcohol ingestion per se Brunicardi_Ch33_p1429-p1516.indd 148401/03/19 6:46 PM 1485PANCREASCHAPTER 33on the risk of pancreatic carcinoma. The mechanisms involved in carcinogenesis in patients with preexisting pancreatitis are unknown. However, the mutated K-ras oncogene, which is pres-ent in most cases of pancreatic cancer, has been detected in the ductal epithelium of some patients with chronic pancreatitis.Genetics of Pancreatic Cancer.The K-ras oncogene is currently thought to be the most commonly mutated gene in pancreatic cancer, with approximately 90% of tumors having a mutation.310 This prevalent mutation is present in precursor lesions and is therefore thought to occur early and be essential to pancre-atic cancer development.

Most Serratia strains (>80%) are resistant to ampicillin, amoxi cillin-clavulanate, ampicillin-sulbactam, first-generation cepha losporins, cephamycins, nitrofurantoin, and colistin.Some S. marcescens strains and S. rubidaea are red pigmented.Serratiae are readily cultured and identified by the laboratory and are usually lactose and indole negative.Endocarditis is rare.Infection results from either direct inoculation (e.g., via IV fluid) or colonization (primarily of the respiratory tract). Sporadic infection is most common, but epidemics (often involving MDR strains in adult and neonatal ICUs) and common-source outbreaks also occur. The spectrum of extraintestinal infections caused by Serratia is similar to that for other GNB. Serratia species are usually considered causative agents of health care– associated infection and account for 1–3% of hospital-acquired infections. However, population-based laboratory surveillance studies in Canada and Australia demonstrated that community-acquired infections occur more commonly than was previously appreciated. The respiratory tract, the genitourinary tract, intravascular devices, the eye (contact lens–associated keratitis and other ocular infections), surgical wounds, and the bloodstream (from contaminated infusions) are the most common sites of Serratia infection; the former five sites are the most common sources of Serratia bacteremia. Soft tissue infections (including myositis, fasciitis, mastitis), osteomyelitis, abdominal and biliary tract infection (postprocedural), and septic arthritis (primarily from intraarticular injections) occur less commonly. Serratiae are uncommon causes of neonatal or postsurgical meningitis and of bacteremia in neutropenic patients. Endocarditis is rare. Serratiae are readily cultured and identified by the laboratory and are usually lactose and indole negative. Some S. marcescens strains and S. rubidaea are red pigmented. Most Serratia strains (>80%) are resistant to ampicillin, amoxi cillin-clavulanate, ampicillin-sulbactam, first-generation cepha losporins, cephamycins, nitrofurantoin, and colistin.Induction or selection of variants with stable derepression of chromosomal AmpC β-lactamases may develop during therapy.Both in the United States and globally, the prevalence of ESBL-producing isolates is generally low (<5%), but rates of 20–30% have been reported in Asia and Latin America.Acquisition of carbapenemase-encoding genes is uncommon but increasing.

Thus, assays to verify modulation of the target need to be developed to deter-mine at what dosage the desired effect is achieved.Although in traditional phase 1 trials the goal is to identify the maximum tol-erated dosage, the maximum dosage of biologic agents may not be necessary to achieve the desired biologic effect.Several tyrosine kinases have been shown to have oncogenic properties and many other protein kinases have been shown to be aberrantly activated in cancer cells.93 Therefore, protein kinases involved in these aberrantly activated pathways are being aggressively pursued in molecular therapeutics. Potential targets like HER2 can be targeted via dif-ferent strategies, such as transcriptional downregulation, targeting of mRNA, RNA inhibition, antisense strategies, direct inhibition of protein activity, and induction of immunity against the protein. Most of the compounds in development are monoclonal antibod-ies like trastuzumab or small-molecule kinase inhibitors like ima-tinib or vemurafanib. Some other agents, such as sunitinib, are multitargeted kinase inhibitors. Selected FDA-approved targeted therapies are listed in Table 10-11. Many of the promising path-ways, such as the PI3K/Akt/mTOR pathway, are being pursued as therapeutic targets with several drugs in development, targeting different aspects of the pathway (Fig. 10-15).148Development of molecularly targeted agents for clinical use presents several unique challenges. Once an appropriate compound is identified and confirmed to have activity in pre-clinical testing, predictive markers for activity in the preclinical setting must be defined. Expression of a target may not be suf-ficient to predict response because the pathway of interest may not be activated or critical to the cancer’s survival. Although in traditional phase 1 trials the goal is to identify the maximum tol-erated dosage, the maximum dosage of biologic agents may not be necessary to achieve the desired biologic effect. Thus, assays to verify modulation of the target need to be developed to deter-mine at what dosage the desired effect is achieved.Rational dose selec-tion and limitation of study populations to patients most likely to respond to the molecular therapy as determined by predictive markers are most likely to lead to successful clinical transla-tion of a product.Finally, most biologic agents are cytostatic, not cytotoxic.

Although the physiology of aging separates older trauma patients from the younger generation (Table 7-14), treatment must remain indi-vidualized (some octogenarians look and physiologically act 50 years old, whereas others appear closer to 100 years).Penetrating injuries in this patient population also carry a high risk. The gravid uterus is a large target, and any penetrating injury to the abdomen may result in fetal injury depending on trajectory and uterine size. Gunshot wounds to the abdomen are associated with a 70% injury rate to the uterus and 35% mortality rate of the fetus. If the bul-let traverses the uterus and the fetus is viable, cesarean section should be performed. On the other hand, stab wounds do not often penetrate the thick wall of the uterus.Any patient with a viable pregnancy should be monitored after trauma, with the length of monitoring determined by the injury mechanism and patient physiology. Patients who are Brunicardi_Ch07_p0183-p0250.indd 24210/12/18 6:22 PM 243TRAUMACHAPTER 7symptomatic, defined by the presence of uterine irritability or contractions, abdominal tenderness, vaginal bleeding, or blood pressure instability, should be monitored in the hospital for at least 24 hours. In addition, patients at high risk for fetal loss (those experiencing vehicle ejection or involved in motorcycle or pedestrian collisions and those with maternal tachycardia, Injury Severity Score of >9, gestational period of >35 weeks, or history of prior assault) also warrant careful monitoring.151 Patients without these risk factors who are asymptomatic can be monitored for 6 hours in the ED and sent home if no problems develop. They should be counseled regarding warning signs that mandate prompt return to the ED.Geriatric PatientsElderly trauma patients (>65 years of age) are hospitalized twice as often as those in any other age group, and this population accounts for one quarter of all trauma admissions. Although the physiology of aging separates older trauma patients from the younger generation (Table 7-14), treatment must remain indi-vidualized (some octogenarians look and physiologically act 50 years old, whereas others appear closer to 100 years).For example, recognition that a patient is taking β-blockers affects the physician’s evaluation of vital signs in the ED and impacts treatment course in the ICU.Early monitoring of arterial blood gas values will identify occult shock.

A change in SV of ≥10% suggests preload responsiveness, and additional resuscitation fluid should be given.A patient’s volume status may be ascertained by measur-ing the SV following either 10 cc/kg volume bolus or following a passive leg raise, which augments preload by 250 to 500 mL.The period of acute resuscitation, typically last-ing for the first 12 to 24 hours after injury, combines several key principles: optimizing tissue perfusion, ensuring normother-mia, and restoring coagulation status.143 There are a multitude of management algorithms aimed at accomplishing these goals, the majority of which involve goal-directed resuscitation with initial volume loading to attain adequate preload, followed by judicious use of inotropic agents or vasopressors.144 Although the optimal hemoglobin level remains debated, during shock resuscitation a hemoglobin level of >10 g/dL is generally accepted to optimize hemostasis and ensure adequate oxygen delivery. After the first 24 hours of resuscitation, a more judicious transfusion trigger of a hemoglobin level of <7 g/dL in the euvolemic patient limits the adverse inflammatory effects of stored RBCs. Recent trends have focused on limiting crystalloid loading. In fact, optimiz-ing crystalloid administration is a challenging aspect of early care (i.e., balancing cardiac performance against generation of an abdominal compartment syndrome and generalized tissue edema). Although early colloid administration is appealing, evi-dence to date does not support this concept.Invasive monitoring with pulmonary artery catheters has been supplanted with specialized catheters that measure arte-rial pulse contour analysis; in mechanically ventilated patients, stroke volume (SV) and continuous cardiac output can be mea-sured. A patient’s volume status may be ascertained by measur-ing the SV following either 10 cc/kg volume bolus or following a passive leg raise, which augments preload by 250 to 500 mL. A change in SV of ≥10% suggests preload responsiveness, and additional resuscitation fluid should be given.The role of rela-tive adrenal insufficiency is another controversial area.Optimal early resuscitation is mandatory and determines when the patient can (a) undergo additional necessary imaging, and (b) be returned to the OR after initial damage control surgery for definitive repair of injuries.

Chylothorax A chylothorax occurs when the thoracic duct is disrupted and chyle accumulates in the pleural space.The importance of these effusions is that one should not be too aggressive in trying to establish a diagnosis for the undiagnosed effusion, particularly if the patient is improving clinically.The diagnosis is established by spiral CT scan or pulmonary arteriography (Chap. 300). Treatment of a patient with a pleural effusion secondary to pulmonary embolism is the same as it is for any patient with pulmonary emboli. If the pleural effusion increases in size after anticoagulation, the patient probably has recurrent emboli or another complication, such as a hemothorax or a pleural infection. Disorders of the Pleura 1718 Tuberculous Pleuritis (See also Chap. 202) In many parts of the world, the most common cause of an exudative pleural effusion is tuberculosis (TB), but tuberculous effusions are relatively uncommon in the United States. Tuberculous pleural effusions usually are associated with primary TB and are thought to be due primarily to a hypersensitivity reaction to tuberculous protein in the pleural space. Patients with tuberculous pleuritis present with fever, weight loss, dyspnea, and/or pleuritic chest pain. The pleural fluid is an exudate with predominantly small lymphocytes. The diagnosis is established by demonstrating high levels of TB markers in the pleural fluid (adenosine deaminase >40 IU/L or interferon γ >140 pg/mL). Alternatively, the diagnosis can be established by culture of the pleural fluid, needle biopsy of the pleura, or thoracoscopy. The recommended treatments of pleural and pulmonary TB are identical (Chap. 202). Effusion Secondary to Viral Infection Viral infections are probably responsible for a sizable percentage of undiagnosed exudative pleural effusions. In many series, no diagnosis is established for ~20% of exudative effusions, and these effusions resolve spontaneously with no long-term residua. The importance of these effusions is that one should not be too aggressive in trying to establish a diagnosis for the undiagnosed effusion, particularly if the patient is improving clinically. Chylothorax A chylothorax occurs when the thoracic duct is disrupted and chyle accumulates in the pleural space.Patients with chylothorax present with dyspnea, and a large pleural effusion is present on the chest radiograph.Thoracentesis reveals milky fluid, and biochemical analysis reveals a triglyceride level that exceeds 1.2 mmol/L (110 mg/ dL).Patients with chylothorax and no obvious trauma should have a lymphangiogram and a mediastinal CT scan to assess the mediastinum for lymph nodes.

To prevent ischemic injury, extensive collateralization occurs between major mesenteric trunks and branches of the mesenteric arcades.354-1.The blood supply to the intestines is depicted in Fig.Mesenteric ischemia affects 2–3 people per 100,000, and the incidence of mesenteric ischemia is bound to increase in the aging population. Delay in diagnosis and management results in a high mortality, and prompt interventions may be life-saving. Intestinal ischemia is further classified based on etiology, which dictates management: (1) arterioocclusive mesenteric ischemia, (2) nonocclusive mesenteric ischemia, and (3) mesenteric venous thrombosis. Risk factors for arterioocclusive mesenteric ischemia are generally acute in onset and include atrial fibrillation, recent myocardial infarction, valvular heart disease, and recent cardiac or vascular catheterization, all of which result in embolic clots reaching the mesenteric circulation. Nonocclusive mesenteric ischemia, also known as “intestinal angina,” is generally more insidious and most often seen in the aging population affected by atherosclerotic disease. Patients with chronic atherosclerotic disease could also suffer an acute insult from emboli leading to complete occlusion. Nonocclusive mesenteric ischemia is also seen in patients receiving high-dose vasopressor infusions, patients with cardiogenic or septic shock, and patients with cocaine overdose. Nonocclusive mesenteric ischemia is the most prevalent gastrointestinal disease complicating cardiovascular surgery. The incidence of ischemic colitis following elective aortic repair is 5–9%, and the incidence triples in patients following emergent repair. Mesenteric venous thrombosis is less common and is associated with the presence of a hypercoagulable state including protein C or S deficiency, antithrombin III deficiency, polycythemia vera, and carcinoma. The blood supply to the intestines is depicted in Fig. 354-1. To prevent ischemic injury, extensive collateralization occurs between major mesenteric trunks and branches of the mesenteric arcades.Collateral vessels within the colon meet at the splenic flexure and descending/sigmoid colon.These areas, which are inherently at risk for decreased blood flow, are known as Griffiths’ point and Sudeck’s point, respectively, and are the most common locations for colonic ischemia (Fig.354-1, shaded areas).The splanchnic circulation can receive up to 30% of the cardiac output.

In general, the best activity recommendation is for early resumption of normal physical activity, avoiding only strenuous manual labor.Several randomized trials suggest that bed rest does not hasten the pace of recovery.In general, bed rest should be avoided for relief of severe symptoms or kept to a day or two at most.The initial assessment excludes serious causes of spine pathology that require urgent intervention including infection, cancer, or trauma. Risk factors for a serious cause of ALBP are shown in Table 22-1. Laboratory and imaging studies are unnecessary if risk factors are absent. CT, MRI, or plain spine films are rarely indicated in the first month of symptoms unless a spine fracture, tumor, or infection is suspected. The prognosis is generally excellent. Many patients do not seek medical care and improve on their own. Even among those seen in primary care, two-thirds report being substantially improved after 7 weeks. This spontaneous improvement can mislead clinicians and researchers about the efficacy of treatment interventions unless subjected to rigorous prospective trials. Many treatments commonly used in the past but now known to be ineffective, including bed rest, lumbar traction, and coccygectomy, have been largely abandoned. Clinicians should reassure patients that improvement is very likely and instruct them in self-care. Education is an important part of treatment. Satisfaction and the likelihood of follow-up increase when patients are educated about prognosis, treatment methods, 119 activity modifications, and strategies to prevent future exacerbations. Patients who report that they did not receive an adequate explanation for their symptoms are likely to request further diagnostic tests. In general, bed rest should be avoided for relief of severe symptoms or kept to a day or two at most. Several randomized trials suggest that bed rest does not hasten the pace of recovery. In general, the best activity recommendation is for early resumption of normal physical activity, avoiding only strenuous manual labor.Specific back exercises or early vigorous exercise have not shown benefits for acute back pain, but may be useful for chronic pain.Use of heating pads or blankets is sometimes helpful.Evidence-based guidelines recommend over-the-counter medicines such as acetaminophen and NSAIDs as first-line options for treatment of ALBP.

An elegant example comes from studies of the heart.But now, with the insights that have come from the study of ES and iPS cells, ways are being found to bring about such interconversions in a much wider range of cases.macrophage colony-interleukin-3, stimulating factor, interleukin-1 macrophage iPS cells (about 1,000 cells) dibutyryl cAMP, retinoic acid smooth muscle cell fbroblast fbroblast fbroblast growth factor 2, growth factor 2, growth epidermal platelet-derived factor growth factor growth factor 1258 Chapter 22: Stem Cells and tissue Renewal aggregate of hollow ball of budding of optic vesicle invaginates cultured ES cells neural cells optic vesicle to form optic cup (B) 100 µm Figure 22–46 Cultured eS cells can give rise to a three-dimensional organ. (a) Remarkably, under appropriate conditions, mouse eS cells in culture can proliferate, differentiate, and interact to form a three-dimensional, eye-like structure, which includes a multilayered retina similar in organization to the one that forms in vivo. (b) Fluorescent micrograph of an optic cup formed by eS cells in culture. the structure includes a developing retina, containing multiple layers of neural cells, which produce a protein (pink) that serves as a marker for retinal tissue. (b, from m. eiraku, n. takata, h. ishibashi et al., Nature 472:51–56, 2011. with permission from macmillan publishers ltd.) Cells of one Specialized type Can be Forced to transdifferentiate directly into another The route we have just described, from one mode of differentiation to another via conversion to an iPS cell, seems needlessly roundabout. Could we not convert cell type A into cell type B directly, without backtracking to the embryonic-like iPS state? For many years, it has been known that such transdifferentiation can be achieved in a few special cases, such as the conversion of fibroblasts into skeletal muscle cells by forced expression of MyoD (see p. 396). But now, with the insights that have come from the study of ES and iPS cells, ways are being found to bring about such interconversions in a much wider range of cases. An elegant example comes from studies of the heart.This has been done in the living mouse, using retroviral vectors, and the transformation occurs with high efficiency when the vectors carrying the transgenes are injected directly into the heart muscle tissue itself.

Although even high-powered, low-bias meta analyses are not perfect, they do approach a theoretical “gold standard” of research, and although increasing power is important in arriving at correct conclusions, even high-powered studies can have significant biases. Additionally, obtaining large-scale evidence may not be possible for many research questions.Brunicardi_Ch51_p2137-p2152.indd 214928/02/19 4:19 PM 2150SPECIFIC CONSIDERATIONSPART IICrisis of Reproducibility and Medical Reversal: Implications for EBM“You keep using that word. I do not think it means what you think it means.”—Inigo Montoya from The Princess BrideThis chapter started by noting that the landscape of scientific knowledge is constantly evolving and that this fact impacts how we use and evaluate evidence as well. This 11th edition of Schwartz’s Principles of Surgery is being produced at a particularly volatile period in biomedical research as basic assumptions as to how scientific literature determines what constitutes “evidence” are being reassessed in a critical fashion. We believe it does a disservice to our readers if we fail to note and describe these trends, as they directly affect the basis of this chapter. The reassessment of biomedical literature and clinical trials can be loosely grouped into two distinct, but related topics: the crisis of reproducibility and the issue of medical reversal.The Crisis of ReproducibilityOver the past decade it has become increasingly recognized that certain medical studies, held forth as index publications upon which were based either fundamental precepts of practice or to justify entire directions of drug discovery, could not be repro-duced independently.

These channels transport calcium in the setting of acidosis and substrate depletion, and pharmacologic blockade of these channels markedly attenuates stroke injury.In addition, glutamate-independent pathways of calcium influx via acid-sensing ion channels have been identified.Drug targets for the development of therapeutics include: (1) lowering the precursor protein, (2) inhibiting prion formation, and (3) enhancing prion clearance. B. Late-onset heritable neurodegeneration argues for two discrete events: The (i) first event is the synthesis of mutant precursor protein (green circle), and the (ii) second event is the age-dependent formation of mutant prions (red square). The highlighted yellow bar in the DNA structure represents mutation of a base pair within an exon, and the small yellow circles signify the corresponding mutant amino acid substitution. Green arrows represent a normal process; red arrows, a pathogenic process; and blue arrows, a process that is known to occur but unknown whether it is normal or pathogenic. (Micrographs prepared by Stephen J. DeArmond. Reprinted with permission from SB Prusiner: Biology and genetics of prions causing neurodegeneration. Annu Rev Genet 47:601, 2013.) Huntington’s disease, in which using low-dose memantine to selectively block the extrasynaptic receptors is beneficial. Although excitotoxicity is clearly implicated in the pathogenesis of cell death in stroke, to date treatment with NMDA antagonists has not proven to be clinically useful. One approach has been to use an inhibitor of the postsynaptic density-95 protein that uncouples NMDA receptors from neurotoxic pathways, including the generation of nitric oxide. This approach was effective in a primate stroke model and in a phase 2 clinical trial of stroke associated with endovascular repair of cerebral aneurysms. Transient receptor potentials (TRPs) are calcium channels that are activated by oxidative stress in parallel with excitotoxic signal pathways. In addition, glutamate-independent pathways of calcium influx via acid-sensing ion channels have been identified. These channels transport calcium in the setting of acidosis and substrate depletion, and pharmacologic blockade of these channels markedly attenuates stroke injury.Apoptosis, or programmed cell death, plays an important role in both physiologic and pathologic conditions.During embryogenesis, apoptotic pathways operate to destroy neurons that fail to differentiate appropriately or reach their intended targets.There is mounting evidence for an increased rate of apoptotic cell death in a variety of acute and chronic neurologic diseases.

In prokaryotes, the extent of strand methylation is used to discriminate between the strands.Mismatched-base repair (MMR) involves identification and repair of the newly synthesized (daughter) strand.It is also released from the adrenal medulla and, along with epinephrine, functions as a counterregulatory hormone that results in mobilization of stored fuels (for example, glucose and triacylglycerols). These actions are mediated by the binding of NE to adrenergic receptors, which are G protein–coupled receptors of the plasma membrane, and not to nuclear receptors like those of steroid hormones or membrane tyrosine kinase receptors like that of insulin. Septic shock is vasodilatory hypotension (low blood pressure caused by blood vessel dilation) resulting from the production of large amounts of nitric oxide by inducible nitric oxide synthase in response to infection. NE bound to receptors on smooth muscle cells causes vasoconstriction and, thus, raises blood pressure. Case 5: Sun Sensitivity with Xeroderma Pigmentosum Answer = D. Pyrimidine dimers are the characteristic DNA lesions caused by ultraviolet (UV) radiation. Their repair involves the excision of an oligonucleotide containing the dimer and replacement of that oligonucleotide, a process known as nucleotide excision repair (NER). (See figure at right for a representation of the process in prokaryotes.) DNA repair systems are found in prokaryotes and eukaryotes. Nothing is error free, but the homologous recombination (HR) method of double-strand break repair is much less prone to error than is the nonhomologous end joining (NHEJ) method because any DNA that was lost is replaced. Mismatched-base repair (MMR) involves identification and repair of the newly synthesized (daughter) strand. In prokaryotes, the extent of strand methylation is used to discriminate between the strands.The sugar-phosphate is then removed by the actions of an endo-and exonuclease.Answer = A.All replication requires an RNA primer because DNA polymerases (pol) cannot initiate DNA synthesis.The chromatin of eukaryotes gets decondensed (relaxed) for replication.Relaxation can be accomplished, for example, by acetylation via histone acetyltransferases.Prokaryotes have more than one DNA pol.

(Reproduced with permission from Centers for Disease Control and Prevention, Edwin P. Ewing, Jr.)Due to the variety in operations and etiologies of MV dis-ease, there is heterogeneity in outcomes following MV repair.The aorta has been removed to demonstrate the thickened, fused aortic valve leaflets associated with rheumatic heart disease.Aortic stenosis.21-9).136 A number of devices are available and include rigid or semirigid rings that geometrically remodel the annulus, flexible rings or bands that restrict annular dilation while main-taining the physiologic sphincter motion of the annulus, and semirigid bands that provide a combination of annular remodel-ing and support of physiologic motion.Another technique known as the “double-orifice” or “edge-to-edge” repair was introduced by Alfieri in 1995, and it involves tacking the free edge of the anterior leaflet to the opposing free edge of the posterior leaflet.137 This procedure effectively gives the valve a double-orifice “bow tie” configura-tion, and it has been used as both a primary repair technique and an adjunct to other repair techniques, usually in cases of anterior leaflet pathology or Barlow’s disease. While some groups report excellent late results, its use remains controversial, and it is used mainly as a bail-out procedure of last resort in many centers.Brunicardi_Ch21_p0801-p0852.indd 82201/03/19 5:32 PM 823ACQUIRED HEART DISEASECHAPTER 21Figure 21-9. Mitral valve repair. The narrow arrow indicates the posterior leaflet repair, and the wide arrow indicates the ring annu-loplasty as viewed through a left atriotomy.Figure 21-10. Aortic stenosis. The aorta has been removed to demonstrate the thickened, fused aortic valve leaflets associated with rheumatic heart disease. (Reproduced with permission from Centers for Disease Control and Prevention, Edwin P. Ewing, Jr.)Due to the variety in operations and etiologies of MV dis-ease, there is heterogeneity in outcomes following MV repair.However, increasing experi-ence and the expanded use of chordal replacement has greatly improved these results in recent series.139 Independent predic-tors of mortality have included higher NYHA class, lower left ventricular ejection fraction, renal dysfunction, and age.

The GAPS report extends the framework of services provided to adolescents.The urgency for preventing these crises is evident.Obstetricians-gynecologists typically see adolescents in crisis to provide care for unintended pregnancies or STDs, including pelvic inflammatory disease.Other Web sites that provide tools and information about evidence-based health care include the Oxford Centre for Table 8.6 U.S. Preventive Services Task Force Ratings The U.S. Preventive Services Task Force (USPSTF) grades its recommendations according to one of five classifications (A, B, C, D, I) reflecting the strength of evidence and magnitude of net benefit (benefits minus harms). After May 2007, updated definitions of the grades it assigns to recommendations are noted below with “suggestions for practice” with each grade (50). Evidence-Based Medicine, the Database of Abstracts of Reviews of Effects (DARE), and the American College of Physicians (ACP) Journal Club (23–25). Around the same time that clinicians were evaluating the primary health care needs of adults, clinicians who practice adolescent medicine (with backgrounds in pediatrics, internal medicine, family medicine, gynecology, nursing, psychology, nutrition, and other professions) recognized that the guidelines for adult and pediatric health services did not always fit the needs and health risks of adolescence. Neither the ACOG Guidelines for Primary Preventive Care nor the USPSTF recommendations is sufficiently comprehensive or focused on this age group, although both documents include many important aspects of adolescent health care (10,13). The American Medical Association, with the assistance of a national scientific advisory board, developed the Guidelines for Adolescent Preventive Services (GAPS) in response to this perceived need for recommendations for delivering comprehensive adolescent preventive services (13,14,26). Obstetricians-gynecologists typically see adolescents in crisis to provide care for unintended pregnancies or STDs, including pelvic inflammatory disease. The urgency for preventing these crises is evident. The GAPS report extends the framework of services provided to adolescents.This concept is strongly supported by the Society for Adolescent Medicine, the American Academy of Pediatrics, and the American Academy of Family Physicians (27).Gynecologists could easily provide most, if not all, of the recommended services.

Basal cell carcinomas (BCCs) account for 70–80% of NMSCs.Although tumor registries do not routinely gather data on the incidence of basal cell and squamous cell skin cancers, it is estimated that the annual incidence is 1.5–2 million cases in the United States.Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States.Therefore, enrollment in a clinical trial is always an important consideration, even for previously untreated patients. Most patients with stage IV disease will eventually progress despite advances in therapy, and many, because of disease burden, poor performance status, or concomitant illness, will be unsuitable for therapy. Therefore, a major focus of care should be the timely integration of palliative care and hospice. Skin examination and surveillance at least once a year are recommended for all patients with melanoma. The National Comprehensive Cancer Network (NCCN) guidelines for patients with stage IA–IIA Cancer of the Skin 500 melanoma recommend a comprehensive history and physical examination every 6–12 months for 5 years, and then annually as clinically indicated. Particular attention should be paid to the draining lymph nodes in stage I–III patients as resection of lymph node recurrences may still be curative. A CBC, LDH, and chest x-ray are recommended at the physician’s discretion, but are ineffective tools for the detection of occult metastases. Routine imaging for metastatic disease is not recommended at this time. For patients with higher stage disease (IIB–IV), imaging (chest x-ray, CT, and/or PET/CT scans) every 4–12 months can be considered. Because no discernible survival benefit has been demonstrated for routine surveillance, it is reasonable to perform scans only if clinically indicated. Nonmelanoma skin cancer (NMSC) is the most common cancer in the United States. Although tumor registries do not routinely gather data on the incidence of basal cell and squamous cell skin cancers, it is estimated that the annual incidence is 1.5–2 million cases in the United States. Basal cell carcinomas (BCCs) account for 70–80% of NMSCs.There has also been an increase in the incidence of nonepithelial skin cancer, especially Merkel cell carcinoma, with nearly 5000 new diagnoses and 3000 deaths annually.The most significant cause of BCC and SCC is UV exposure, whether through direct exposure to sunlight or by artificial UV light sources (tanning beds).

2.3 Multiple Choice: Choose the option that correctly describes ficolins.A. Phospholipase A B. Lysozyme C. Defensins D. Histatins 2.2 Short Answer: Why is the capacity of mannose-binding lectin (MBL) trimers to oligomerize important for their function?Which of the following is an antimicrobial enzyme that functions to disrupt the same bacterial structure that β-lactams ultimately target?The main event in complement activation is accumulation of C3b on microbial membranes, which is recognized by complement receptors on phagocytic cells to promote microbial clearance by cells recruited to sites of infection by C3a and C5a. In addition, C5b initiates the membrane-attack complex that is able to lyse some microbes directly. The complement cascade is under regulation to prevent attack on host tissues, and genetic variation in regulatory pathways can result in autoimmune syndromes and age-related tissue damage. Questions. 2.1 Multiple Choice: The widely used β-lactam antibiotics are mainly active against Gram-positive bacteria. These inhibit the transpeptidation step in synthesis of peptidoglycan, a major component of the bacterial cell wall that is critical for the survival of the microorganism. Which of the following is an antimicrobial enzyme that functions to disrupt the same bacterial structure that β-lactams ultimately target? A. Phospholipase A B. Lysozyme C. Defensins D. Histatins 2.2 Short Answer: Why is the capacity of mannose-binding lectin (MBL) trimers to oligomerize important for their function? 2.3 Multiple Choice: Choose the option that correctly describes ficolins.Not all words will be used; each word should be used only once.Like MBLs, ficolins form oligomers with ________ and ________.Such interaction allows the oligomer to cleave the complement components ________ and ________.Once these are cleaved, they form ________, a C3 convertase, which cleaves ________ and permits the formation of the membrane-attack complex.

In this section, we consider how the location of each amino acid in the long string of amino acids that forms a protein determines its three-dimensional shape.Yet, even to experts, the remarkable versatility of proteins can seem truly amazing.Proteins constitute most of a cell’s dry mass. They are not only the cell’s building blocks; they also execute the majority of the cell’s functions. Thus, proteins that are enzymes provide the intricate molecular surfaces inside a cell that catalyze its many chemical reactions. Proteins embedded in the plasma membrane form channels and pumps that control the passage of small molecules into and out of the cell. Other proteins carry messages from one cell to another, or act as signal integrators that relay sets of signals inward from the plasma membrane to the cell nucleus. Yet others serve as tiny molecular machines with moving parts: kinesin, for example, propels organelles through the cytoplasm; topoisomerase can untangle knotted DNA molecules. Other specialized proteins act as antibodies, toxins, hormones, antifreeze molecules, elastic fibers, ropes, or sources of luminescence. Before we can hope to understand how genes work, how muscles contract, how nerves conduct electricity, how embryos develop, or how our bodies function, we must attain a deep understanding of proteins. From a chemical point of view, proteins are by far the most structurally complex and functionally sophisticated molecules known. This is perhaps not surprising, once we realize that the structure and chemistry of each protein has been developed and fine-tuned over billions of years of evolutionary history. The theoretical calculations of population geneticists reveal that, over evolutionary time periods, a surprisingly small selective advantage is enough to cause a randomly altered protein sequence to spread through a population of organisms. Yet, even to experts, the remarkable versatility of proteins can seem truly amazing. In this section, we consider how the location of each amino acid in the long string of amino acids that forms a protein determines its three-dimensional shape.The Shape of a Protein Is Specified by Its Amino Acid Sequence There are 20 different of amino acids in proteins that are coded for directly in an organism’s DNA, each with different chemical properties.A protein molecule is made from a long unbranched chain of these amino acids, each linked to its neighbor through a covalent peptide bond.Proteins are therefore also known as polypeptides.

While in most cases H. pylori gastritis is limited to the antrum, in some individuals it progresses to involve the gastric body and fundus, resulting in reduced parietal cell mass and acid secretion.The increased acid production may give rise to peptic ulcer disease of the duodenum or stomach.H. pylori infection most often presents as an antral gastritis with increased acid production.Bleeding from superficial gastric erosions or ulcers that may require transfusion develop in 1% to 4% of these patients. Other complications, including perforation, also may occur. Prophylaxis with proton pump inhibitors may blunt the impact of stress ulceration, but the most important determinant of outcome is the severity of the underlying condition. The most common cause of chronic gastritis is infection with the bacillus Helicobacter pylori. Autoimmune http://ebooksmedicine.net gastritis, typically associated with gastric atrophy, represents less than 10% of cases of chronic gastritis but is the most common cause in patients without H. pylori infection. Chronic NSAID use is a third important cause of gastritis in some populations, as discussed later. Less common causes include radiation injury and chronic bile reflux. The signs and symptoms associated with chronic gastritis typically are less severe but more persistent than those of acute gastritis. Nausea and upper-abdominal discomfort may occur, sometimes with vomiting, but hematemesis is uncommon. The discovery of the association of H. pylori with peptic ulcer disease revolutionized the understanding of chronic gastritis. These spiral-shaped or curved bacilli are present in gastric biopsy specimens from almost all patients with duodenal ulcers and a majority of those with gastric ulcers or chronic gastritis. Acute H. pylori infection is subclinical in most cases; rather, it is the chronic gastritis that ultimately brings the afflicted person to medical attention. H. pylori infection most often presents as an antral gastritis with increased acid production. The increased acid production may give rise to peptic ulcer disease of the duodenum or stomach. While in most cases H. pylori gastritis is limited to the antrum, in some individuals it progresses to involve the gastric body and fundus, resulting in reduced parietal cell mass and acid secretion.In addition, extension of the gastritis to the gastric body and fundus results in intestinal metaplasia and increased risk of gastric cancer.In the United States, H. pylori infection is associated with poverty, household crowding, limited education, residence in areas with poor sanitation, and birth outside of the United States.

The distinction between femoral neuropathy and a third lumbar root lesion is made by detecting weakness of the hip adductor (innervated by the obturator nerve) in the case of the root lesion.A few with the most painful symptoms have demanded a neurectomy or section of the nerve, but it is always wise to perform a lidocaine block first, so that the patient can decide whether the persistent numbness is preferable. In one specimen of nerve obtained at operation, we found a discrete traumatic neuroma. Corticosteroid injections at the point of entrapment may have helped in a few cases, but this has not been studied in a systematic way. This nerve arises from the third and fourth and to a lesser extent the second lumbar roots. It supplies the adductors of the thigh and contributes to the innervation of the internal and external rotators. The adductors have the added function of contributing to flexing the hip. The nerve may be injured by the fetal head or forceps during the course of a difficult labor or compressed by an obturator hernia. Rarely, it is affected with diabetes, polyarteritis nodosa, and osteitis pubis and by retroperitoneal spread of carcinoma of the cervix, uterus, and other tumors (Rogers et al). This nerve is formed from the second, third, and fourth lumbar roots. Within the pelvis it passes along the lateral border of the psoas muscle and enters the thigh beneath the Poupart ligament, lateral to the femoral artery. Branches arising within the pelvis supply the iliacus and psoas muscles. Just below the Poupart ligament the nerve splits into anterior and posterior divisions. The former supplies the pectineus and sartorius muscles and carries sensation from the anteromedial surface of the thigh; the posterior division provides the motor innervation to the quadriceps and the cutaneous innervation to the medial side of the leg from the knee to the internal malleolus. The distinction between femoral neuropathy and a third lumbar root lesion is made by detecting weakness of the hip adductor (innervated by the obturator nerve) in the case of the root lesion.The knee jerk is abolished.If the nerve is injured proximal to the origin of the branches to the iliacus and psoas muscles, there is additionally weakness of hip flexion.The most common cause of femoral neuropathy is diabetes.The nerve may also be involved by pelvic tumors.Not uncommon is injury to the nerve during pelvic operations.

An instruction to “take as directed” may save the time it takes to write the orders out but often leads to noncompliance, patient confusion, and medication error.Furthermore, the drug name, the purpose for which it is given, and the duration of therapy should be written on each label so that the drug may be identified easily in case of overdose.(Neither should assume that the other will do it.)Some third-party (insurance) plans limit the amount of medicine that can be dispensed—often to only one month’s supply. Finally, when first prescribing medications that are to be used for the treatment of a chronic disease, the initial quantity should be small, with refills for larger quantities. The purpose of beginning treatment with a small quantity of drug is to reduce the cost if the patient cannot tolerate it. Once it is determined that intolerance is not a problem, a larger quantity purchased less frequently is sometimes less expensive. The directions for use (element [11]) must be both drug-specific and patient-specific. The simpler the directions, the better; and the fewer the number of doses (and drugs) per day, the better. Patient noncompliance (also known as nonadherence, failure to adhere to the drug regimen) is a major cause of treatment failure. To help patients remember to take their medications, prescribers often give an instruction that medications be taken at or around mealtimes and at bedtime. However, it is important to inquire about the patient’s eating habits and other lifestyle patterns, because many patients do not eat three regularly spaced meals a day. The instructions on how and when to take medications, the duration of therapy, and the purpose of the medication must be explained to each patient both by the prescriber and by the pharmacist. (Neither should assume that the other will do it.) Furthermore, the drug name, the purpose for which it is given, and the duration of therapy should be written on each label so that the drug may be identified easily in case of overdose. An instruction to “take as directed” may save the time it takes to write the orders out but often leads to noncompliance, patient confusion, and medication error.Although directions for use are no longer written in Latin, many Latin apothecary abbreviations (and some others included below) are still in use.Knowledge of these abbreviations is essential for the dispensing pharmacist and often useful for the prescriber.Some of the abbreviations still used are listed in Table 65–1.Note: It is always safer to write out the direction without abbreviating.

A subsequent corticosteroid taper for several months may be considered.Acute exacerbation of confirmed or suspected NMOSD have been treated promptly with high-dose intravenous corticosteroids.Pittock and colleagues (2008) give the frequency of these antibodies as approximately one-third in patients with systemic autoimmune disease and clinical features of Devic disease. Case reports of NMOSD coexisting with cancer suggest that the disease may also occasionally be a paraneoplastic immune phenomenon. Differential diagnosis There is in addition to the myelitis described earlier a progressive and sometimes saltatory subacute necrotic myelopathy without optic neuritis that shares the features of Devic disease but not the optic neuropathy and, in our view, they probably represent the same entity (Katz and Ropper). The differential diagnosis is broader and includes vascular malformations of the cord or dura and infarction or neoplasm of the cord. The cord in the cases we have studied was swollen on MRI in the early stages, often with edema extending many segments above and below the area of primary disease, and later became atrophic, similar to what has been reported in Devic disease. Up to 50 cells are typical in the CSF and the protein is elevated but the spinal fluid may be normal during periods of clinical stability. Several, but not all, of these cases have had positive NMO IgG antibodies (see above), further supporting the notion that most of these aggressive, purely spinal cases are allied with Devic disease. Treatment Although no adequate randomized treatment trials have been conducted, retrospective and open-label uncontrolled data permit several tentative conclusions about the use of immunomodulating therapies for acute attacks and prevention of future relapses. Acute exacerbation of confirmed or suspected NMOSD have been treated promptly with high-dose intravenous corticosteroids. A subsequent corticosteroid taper for several months may be considered.Its use is supported by results of a randomized, sham-controlled double-masked clinical trial by Weinshenker and colleagues (1999) in 22 patients with demyelinating disease, of whom 2 had NMO.Retrospective studies have also shown that acute treatment PLEX yields better visual outcomes than corticosteroids alone (Merle).

This receptor binds the natriuretic peptides with equal affinity.The peptides are also removed from the circulation by binding to ANP-C receptors in the vascular endothelium.Inhibition of this endopeptidase results in increases in circulating levels of the natriuretic peptides, natriuresis, and diuresis.It has not been found in significant concentrations in the circulation. CNP has less natriuretic and diuretic activity than ANP and BNP but is a potent vasodilator and may play a role in the regulation of peripheral resistance. Urodilatin is synthesized in the distal tubules of the kidneys by alternative processing of the ANP precursor. It elicits potent natriuresis and diuresis, and thus functions as a paracrine regulator of sodium and water excretion. It also relaxes vascular smooth muscle. The biologic actions of the natriuretic peptides are mediated through association with specific high-affinity receptors located on the surface of the target cells (Figure 17–5). Three receptor subtypes termed NPR-A (ANP-A), NPR-B (ANP-B), and NPR-C (ANP-C) have been identified. The NPR-A and NPR-B receptors contain guanylyl cyclase at their intracellular domains. The primary ligands of the NPR-A receptor are ANP and BNP. The NPR-B receptor is similar in structure to the ANP-A receptor, but its primary ligand appears to be CNP. The NPR-C receptor may be coupled to adenylyl cyclase or phospholipase C; it binds all three natriuretic peptides and functions as a clearance receptor. The natriuretic peptides have a short half-life in the circulation. They are metabolized in the kidneys, liver, and lungs by the neutral endopeptidase NEP 24.11 (neprilysin). Inhibition of this endopeptidase results in increases in circulating levels of the natriuretic peptides, natriuresis, and diuresis. The peptides are also removed from the circulation by binding to ANP-C receptors in the vascular endothelium. This receptor binds the natriuretic peptides with equal affinity.Patients with heart failure have high plasma levels of ANP and BNP; the latter has emerged as a diagnostic and prognostic marker in this condition.Signaling?

Click and murmur become softer with squatting (increased systemic resistance decreases left ventricular emptying).Etiology is unknown; may be seen in Marfan syndrome or Ehlers-Dantos syndrome C. Presents with an incidental mid-systolic click followed by a regurgitation murmur; usually asymptomatic 1.8.15) 1.D. Cardiac compensation leads to a prolonged asymptomatic stage during which a systolic ejection click followed by a crescendo-decrescendo murmur is heard. E. Complications include 1. Concentric left ventricular hypertrophy-may progress to cardiac failure 2. Angina and syncope with exercise-Limited ability to increase blood flow across the stenotic valve leads to decreased perfusion of the myocardium and brain. 3. Microangiopathic hemolytic anemia-RBCs are damaged (producing schistocytes) while crossing the calcified valve. F. Treatment is valve replacement after onset of complications. V. A. Backflow of blood from the aorta into the left ventricle during diastole B. Arises due to aortic root dilation (e.g., syphilitic aneurysm and aortic dissection) or valve damage (e.g., infectious endocarditis); most common cause is isolated root dilation C. Clinical features include 1. Early, blowing diastolic murmur 2. Hyperdynamic circulation due to increased pulse pressure i. Pulse pressure is the difference between systolic and diastolic pressures. ii. Diastolic pressure decreases due to regurgitation, while systolic pressure increases due to increased stroke volume. iii. Presents with bounding pulse (water-hammer pulse), pulsating nail bed (Quincke pulse), and head bobbing 3. Results in LV dilation and eccentric hypertrophy (due to volume overload) D. Treatment is valve replacement once LV dysfunction develops. VI. MITRAL VALVE PROLAPSE A. Ballooning of mitral valve into left atrium during systole 1. Seen in 2-3% of US adults B. Due to myxoid degeneration (accumulation of ground substance) of the valve, making it floppy (Fig. 8.15) 1. Etiology is unknown; may be seen in Marfan syndrome or Ehlers-Dantos syndrome C. Presents with an incidental mid-systolic click followed by a regurgitation murmur; usually asymptomatic 1. Click and murmur become softer with squatting (increased systemic resistance decreases left ventricular emptying).E. Treatment is valve replacement.VII.MITRAL REGURGITATION A. Reflux of blood from the left ventricle into the left atrium during systole B.Usually arises as a complication of mitral valve prolapse; other causes include LV dilatation (e.g., left-sided cardiac failure), infective endocarditis, acute rheumatic heart disease, and papillary muscle rupture after a myocardial infarction.

There may be many dozens of attacks per day or occasional ones.It is characterized by numerous brief (several minutes) attacks of dystonia or choreoathetosis provoked by sudden movement, startle, or hyperventilation—hence the name paroxysmal kinesigenic choreoathetosis.Reinstitution of the offending drug or high doses of anticholinergic agents is then sometimes necessary but is only partially effective, and requires that the patient tolerate the other effects of the medication such as sedation and parkinsonism. The problem has become less frequent with the introduction of the newer classes of antipsychosis drugs. Stereotactic surgery on the pallidum and ventrolateral thalamus, a treatment introduced by Cooper in the middle of the last century, had generally positive but unpredictable results in generalized dystonia. In recent years there has been a renewed interest in a modern derivative of this form of treatment, deep brain stimulation. In a controlled trial, Vidailhet and colleagues demonstrated the effectiveness of this approach by stimulating the posteroventral globus pallidus bilaterally. Their patients had an average improvement of 50 percent on most scores of dystonic movement over 1 year. Increasingly, this is the method resorted to in cases of severe generalized dystonia. Under the names paroxysmal kinesigenic dyskinesia, familial paroxysmal choreoathetosis, and periodic dystonia, among others, are a number of uncommon sporadic or familial disorders characterized by paroxysmal attacks of choreoathetotic movements or dystonic spasms of the limbs and trunk. Both children and young adults are affected. There are three main forms of familial paroxysmal choreoathetosis and dystonia. Various genes and mutations have been implicated, some of which involve ion channels. One clinical type, which has an autosomal dominant (less often recessive) pattern of inheritance and a tendency to affect males, begins in adolescence or earlier and abates later in life. It is characterized by numerous brief (several minutes) attacks of dystonia or choreoathetosis provoked by sudden movement, startle, or hyperventilation—hence the name paroxysmal kinesigenic choreoathetosis. There may be many dozens of attacks per day or occasional ones.Mutations of PRRT2, the proline-rich transmembrane protein, have been identified as the cause in some families and link the disease to a variety of infantile convulsions as summarized by Gardiner and colleagues.

295), initial therapy is aimed at maintaining adequate systemic and coronary perfusion by raising systemic BP with vasopressors and adjusting volume status to a level that ensures optimum LV filling pressure.326-2) In addition to the usual treatment of acute MI (Chap.(Fig.Pulmonary artery catheterization The use of pulmonary artery (Swan-Ganz) catheters in patients with established or suspected CS is controversial (Chaps. 272 and 321). Their use is generally recommended for measurement of filling pressures and cardiac output to confirm the diagnosis and to optimize the use of IV fluids, inotropic agents, and vasopressors in persistent shock (Table 326-2). O2 saturation measurement from right atrial, RV, and pulmonary arterial blood samples can rule out a left-to-right shunt. In CS, low mixed venous O2 saturations and elevated arteriovenous (AV) O2 differences reflect low cardiac index and high fractional O2 extraction. However, when sepsis accompanies CS, AV O2 differences may not be elevated (Chap. 324). The PCWP is elevated. Use of sympathomimetic amines may return these measurements and the systemic BP to normal. Systemic vascular resistance may be low, normal, or elevated in CS. Equalization of rightand left-sided filling pressures (right atrial and PCWP) suggests cardiac tamponade as the cause of CS (Chap. 288). left heart catheterization and coronary angiograPhy Measurement of LV pressure and definition of the coronary anatomy provide useful information and are indicated in most patients with CS complicating MI. Cardiac catheterization should be performed when there is a plan and capability for immediate coronary intervention (see below) or when a definitive diagnosis has not been made by other tests. (Fig. 326-2) In addition to the usual treatment of acute MI (Chap. 295), initial therapy is aimed at maintaining adequate systemic and coronary perfusion by raising systemic BP with vasopressors and adjusting volume status to a level that ensures optimum LV filling pressure.Hypoxemia and acidosis must be corrected; most patients require ventilatory support (see “Pulmonary Edema,” below).Negative inotropic agents should be discontinued and the doses of renally cleared medications adjusted.Hyperglycemia should be controlled with insulin.Bradyarrhythmias may require transvenous pacing.

Smokingisthemostimportantriskfactorforlungcancer.•Thethreemajorhistologicsubtypesareadenocarcinoma(mostcommon),squamouscellcarcinoma,andsmallcellcarcinoma,eachofwhichisclinicallyandgeneticallydistinct.Adenocarcinomasarethemostcommoncancersoverallandareespeciallycommoninwomenandinnonsmokers.SCLCs have invariably spread by the time they are detected, even if the primary tumor appears to be small and localized; thus, surgical resection is not a viable option. SCLCs are very sensitive to chemotherapy but invariably recur, and as of yet targeted therapies are unavailable. The median survival even with treatment remains only 1 year, and only 5% are alive at 10 years. Because these tumors have a very high mutation burden, they are likely to be immunogenic. Accordingly, immune checkpoint therapies have produced encouraging responses in patients with advanced SCLC. In addition to the direct effects of the tumor cells, it is estimated that 3% to 10% of patients with lung cancer develop paraneoplastic syndromes (Chapter 6). These include hypercalcemia caused by secretion of a parathyroid hormone–related peptide; (2) Cushing syndrome (from increased production of adrenocorticotropic hormone); syndrome of inappropriate secretion of anti-diuretic hormone; (4) neuromuscular syndromes, including a myasthenic syndrome, peripheral neuropathy, and polymyositis; clubbing of the fingers and hypertrophic pulmonary osteoarthropathy; and (6) coagulation abnormalities, including migratory thrombophlebitis, nonbacterial endocarditis, and disseminated intravascular coagulation. Hypercalcemia most often is encountered with squamous cell neoplasms, the hematologic syndromes with adenocarcinomas, and the neurologic syndromes with small cell neoplasms, but exceptions abound. •Thethreemajorhistologicsubtypesareadenocarcinoma(mostcommon),squamouscellcarcinoma,andsmallcellcarcinoma,eachofwhichisclinicallyandgeneticallydistinct.Adenocarcinomasarethemostcommoncancersoverallandareespeciallycommoninwomenandinnonsmokers. Smokingisthemostimportantriskfactorforlungcancer.Tumors3cmorlessindiametercharacterizedbypuregrowthalongpreexistingstructureswithoutstromalinvasionarecalledadenocarcinomainsitu.

Environmental.Individuals who develop anxiety disorders or display obsessional traits in childhood are at increased risk of developing anorexia nervosa.Temperamental.Death most commonly results from medical complications associated with the disorder itself or from suicide.The crude mortality rate (CMR) for anorexia nervosa is approximately 5% per decade.Anorexia nervosa commonly begins during adolescence or young adulthood. It rarely be- gins before puberty or after age 40, but cases of both early and late onset have been de- scribed. The onset of this disorder is often associated with a stressful life event, such as leaving home for college. The course and outcome of anorexia nervosa are highly variable. Younger individuals may manifest atypical features, including denying "fear of fat.” Older individuals more likely have a longer duration of illness, and their clinical presentation may include more signs and symptoms of long-standing disorder. Clinicians should not exclude anorexia nervosa from the differential diagnosis solely on the basis of older age. Many individuals have a period of changed eating behavior prior to full criteria for the disorder being met. Some individuals with anorexia nervosa recover fully after a single episode, with some exhibiting a fluctuating pattern of weight gain followed by relapse, and others experiencing a chronic course over many years. Hospitalization may be re— quired to restore weight and to address medical complications. Most individuals with an- orexia nervosa experience remission within 5 years of presentation. Among individuals admitted to hospitals, overall remission rates may be lower. The crude mortality rate (CMR) for anorexia nervosa is approximately 5% per decade. Death most commonly results from medical complications associated with the disorder itself or from suicide. Temperamental. Individuals who develop anxiety disorders or display obsessional traits in childhood are at increased risk of developing anorexia nervosa. Environmental.Oc- cupations and avocations that encourage thinness, such as modeling and elite athletics, are also associated with increased risk.Genetic and physiological.There is an increased risk of anorexia nervosa and bulimia nervosa among first-degree biological relatives of individuals with the disorder.

The facial dysmorphism can be explained by the neural crest origin of the connective tissues of the head and neck.The latter syndrome is characterized by congenital sensorineural hearing loss, dystopia canthorum (lateral displacement of the inner canthi but normal interpupillary distance), heterochromic irises, and a broad nasal root, in addition to the piebaldism.vitiligo-like leukoderma seen in patients with systemic sclerosis has a clinical resemblance to idiopathic vitiligo that has begun to repigment as a result of treatment; that is, perifollicular macules of normal pigmentation are seen within areas of depigmentation. The basis of this leukoderma is unknown; there is no evidence of inflammation in areas of involvement, but it can resolve if the underlying connective tissue disease becomes inactive. In contrast to idiopathic vitiligo, melanoma-associated leukoderma often begins on the trunk, and its appearance, if spontaneous, should prompt a search for metastatic disease. It is also seen in patients undergoing immunotherapy for melanoma, including ipilimumab, with cytotoxic T lymphocytes presumably recognizing cell surface antigens common to melanoma cells and melanocytes, and is associated with a greater likelihood of a clinical response. There are two systemic disorders (neurocristopathies) that may have the cutaneous findings of piebaldism (Table 72-9). They are Shah-Waardenburg syndrome and Waardenburg syndrome. A possible explanation for both disorders is an abnormal embryonic migration or survival of two neural crest–derived elements, one of them being melanocytes and the other myenteric ganglion cells (leading to Hirschsprung disease in Shah-Waardenburg syndrome) or auditory nerve cells (Waardenburg syndrome). The latter syndrome is characterized by congenital sensorineural hearing loss, dystopia canthorum (lateral displacement of the inner canthi but normal interpupillary distance), heterochromic irises, and a broad nasal root, in addition to the piebaldism. The facial dysmorphism can be explained by the neural crest origin of the connective tissues of the head and neck.In tuberous sclerosis, the earliest cutaneous sign is macular hypomelanosis, referred to as an ash leaf spot.These lesions are often present at birth and are usually multiple; however, detection may require Wood’s lamp examination, especially in fair-skinned individuals.The pigment within them is reduced, but not absent.

Dysmenorrhea is a syndrome of painful menses, but this is distinct from a syndrome characterized by affective changes.Dysmenorrhea.The pres- ence of physical or behavioral symptoms in the premenstruum, without the required affective symptoms, likely meets criteria for premenstrual syndrome and not for premen- strual dysphoric disorder.The Premenstrual Tension Syndrome Rating Scale has a self—report and an observer version, both of which have been validated and used widely to measure illness severity in women who have premenstrual dysphoric disorder. Symptoms must be associated with clinically meaningful distress and/ or an obvious and marked impairment in the ability to function socially or occupationally in the week prior to menses. Impairment in social functioning may be manifested by marital discord and problems with children, other family members, or friends. Chronic marital or job prob- lems should not be confused with dysfunction that occurs only in association with pre- menstrual dysphoric disorder. Premenstrual syndrome. Premenstrual syndrome differs from premenstrual dysphoric disorder in that a minimum of five symptoms is not required, and there is no stipulation of affective symptoms for individuals who have premenstrual syndrome. This condition may be more common than premenstrual dysphoric disorder, although the estimated prevalence of premenstrual syndrome varies. While premenstrual syndrome shares the feature of symptom expression during the premenstrual phase of the menstrual cycle, it is generally considered to be less severe than premenstrual dysphoric disorder. The pres- ence of physical or behavioral symptoms in the premenstruum, without the required affective symptoms, likely meets criteria for premenstrual syndrome and not for premen- strual dysphoric disorder. Dysmenorrhea. Dysmenorrhea is a syndrome of painful menses, but this is distinct from a syndrome characterized by affective changes.Bipolar disorder, major depressive disorder, and persistent depressive disorder (dysthymia).Many women with (either naturally occurring or substance/ medication- that they have premenstrual dysphoric disorder.However, when they chart symptoms, they realize that the symptoms do not follow a premenstrual pattern.Women with an- are unrelated to menstrual cycle phase.

In addition, physical activity increases cardiopulmonary fitness and reduces the risk of CVD, independent of weight loss.Although adding exercise to a hypocaloric regimen may not produce a greater weight loss initially, exercise is a key component of programs directed at maintaining weight loss.Physical activity An increase in physical activity can create an energy deficit.A.Typically, a plan for weight reduction combines dietary change; increased physical activity; and behavioral modification, which can include nutrition education and meal planning, recording food intake through food diaries, modifying factors that lead to overeating, and relearning cues to satiety. Medications or surgery may be recommended. Once weight loss is achieved, weight maintenance is a separate process that requires vigilance because the majority of patients regain weight after they stop their weight-loss efforts. B. Caloric restriction Dieting is the most commonly practiced approach to weight control. Because 1 lb of adipose tissue corresponds to ~3,500 kcal, the effect that caloric restriction will have on the amount of adipose tissue can be estimated. Weight loss on calorie-restricted diets is determined primarily by caloric intake and not nutrient composition. [Note: However, compositional aspects can affect glycemic control and the blood lipid profile.] Caloric restriction is ineffective over the long term for many individuals. Over 90% of people who attempt to lose weight regain the lost weight when dietary intervention is suspended. Nonetheless, although few individuals will reach their ideal weight with treatment, weight losses of 10% of body weight over a 6-month period often reduce blood pressure and lipid levels and enhance control of T2D. A. Physical activity An increase in physical activity can create an energy deficit. Although adding exercise to a hypocaloric regimen may not produce a greater weight loss initially, exercise is a key component of programs directed at maintaining weight loss. In addition, physical activity increases cardiopulmonary fitness and reduces the risk of CVD, independent of weight loss.Studies show that individuals who maintain their exercise program regain less weight after their initial weight loss.C. Pharmacologic treatment The U.S. Food and Drug Administration has approved several weight-loss medications for use in adults.

With the availability of sensitive and specific LH assays, GnRH stimulation testing is used rarely except to evaluate gonadotrope function in patients who have undergone pituitary surgery or have a space-occupying lesion in the hypothalamic-pituitary region.LH and FSH are measured using two-site immunoradiometric, immunofluorometric, or chemiluminescent assays, which have very low cross-reactivity with other pituitary glycoprotein hormones and human chorionic gonadotropin (hCG) and have sufficient sensitivity to measure the low levels present in patients with hypogonadotropic hypogonadism. In men with a low testosterone level, an LH level can distinguish primary (high LH) versus secondary (low or inappropriately normal LH) hypogonadism. An elevated LH level indicates a primary defect at the testicular level, whereas a low or inappropriately normal LH level suggests a defect at the hypothalamic-pituitary level. LH pulses occur about every 1–3 h in normal men. Thus, gonadotropin levels fluctuate, and samples should be pooled or repeated when results are equivocal. FSH is less pulsatile than LH because it has a longer half-life. Selective increase in FSH suggests damage to the seminiferous tubules. Inhibin B, a Sertoli cell product that suppresses FSH, is reduced with seminiferous tubule damage. Inhibin B is a dimer with α-βB subunits and is measured by two-site immunoassays. GnRH Stimulation Testing The GnRH test is performed by measuring LH and FSH concentrations at baseline and at 30 and 60 min after intravenous administration of 100 μg of GnRH. A minimally acceptable response is a twofold LH increase and a 50% FSH increase. In the prepubertal period or with severe GnRH deficiency, the gonadotrope may not respond to a single bolus of GnRH because it has not been primed by endogenous hypothalamic GnRH; in these patients, GnRH responsiveness may be restored by chronic, pulsatile GnRH administration. With the availability of sensitive and specific LH assays, GnRH stimulation testing is used rarely except to evaluate gonadotrope function in patients who have undergone pituitary surgery or have a space-occupying lesion in the hypothalamic-pituitary region.LC-MS/MS involves extraction of serum by organic solvents, separation of testosterone from other steroids by high-performance liquid chromatography and mass spectrometry, and quantitation of unique testosterone fragments by mass spectrometry.

This slowing in progression of CKD is strongly associated with the proteinuria-lowering effect.Several controlled studies have shown that these drugs are effective in slowing the progression of renal failure in patients with advanced stages of both diabetic and nondiabetic CKD.This inhibition leads to a reduction in both intraglomerular filtration pressure and proteinuria.These include ECFV depletion, uncontrolled hypertension, urinary tract infection, new obstructive uropathy, exposure to nephrotoxic agents (such as nonsteroidal anti-inflammatory drugs [NSAIDs] or radiographic dye), and reactivation or flare of the original disease, such as lupus or vasculitis. There is variation in the rate of decline of GFR among patients with CKD. However, the following interventions should be considered in an effort to stabilize or slow the decline of renal function. Reducing Intraglomerular Hypertension and Proteinuria Increased intraglomerular filtration pressures and glomerular hypertrophy develop as a response to loss of nephron number from different kidney diseases. This response is maladaptive, as it promotes the ongoing decline of kidney function even if the inciting process has been treated or spontaneously resolved. Control of glomerular hypertension is important in slowing the progression of CKD. Moreover, elevated blood pressure increases proteinuria by increasing its flux across the glomerular capillaries. Conversely, the renoprotective effect of antihypertensive medications is gauged through the consequent reduction of proteinuria. Thus, the more effective a given treatment is in lowering protein excretion, the greater the subsequent impact on protection from decline in GFR. This observation is the basis for the treatment guideline establishing 130/80 mmHg as the target blood pressure in proteinuric CKD patients. ACE inhibitors and ARBs inhibit the angiotensin-induced vasoconstriction of the efferent arterioles of the glomerular microcirculation. This inhibition leads to a reduction in both intraglomerular filtration pressure and proteinuria. Several controlled studies have shown that these drugs are effective in slowing the progression of renal failure in patients with advanced stages of both diabetic and nondiabetic CKD. This slowing in progression of CKD is strongly associated with the proteinuria-lowering effect.The combination is associated with a greater reduction in proteinuria compared to either agent alone.Insofar as reduction in proteinuria is a surrogate for improved renal outcome, the combination would appear to be advantageous.However, there is a greater incidence of acute kidney injury and adverse cardiac events from such combination therapy.

Among patients without disease, the proportion who have a positive test is the false-positive rate, calculated as 1 – specificity.This measure reflects how well the new test correctly identifies patients without disease.Among patients without disease, the proportion who have a negative test is the specificity, or true-negative rate.In clinical medicine, it is common to reduce the results of a test to a dichotomous outcome, such as positive or negative, normal or abnormal. Although this simplification ignores useful information (such as the degree of abnormality), such simplification does make it easier to demonstrate the fundamental principles of test interpretation discussed below. The accuracy of diagnostic tests is defined in relation to an accepted “gold standard,” which defines the presumably true state of the patient (Table 3-1). Characterizing the diagnostic performance of a new test requires identifying an appropriate population (ideally, patients in whom the new test would be used) and applying both the new and the gold standard tests to all subjects. Biased estimates of test performance may occur from using an inappropriate population or from incompletely applying the gold standard test. By comparing the two tests, the characteristics of the new test are determined. The sensitivity or true-positive rate of the new test is the proportion of patients with disease (defined by the gold standard) who have a positive (new) test. This measure reflects how well the new test identifies patients with disease. The proportion of patients with disease who have a negative test is the false-negative rate and is calculated as 1 – sensitivity. Among patients without disease, the proportion who have a negative test is the specificity, or true-negative rate. This measure reflects how well the new test correctly identifies patients without disease. Among patients without disease, the proportion who have a positive test is the false-positive rate, calculated as 1 – specificity.Calculating sensitivity and specificity requires selection of a threshold value or cut point above which the test is considered “positive.” Making the cut point “stricter” (e.g., raising it) lowers sensitivity but improves specificity, whereas making it “laxer” (e.g., lowering it) raises sensitivity but lowers specificity.

36.Certain qualitative changes in the CSF immunoglobulin pattern, particularly the demonstration of several discrete (oligoclonal) electrophoretic “bands,” each representing a specific immune globulin, and the ratio of IgG to total protein, are of special diagnostic importance in multiple sclerosis, as discussed in Chap.Although derived from plasma, this fraction, for an unknown reason, concentrates in the CSF, and its level is greater in ventricular than in lumbar CSF, perhaps because of its concentration by choroidal cells. Also, tau (also identified as beta2-transferrin) is detected only in the CSF and not in other fluids; its concentration is higher in the ventricular than in the spinal fluid. The concentration of tau protein and in particular the ratio of tau to beta-amyloid, has found use in the diagnosis of Alzheimer disease, as discussed in Chap. 38. At present only a few of these proteins are known to be associated with specific diseases of the nervous system. The most important is IgG, which may exceed 12 percent of the total CSF protein in diseases such as multiple sclerosis, neurosyphilis, subacute sclerosing panencephalitis and other chronic viral meningoencephalitides. The serum IgG is not correspondingly increased, which means that this immune globulin originates in (or perhaps is preferentially transported into) the nervous system. However, an elevation of serum gamma globulin—as occurs in cirrhosis, sarcoidosis, myxedema, and multiple myeloma—will be accompanied by a rise in the CSF globulin. Therefore, in patients with an elevated CSF gamma globulin, it is necessary to determine the electrophoretic pattern of the serum proteins as well. Certain qualitative changes in the CSF immunoglobulin pattern, particularly the demonstration of several discrete (oligoclonal) electrophoretic “bands,” each representing a specific immune globulin, and the ratio of IgG to total protein, are of special diagnostic importance in multiple sclerosis, as discussed in Chap. 36.Certain enzymes that originate in the brain, especially the brain-derived fraction of creatine kinase (CK-BB) but also enolase and neopterin, are found in the CSF after stroke, global ischemic hypoxia, or trauma, and have been used as markers of brain damage in experimental work.

As we discuss in Chapter 15, mitogens interact with cell-surface receptors to trigger multiple intracellular signaling pathways.Mitogens release these brakes on Cdk activity, thereby allowing entry into a new cell cycle.As discussed earlier, multiple mechanisms act during G1 to suppress Cdk activity.In the absence of a mitogenic signal to proliferate, Cdk inhibition in G1 is maintained by the multiple mechanisms discussed earlier, and progression into a new cell cycle is blocked. In some cases, cells partly disassemble their cell-cycle control system and withdraw from the cycle to a specialized nondividing state called G0. Most cells in our body are in G0, but the molecular basis and reversibility of this state vary in different cell types. Most of our neurons and skeletal muscle cells, for example, are in a terminally differentiated G0 state, in which their cell-cycle control system is completely dismantled: the expression of the genes encoding various Cdks and cyclins is permanently turned off, and cell division rarely occurs. Some cell types withdraw from the cell cycle only transiently and retain the ability to reassemble the cell-cycle control system quickly and re-enter the cycle. Most liver cells, for example, are in G0, but they can be stimulated to divide if the liver is damaged. Still other types of cells, including fibroblasts and some lymphocytes, withdraw from and re-enter the cell cycle repeatedly throughout their lifetime. Almost all the variation in cell-cycle length in the adult body occurs during the time the cell spends in G1 or G0. By contrast, the time a cell takes to progress from the beginning of S phase through mitosis is usually brief (typically 12–24 hours in mammals) and relatively constant, regardless of the interval from one division to the next. For the vast majority of animal cells, mitogens control the rate of cell division by acting in the G1 phase of the cell cycle. As discussed earlier, multiple mechanisms act during G1 to suppress Cdk activity. Mitogens release these brakes on Cdk activity, thereby allowing entry into a new cell cycle. As we discuss in Chapter 15, mitogens interact with cell-surface receptors to trigger multiple intracellular signaling pathways.This leads to an increase in the production of transcription regulatory proteins, including Myc.Myc is thought to promote cell-cycle entry by several mechanisms, one of which is to increase the expression of genes encoding G1 cyclins (D cyclins), thereby increasing G1-Cdk (cyclin D–Cdk4) activity.Myc also has a major role in stimulating the transcription of genes that increase cell growth.

Postlapa-rotomy adhesions may decrease the mobility of the small bowel loops, increasing the risk for radiation injury in abdominal or pel-vic irradiation.Another circumstance in which radiation therapy might be appropriate is spinal cord compression due to metastases to the vertebral body that extend posteriorly to the spinal canal.The goal of adjuvant radiation therapy is to decrease local-regional recurrence rates. Adjuvant radiation therapy can be given before surgery, after surgery, or, in selected cases, during surgery. Preoperative radiation therapy has several advantages. It may minimize seeding of the tumor during surgery and it allows for smaller treatment fields because the operative bed has not been contaminated with tumor cells. Also, radiation therapy for inoperable tumors may achieve adequate reduction to make them operable. The disadvantages of preoperative therapy are an increased risk of postoperative wound healing problems and the difficulty in planning subsequent radiation therapy in patients who have positive surgical margins. If radiation therapy is given postoperatively, it is usually given 3 to 4 weeks after surgery to allow for wound healing. The advantage of postoperative radia-tion therapy is that the surgical specimen can be evaluated histo-logically and radiation therapy can be reserved for patients who are most likely to benefit from it. Further, the radiation therapy can be modified on the basis of margin status. The disadvantages of postoperative radiation therapy are that the volume of nor-mal tissue requiring irradiation may be larger owing to surgical contamination of the tissue planes and that the tumor may be less sensitive to radiation owing to poor oxygenation. Postlapa-rotomy adhesions may decrease the mobility of the small bowel loops, increasing the risk for radiation injury in abdominal or pel-vic irradiation.In brachytherapy, unlike in external beam therapy, the radiation source is in contact with the tissue being irradiated.The radiation source may be cesium, gold, iridium, or radium.Brachytherapy is administered via temporary or per-manent delivery implants such as needles, seeds, or catheters.

Survival of the transfused platelets is usually short.Primary immune thrombocytopenia is also known as idio-pathic thrombocytopenic purpura (ITP).Platelet transfusions are not usually needed unless cen-tral nervous system bleeding or active bleeding from other sites occurs.Both gamma globulin and anti-D immunoglobulin are rapid in onset.With more severe bleeding, platelet transfusion is required.ACQUIRED HEMOSTATIC DEFECTSPlatelet AbnormalitiesAcquired congenital abnormalities of platelets are much more common than acquired defects and may be quantitative or quali-tative, although some patients have both types of defects. Quan-titative defects may be a result of failure of production, shortened survival, or sequestration. Failure of production is generally a result of bone marrow disorders such as leukemia, myelodys-plastic syndrome, severe vitamin B12 or folate deficiency, che-motherapeutic drugs, radiation, acute ethanol intoxication, or viral infection. If a quantitative abnormality exists and treatment is indicated either due to symptoms or the need for an invasive procedure, platelet transfusion is utilized. The etiologies of both qualitative and quantitative defects are reviewed in Table 4-1.Quantitative Defects. Shortened platelet survival is seen in immune thrombocytopenia, disseminated intravascular coagu-lation, or disorders characterized by platelet thrombi such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Immune thrombocytopenia may be idiopathic or associated with other autoimmune disorders or low-grade B-cell malignancies, and it may also be secondary to viral infections (including HIV) or drugs. Secondary immune thrombocytopenia often presents with a very low platelet count, petechiae and pur-pura, and epistaxis. Large platelets are seen on peripheral smear. Initial treatment consists of corticosteroids, intravenous gamma globulin, or anti-D immunoglobulin in patients who are Rh posi-tive. Both gamma globulin and anti-D immunoglobulin are rapid in onset. Platelet transfusions are not usually needed unless cen-tral nervous system bleeding or active bleeding from other sites occurs. Survival of the transfused platelets is usually short.Primary immune thrombocytopenia is also known as idio-pathic thrombocytopenic purpura (ITP).In contrast, ITP in adults is gradual in onset, chronic in nature, and has no identifiable cause.Because the circulating platelets in ITP are young and functional, bleeding is less for a given platelet count than when there is failure of platelet production.

The detection of chromosomal loci that segregate with a disease by linkage can be used to identify the gene responsible for the disease (positional cloning) and to predict the odds of disease gene transmission in genetic counseling.Thus, genes that are farther apart are more likely to undergo a recombination event than genes that are very close together.Genome scans have identified numerous genes and loci that may be associated with susceptibility to development of diabetes mellitus in certain populations. Efforts to identify susceptibility genes require very large sample sizes, and positive results may depend on ethnicity, ascertainment criteria, and statistical analysis. Association studies analyzing the potential influence of (biologically functional) SNPs and SNP haplotypes on a particular phenotype are providing new insights into the genes involved in the pathogenesis of these common disorders. Large variants ([micro]deletions, duplications, and inversions) present in the human population also contribute to the pathogenesis of complex disorders, but their contributions remain poorly understood. Linkage and Association Studies There are two primary strategies for mapping genes that cause or increase susceptibility to human disease: (1) classic linkage can be performed based on a known genetic model or, when the model is unknown, by studying pairs of affected relatives; or (2) disease genes can be mapped using allelic association studies (Table 82-6). Genetic linkaGe Genetic linkage refers to the fact that genes are physically connected, or linked, to one another along the chromosomes. Two fundamental principles are essential for understanding the concept of linkage: (1) when two genes are close together on a chromosome, they are usually transmitted together, unless a recombination event separates them (Figs. 82-6); and (2) the odds of a crossover, or recombination event, between two linked genes is proportional to the distance that separates them. Thus, genes that are farther apart are more likely to undergo a recombination event than genes that are very close together. The detection of chromosomal loci that segregate with a disease by linkage can be used to identify the gene responsible for the disease (positional cloning) and to predict the odds of disease gene transmission in genetic counseling.On average, 1 out of every 1000 bp varies from one person to the next.Although this degree of variation seems low (99.9% identical), it means that >3 million sequence differences exist between any two unrelated individuals and the probability that the sequence at such loci will differ on the two homologous chromosomes is high (often >70–90%).

Fig.21.28Aneurysmalbonecystwithblood-filledcysticspacesurroundedbyafibrouswallcontainingproliferatingfibroblasts,reactivewovenbone,andosteoclast-typegiantcells.Most small NOFs undergo spontaneous resolution within several years.Hemosiderin is commonly present.21.30 ).Increased NF-κB activity may upregulate matrix metalloproteases, leading to cystic resorption of bone. MORPHOLOGYAneurysmalbonecystconsistsofmultipleblood-filledcysticspacesseparatedbythin,tan-whiteseptae( Fig.21.28).Theseptae arecomposedofplumpuniformfibroblasts,multinucleatedosteoclast-likegiantcells,andreactivewovenbone,buttheyarenotcoveredbyendothelium. The treatment of ABC is surgical. Curettage is effective with low risk of recurrence. Nonossifying fibroma (NOF) is a benign, likely reactive, mesenchymal proliferation that may be present in http://ebooksmedicine.net Fig.21.27(A)Coronalcomputedaxialtomographyscanshowingeccentricaneurysmalbonecystoftibia.Thesofttissuecomponentisdelineatedbyathinrimofreactivesubperiostealbone.(B)Axialmagneticresonanceimagedemonstratingcharacteristicfluid-fluidlevels(arrow). as many as 50% of children and young adults aged 2–25 years. It is synonymous with fibrous cortical defect or metaphyseal fibrous defect if localized to the cortex or medulla, respectively. The vast majority arises eccentrically in the metaphysis of the distal femur and proximal tibia. Plain radiographs show a sharply demarcated oval radiolucency with the long axis parallel to the cortex ( Fig. 21.29 ). The findings are sufficiently specific on plain radiography that biopsy is rarely necessary. NOFs form gray to yellow-brown cellular lesions containing fibroblasts and macrophages. The cytologically bland fibroblasts are frequently arranged in a storiform (pinwheel) pattern, and the macrophages may take the form of clustered cells with foamy cytoplasm or multinucleated giant cells ( Fig. 21.30 ). Hemosiderin is commonly present. Most small NOFs undergo spontaneous resolution within several years. Fig.21.28Aneurysmalbonecystwithblood-filledcysticspacesurroundedbyafibrouswallcontainingproliferatingfibroblasts,reactivewovenbone,andosteoclast-typegiantcells.The lesions arise during skeletal development, and they appear in several distinctive but sometimes overlapping clinical patterns: Monostotic: involvement of a single bone Polyostotic: involvement of multiple bones Fig.21.29Nonossifyingfibromaofthedistaltibiametaphysisproducinganeccentriclobulatedradiolucencysurroundedbyascleroticmargin.

NCDs are frequently managed by clinicians in multiple disciplines.Typically, the differ- clearer at the level of major NCD than at the level of mild NCD, but sometimes characteristic symptoms and associated features are present at the mild level as well.For substance/medication-induced mild neurocognitive disorder, code based on type of substance; see “Substance/Medication-Induced Major or Mild Neurocog- nitive Disorder." For unspecified mild neurocognitive disorder, code 799.59 (R41.9). Specify: Without behavioral disturbance: If the cognitive disturbance is not accompanied by any clinically significant behavioral disturbance. With behavioral disturbance (specify disturbance): If the cognitive disturbance is ac- companied by a clinically significant behavioral disturbance (e.g., psychotic symptoms, mood disturbance, agitation, apathy, or other behavioral symptoms). Major and mild neurocognitive disorders (NCDs) are primarily subtyped according to the known or presumed etiological/ pathological entity or entities underlying the cognitive de- cline. These subtypes are distinguished on the basis of a combination of time course, charac- teristic domains affected, and associated symptoms. For certain etiological subtypes, the diagnosis depends substantially on the presence of a potentially causative entity, such as Par- kinson’s or Huntington’s disease, or a traumatic brain injury or stroke in the appropriate time period. For other etiological subtypes (generally the neurodegenerative diseases like Alzhei- mer’s disease, frontotemporal lobar degeneration, and Lewy body disease), the diagnosis is based primarily on the cognitive, behavioral, and functional symptoms. Typically, the differ- clearer at the level of major NCD than at the level of mild NCD, but sometimes characteristic symptoms and associated features are present at the mild level as well. NCDs are frequently managed by clinicians in multiple disciplines.The subtype criteria here have been harmonized with those expert criteria.Evidence for distinct behavioral features in NCDs has been recognized, particularly in the areas of psychotic symptoms and depression.Psychotic features are common in many NCDs, particularly at the mild-to-moderate stage of major NCDs due to Alzheimer’s dis- ease, Lewy body disease, and frontotemporal lobar degeneration.

32); and the Vogt-Koyanagi-Harada syndrome, in which recurrent meningitis is associated with iridocyclitis and depigmentation of the hair and skin (poliosis and vitiligo).Viral meningitis (which is far more common than bacterial meningitis), subarachnoid hemorrhage, chemical meningitis (following lumbar puncture, spinal anesthesia, myelography, or rupture of a intracranial lesion containing irritative material, e.g., craniopharyngioma or dermoid), and tuberculous, leptospiral, sarcoid, and fungal meningoencephalitis, and allergic-immune reactions, for example, due to certain medications, enter into the differential diagnosis as well, as discussed in later sections. Overwhelming sepsis itself, or the multiorgan failure that it engenders, may cause an encephalopathy but if there is meningitis, it is imperative, in deciding on the choice of antibiotics, to identify it early. The same can be said for the confused alcoholic patient. Too often, the symptoms are ascribed to alcohol intoxication or withdrawal, or to hepatic encephalopathy, until examination of the CSF reveals meningitis. Although this approach undoubtedly results in many negative spinal fluid examinations, it is preferable to the consequence of overlooking bacterial meningitis. A number of nonbacterial meningitides must be considered in the differential diagnosis when the meningitis recurs repeatedly and all cultures are negative. Included in this group are Epstein-Barr virus (EBV) infections; Behçet disease, which is characterized by recurrent oropharyngeal mucosal ulceration, uveitis, orchitis, and meningitis; Mollaret meningitis, which consists of recurrent episodes of fever and headache in addition to signs of meningeal irritation (in many cases caused by herpes simplex, as discussed in Chap. 32); and the Vogt-Koyanagi-Harada syndrome, in which recurrent meningitis is associated with iridocyclitis and depigmentation of the hair and skin (poliosis and vitiligo).32).These recurrent syndromes rarely present in the fulminant manner of acute bacterial meningitis but sometimes they do, and the CSF formulas can be similar, including a reduction in glucose concentration.Rarely, a fulminant case of cerebral angiitis or intravascular lymphoma will present with headache, fever, and confusion in conjunction with a meningeal inflammatory reaction.

These agents produce less reflex tachycardia when lowering blood pressure than do nonselective α antagonists such as phentolamine.Mechanism & Sites of Action Prazosin, terazosin, and doxazosin produce most of their antihypertensive effects by selectively blocking α1 receptors in arterioles and venules.The hemodynamic effects of nebivolol therefore differ from those of pure β blockers in that peripheral vascular resistance is acutely lowered (by nebivolol) as opposed to increased acutely (by the older agents). Nebivolol is extensively metabolized and has active metabolites. The half-life is 10–12 hours, but the drug can be given once daily. Dosing is generally started at 5 mg/d, with dose escalation as high as 40 mg/d, if necessary. The efficacy of nebivolol is similar to that of other antihypertensive agents, but several studies report fewer adverse effects. Esmolol is a β1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. It has a short half-life (9–10 minutes) and is administered by intravenous infusion. Esmolol is generally administered as a loading dose (0.5–1 mg/kg), followed by a constant infusion. The infusion is typically started at 50–150 mcg/kg/min, and the dose increased every 5 minutes, up to 300 mcg/kg/min, as needed to achieve the desired therapeutic effect. Esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure, in which case a drug with a short duration of action that can be discontinued quickly is advantageous. Mechanism & Sites of Action Prazosin, terazosin, and doxazosin produce most of their antihypertensive effects by selectively blocking α1 receptors in arterioles and venules. These agents produce less reflex tachycardia when lowering blood pressure than do nonselective α antagonists such as phentolamine.Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels.As expected, blood pressure is reduced more in the upright than in the supine position.Retention of salt and water occurs when these drugs are administered without a diuretic.The drugs are more effective when used in combination with other agents, such as a β blocker and a diuretic, than when used alone.

Downbeat nystagmus has also been observed in patients with lithium intoxication or with profound magnesium depletion (Saul and Selhorst).It has also been seen with Wernicke disease and may be an initial sign of either paraneoplastic brainstem encephalitis or cerebellar degeneration with opsoclonus.Cold water induces a slow tonic deviation of the eyes toward the irrigated ear and a compensatory nystagmus in the opposite direction in a conscious, awake patient; warm water does the reverse. Thus the acronym taught to generations of medical students: COWS, or “cold opposite, warm same,” to refer to the direction of the fast phase of the induced nystagmus. The slow tonic component reflects impulses originating in the semicircular canals, and the fast component is a corrective movement. Comatose patients with an intact VOR will demonstrate the slow phase gaze deviation without the fast phase nystagmus to which this mnemonic refers. Chapter 14 discusses the production of nystagmus by labyrinthine stimulation and other features of vestibular nystagmus. Brainstem lesions often cause a coarse, unidirectional, gaze-evoked nystagmus, which may be horizontal or vertical, meaning that the nystagmus is exaggerated when the eyes sustain an eccentric position of gaze. Vertical nystagmus, for example, is brought out usually on upward gaze, less often downward. Unlike the vestibular nystagmus discussed above, the central type usually also changes direction depending on the direction of gaze. Vertigo is less common or less intense than with labyrinthine nystagmus, but signs of disease of other nuclear structures and tracts in the brainstem are frequent. Downbeat nystagmus, which is always of central origin, is characteristic of lesions in the medullary–cervical region such as syringobulbia, Chiari malformation, basilar invagination, and demyelinating plaques. It has also been seen with Wernicke disease and may be an initial sign of either paraneoplastic brainstem encephalitis or cerebellar degeneration with opsoclonus. Downbeat nystagmus has also been observed in patients with lithium intoxication or with profound magnesium depletion (Saul and Selhorst).Cases associated with antibodies against glutamic acid decarboxylase (GAD), a substance that has a documented relationship to the stiff man syndrome, have been reported by Antonini and colleagues and by other groups.Whether this antibody explains the idiopathic cases of downbeat nystagmus is not known.

The size of induration that indicates a test is interpreted as follows: ≥ 5 mm: HIV or risk factors, close TB contacts, CXR evidence of TB.BCG vaccination typically renders a patient PPD but should not preclude prophylaxis as recommended for unvaccinated individuals.The diameter of induration is measured at 48–72 hours.PPD is injected intradermally on the volar surface of the forearm.Treatment is as follows: Active TB: Directly observed multidrug therapy with a four-drug regimen (INH, pyrazinamide, rifampin, ethambutol) × 2 months, followed by four months with INH and rifampin. Administer vitamin B6 (pyridoxine) with INH to prevent peripheral neuritis. Latent TB: For conversion of PPD without signs/symptoms of active disease, initiate therapy with INH × 9 months. Alternative regimens include INH × 6 months or rifampin × 4 months. Viral causes are more common (90% in adults), but it is important to identify streptococcal pharyngitis (group A β-hemolytic Streptococcus pyogenes). Etiologies are as follows: Bacterial: Group A streptococci (GAS), Neisseria gonorrhoeae, Corynebacterium diphtheriae, M. pneumoniae. Viral: Rhinovirus, coronavirus, adenovirus, HSV, EBV, CMV, inf uenza virus, coxsackievirus, acute HIV infection. Typical of streptococcal pharyngitis: Fever, sore throat, pharyngeal erythema, tonsillar exudate, cervical lymphadenopathy, soft palate petechiae, headache, vomiting, scarlatiniform rash (indicates scarlet fever). Atypical of streptococcal pharyngitis: Coryza, hoarseness, rhinorrhea, cough, conjunctivitis, anterior stomatitis, ulcerative lesions, GI symptoms. Rifampin turns body fl uids orange. Ethambutol can cause optic neuritis. INH causes peripheral neuritis and hepatitis. PPD is injected intradermally on the volar surface of the forearm. The diameter of induration is measured at 48–72 hours. BCG vaccination typically renders a patient PPD but should not preclude prophylaxis as recommended for unvaccinated individuals. The size of induration that indicates a test is interpreted as follows: ≥ 5 mm: HIV or risk factors, close TB contacts, CXR evidence of TB.≥ 15 mm: Everyone else, including those with no known risk factors.A reaction with controls implies anergy from immunosuppression, old age, or malnutrition and thus does not rule out TB.FIGURE 2.8-4.PPD interpretation.

Timely referral to a nephrologist for advanced planning and creation of a dialysis access, education about ESRD treatment options, and management of the complications of advanced chronic kidney disease (CKD), including hypertension, anemia, acidosis, and secondary hyperparathyroidism, are advisable.335 for estimating equations).Approximately 30% of patients have ESRD that has been attributed to hypertension, although it is unclear whether in these cases hypertension is the cause or a consequence of vascular disease or other unknown causes of kidney failure. Other prevalent causes of ESRD include glomerulonephritis, polycystic kidney disease, and obstructive uropathy. Globally, mortality rates for patients with ESRD are lowest in Europe and Japan but very high in the developing world because of the limited availability of dialysis. In the United States, the mortality rate of patients on dialysis has decreased slightly but remains extremely high, with a 5-year survival rate of approximately 35–40%. Deaths are due mainly to cardiovascular diseases and infections (approximately 40 and 10% of deaths, respectively). Older age, male sex, nonblack race, diabetes mellitus, malnutrition, and underlying heart disease are important predictors of death. Commonly accepted criteria for initiating patients on maintenance dialysis include the presence of uremic symptoms, the presence of hyperkalemia unresponsive to conservative measures, persistent extracellular volume expansion despite diuretic therapy, acidosis refractory to medical therapy, a bleeding diathesis, and a creatinine clearance or estimated glomerular filtration rate (GFR) below 10 mL/min per 1.73 m2 (see Chap. 335 for estimating equations). Timely referral to a nephrologist for advanced planning and creation of a dialysis access, education about ESRD treatment options, and management of the complications of advanced chronic kidney disease (CKD), including hypertension, anemia, acidosis, and secondary hyperparathyroidism, are advisable.Furthermore, there is no benefit to initiating dialysis preemptively at a GFR of 10–14 mL/min per 1.73 m2 compared to initiating dialysis for symptoms of uremia.In ESRD, treatment options include hemodialysis (in center or at home); peritoneal dialysis, as either continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD); or transplantation (Chap.337).

With few exceptions, the patients have been males and severe chronic alcoholics.The disease affects persons in middle and late adult life.We believe the cortical lesions are best explained as secondary to the callosal degeneration.Microscopically, corresponding to the gross lesions, one observes clearly demarcated zones of demyelination, with variable involvement of the axis cylinders and an abundance of fatty macrophages with gliosis at the margins. Inflammatory changes are absent. Infrequently, lesions of a similar nature are found in the central portions of the anterior and posterior commissures and the brachia pontis. These zones of myelin destruction are surrounded by a rim of intact white matter. The predilection of this disease process for commissural fiber systems has been stressed, but it is certainly not confined to these fibers. Symmetrically placed lesions have been observed in the columns of Goll, superior cerebellar peduncles, and cerebral hemispheres, involving the centrum semiovale and extending, in some cases, into the adjacent convolutional white matter. As a rule, the internal capsule and corona radiata, subcortical arcuate fibers, and cerebellum are spared. In several cases, the lesions of deficiency amblyopia (see earlier) have been added; in others, the lesions of Wernicke disease. Many of the reported cases, as first pointed out by Jequier and Wildi, have involved cortical lesions of a special type: The neurons in the third layer of the frontal and temporal lobe cortices had disappeared and were replaced by a fibrous gliosis. Morel, who first described this cortical laminar sclerosis, did not observe its association with Marchiafava-Bignami disease. However, when Jequier and Adams reviewed his original cases (unpublished), all had Marchiafava-Bignami disease. In a subsequent report by Delay and colleagues comprising 14 cases of cortical laminar sclerosis, the cortical lesion was also consistently associated with a corpus callosum lesion. We believe the cortical lesions are best explained as secondary to the callosal degeneration. The disease affects persons in middle and late adult life. With few exceptions, the patients have been males and severe chronic alcoholics.Many patients have presented in a state of terminal stupor or coma, precluding a detailed neurologic assessment.In others, the clinical picture was dominated by the manifestations of chronic inebriation and alcohol withdrawal, namely tremor, seizures, hallucinosis, and delirium tremens.

This selective permeability discriminates among protein molecules according to size (the larger, the less permeable), charge (the more cationic, the more permeable), and shape.Normally, the glomerular filtration system is highly permeable to water and small solutes and almost completely impermeable to molecules of the size and molecular charge of albumin (a 70,000-kDa protein).14.1 14.2 Fenestrated endothelial cells, with each fenestra being 70 to 100 nm in diameter. The glomerular basement membrane (GBM), which has a thick, electron-dense central layer called the lamina densa, and two thinner, electron-lucent peripheral layers, the lamina rara interna and lamina rara externa. The GBM consists of collagen (mostly type IV), laminin, polyanionic proteoglycans, fibronectin, and several other glycoproteins. Podocytes, cells that possess interdigitating foot processes that are embedded in and adherent to the lamina rara externa. Adjacent foot processes are separated by 20to 30-nm–wide filtration slits, which are bridged by a thin slit diaphragm composed mainly of the protein nephrin (see later). Mesangial cells, which lie in a mesangial matrix between the capillaries that supports the glomerular tuft. These Fig. 14.2 Low-powerelectronmicrographofratglomerulus.B, Basementmembrane;CL, capillarylumen;End, endothelium;Ep, visceralepithelialcells(podocytes)withfootprocesses;Mes, mesangium;US, urinaryspace. cells, of mesenchymal origin, are contractile and are capable of proliferation, of laying down collagen and other matrix components, and of secreting a number of biologically active mediators in response to cytokines and other factors (described later). Normally, the glomerular filtration system is highly permeable to water and small solutes and almost completely impermeable to molecules of the size and molecular charge of albumin (a 70,000-kDa protein). This selective permeability discriminates among protein molecules according to size (the larger, the less permeable), charge (the more cationic, the more permeable), and shape.Nephrin, a transmembrane glycoprotein, is the major component of the slit diaphragms between adjacent foot processes.The intracellular part of nephrin interacts with several cytoskeletal and signaling proteins (see Fig.14.1 ).Nephrin and its associated proteins, including podocin, have a crucial role in maintaining the selective permeability of the glomerular filtration barrier.

In appropriate conditions, as in response to hemorrhage, approximately half of the hepatic blood volume can be rapidly expelled by constriction of the capacitance vessels (see also ).The liver contains approximately 15% of the total blood volume of the body.Neural effects on the capacitance vessels are more important, however.However, changes in hepatic and central venous pressure are transmitted almost quantitatively to the hepatic sinusoid capillaries, and they profoundly affect the transsinusoidal exchange of fluids. Regulation of Flow Blood flow in the portal venous and hepatic arterial systems varies reciprocally. When blood flow is curtailed in one system, flow increases in the other but does not fully compensate for the decreased flow in the first system. The portal venous system is not autoregulated. As portal Pv and flow are raised, resistance either remains constant or decreases. The hepatic arterial system is autoregulated, however, and adenosine may be involved in this adjustment of blood flow. The liver tends to maintain constant O2 consumption because O2 extraction from hepatic blood is very efficient. As the rate of O2 delivery to the liver varies, the liver compensates by an appropriate change in the fraction of O2 extracted from blood. Such extraction is facilitated by the distance between the presinusoidal vessels at the acinar center and the postsinusoidal vessels at the periphery of the acinus (see Fig. 17.43 ). The substantial distance between these types of vessels prevents countercurrent exchange of O2, in contrast to the countercurrent exchange that occurs in an intestinal villus. The sympathetic nerves constrict the presinusoidal resistance vessels in the portal venous and hepatic arterial systems. Neural effects on the capacitance vessels are more important, however. The liver contains approximately 15% of the total blood volume of the body. In appropriate conditions, as in response to hemorrhage, approximately half of the hepatic blood volume can be rapidly expelled by constriction of the capacitance vessels (see also ).Whencentralvenouspressureiselevated,asincongestiveheartfailure,largevolumesofplasmawaterdiffusefromtheliverintotheperitonealcavity;thisaccumulationoffluidintheabdomenisknownasascites.

Therefore, the key component of the overlapping technique is preservation of the scarred ends of the ruptured EAS for suture placement.Sutures should be less likely to tear through or pull out of connective tissue than muscle.The use of suppositories or enemas in the morning or at night in conjunction with the gastrocolic reflex may provide further relief of daytime symptoms. The goal is to leave the rectum empty between evacuations. Enema use, typically once or twice daily, should be titrated to the patient’s baseline colonic activity. Regular toileting in elderly patients in nursing homes can improve fecal incontinence caused by overflow incontinence from fecal impaction. The use of cone-tip colostomy-irrigation catheters is reserved for patients in whom other therapeutic modalities have failed. These catheters avoid the risk of rectal perforation and provide a dam to prevent efflux of the irrigating solutions (108). Surgical Treatment In general, surgical treatment should be employed after conservative measures have failed. Although there may be exceptions to this principle, most surgeons follow this recommendation because of the poor long-term outcomes and high complication rates with surgery for fecal incontinence. Overlapping sphincteroplasty is the procedure of choice for fecal incontinence caused by a disrupted anal sphincter. Most authorities believe that an overlapping technique is superior to an end-to-end repair, although there are few direct comparisons in the literature. The rationale for the overlapping technique is that a more secure repair can be accomplished by placing sutures through the scarred connective tissue rather than the sphincter muscle. Sutures should be less likely to tear through or pull out of connective tissue than muscle. Therefore, the key component of the overlapping technique is preservation of the scarred ends of the ruptured EAS for suture placement.This is accomplished through an inverted semilunar perineal incision or a transverse incision near the posterior vaginal fourchette with inferiolateral extension.The latter incision facilitates repair in patients with damage to the rectovaginal septum attachment to the perineal body.

They may present as constitutional disorders with gene abnormalities located on several chromosomes (polygenic, or “complex genetics”) or may arise from single nucleotide polymorphisms or copy number variations.Multifactorial genetic diseases may also be familial.In contrast to autosomal recessive mutations, the abnormality has more often been one of a basic protein than an enzyme deficiency.Other characteristics of mutational diseases are penetrance, a measure of the proportion of individuals with a given genotype who will show the phenotype, and expressivity, referring to the severity of disease in an affected individual. Variable degrees of penetrance and expressivity are characteristic features of dominant patterns of inheritance but not of recessive ones. There is also a general tendency for dominantly inherited disease to first appear long after birth. Autosomal recessive forms of inherited metabolic diseases, in contrast to dominant ones, occur only in the homozygous state (both alleles are abnormal). They are usually characterized by an onset soon after birth. The basic abnormality in the recessively inherited diseases discussed in this chapter is more often an enzyme deficiency than an abnormality of some other protein. In disorders of X-linked genes, in which the mutant gene affects mainly one sex, the female will suffer the same fate as the male if one X chromosome has been inactivated, as happens in most cells during embryonic development (the Lyon phenomenon). However, even if the abnormal X chromosome is not widely expressed, the female carrier may still exhibit minor abnormalities. In the latter case, sex-linked inheritance becomes difficult to distinguish from dominant inheritance. Also, sex linkage is deceptive when a disease is lethal to one sex. In contrast to autosomal recessive mutations, the abnormality has more often been one of a basic protein than an enzyme deficiency. Multifactorial genetic diseases may also be familial. They may present as constitutional disorders with gene abnormalities located on several chromosomes (polygenic, or “complex genetics”) or may arise from single nucleotide polymorphisms or copy number variations.The occurrence of many disorders that display high degrees of familial incidence, such as schizophrenia and Gilles de la Tourette syndrome, but do not strictly conform to classic genetic principles has been attributed to this type of complex genetics.

A low plasma β-hydroxybutyrate concentration (≤2.7 mmol/L) and an increment in plasma glucose level of >25 mg/dL (>1.4 mmol/L) after IV administration of glucagon (1.0 mg) indicate increased insulin (or IGF) actions.Endogenous Hyperinsulinism Hypoglycemia due to endogenous hyperinsulinism can be caused by (1) a primary β-cell disorder—typically a β-cell tumor (insulinoma), sometimes multiple insulinomas, or a functional β-cell disorder with β-cell hypertrophy or hyperplasia; (2) an antibody to insulin or to the insulin receptor; (3) a β-cell secretagogue such as a sulfonylurea; or perhaps (4) ectopic insulin secretion, among other very rare mechanisms. None of these causes is common. The fundamental pathophysiologic feature of endogenous hyperinsulinism caused by a primary β-cell disorder or an insulin secretagogue is the failure of insulin secretion to fall to very low levels during hypoglycemia. This feature is assessed by measurement of plasma insulin, C-peptide (the connecting peptide that is cleaved from proinsulin to produce insulin), proinsulin, and glucose concentrations during hypoglycemia. Insulin, C-peptide, and proinsulin levels need not be high relative to normal, euglycemic values; rather, they are inappropriately high in the setting of a low plasma glucose concentration. Critical diagnostic findings are a plasma insulin concentration ≥3 μU/mL (≥18 pmol/L), a plasma C-peptide concentration ≥0.6 ng/mL (≥0.2 nmol/L), and a plasma proinsulin concentration ≥5.0 pmol/L when the plasma glucose concentration is <55 mg/dL (<3.0 mmol/L) with symptoms of hypoglycemia. A low plasma β-hydroxybutyrate concentration (≤2.7 mmol/L) and an increment in plasma glucose level of >25 mg/dL (>1.4 mmol/L) after IV administration of glucagon (1.0 mg) indicate increased insulin (or IGF) actions.This is straightforward if the patient is hypoglycemic when seen.Since endogenous hyperinsulinemic disorders usually, but not invariably, cause fasting hypoglycemia, a diagnostic episode may develop after a relatively short outpatient fast.Serial sampling during an inpatient diagnostic fast of up to 72 h or after a mixed meal is more problematic.

6.1).For example, in loose connective tissue, many cell types are present (Fig.The functions of the various connective tissues are reflected in the types of cells and fibers present within the tissue and the composition of the ground substance in the ECM.Different types of connective tissue are responsible for a variety of functions.Similar examples of epithelioid tissue are seen in the adrenal and the parathyroid and pituitary glands, all of which are endocrine glands. GENERAL STRUCTURE AND FUNCTION OF CONNECTIVE TISSUE / 158 EMBRYONIC CONNECTIVE TISSUE / 159 CONNECTIVE TISSUE PROPER / 160 CONNECTIVE TISSUE FIBERS / 161 Collagen Fibers and Fibrils / 161 Biosynthesis and Degradation of Collagen Fibers / 164 Reticular Fibers / 171 Elastic Fibers / 171 EXTRACELLULAR MATRIX / 173 CONNECTIVE TISSUE CELLS / 178 Fibroblasts and Myofibroblasts / 178 Macrophages / 181 Mast Cells / 182 Basophils / 187 Adipocytes / 187 Adult Stem Cells and Pericytes / 187 Lymphocytes, Plasma Cells, and Other Cells of the Immune System / 189 Folder 6.1 Clinical Correlation: Collagenopathies / 170 Folder 6.2 Clinical Correlation: Sun Exposure and Molecular Changes in Photoaged Skin / 173 Folder 6.3 Clinical Correlation: Role of Myofibroblasts in Wound Repair / 183 Folder 6.4 Functional Considerations: The Mononuclear Phagocytotic System / 185 Folder 6.5 Clinical Correlation: The Role of Mast Cells and Basophils in Allergic Reactions / 188 Connective tissue comprises a diverse group of cells within a tissue-specific extracellular matrix. In general, connective tissue consists of cells and an extracellular matrix (ECM). ECM includes structural (fibers) and specialized proteins that constitute the ground substance. Connective tissue forms a vast and continuous compartment throughout the body, bounded by the basal laminae of the various epithelia and by the basal or external laminae of muscle cells and nerve-supporting cells. Different types of connective tissue are responsible for a variety of functions. The functions of the various connective tissues are reflected in the types of cells and fibers present within the tissue and the composition of the ground substance in the ECM. For example, in loose connective tissue, many cell types are present (Fig. 6.1).Fibroblasts also produce and maintain the ground substance.Other cell types, such as lymphocytes, plasma cells, macrophages, and eosinophils, are associated with the body’s defense system; they function within the ECM of the tissue.In contrast, bone tissue, another form of connective tissue, contains only a single cell type, the osteocyte.

These conditions immune system–associated disease.conditions are characterized by a selective deficiency in T and B The impaired homeostasis of differentiating T cells thus causes this lymphocytes with autosomal recessive inheritance.An ADA deficiency results in the accumulation of ado and tal and ear anomalies) syndrome (CHD7 deficiency) is a less frequent dAdo metabolites that induce premature cell death of lymphocyte pro-cause of impaired thymus development. Lastly, the very rare “nude” genitors.TheconditionresultsintheabsenceofBandNKlymphocytes defectischaracterizedbytheabsenceofbothhairandthethymus. as well as T cells. The clinical expression of complete ADA deficiency Omenn Syndrome Omenn syndrome consists of a subset of T cell defi typically occurs very early in life. Since ADA is a ubiquitous enzyme, ciencies that present with a unique phenotype, including early-onset its deficiency can also cause bone dysplasia with abnormal costochonerythrodermia, alopecia, hepatosplenomegaly, and failure to thrive. dral junctions and metaphyses (found in 50% of cases) and neurologic These patients usually display T cell lymphocytosis, eosinophilia, and defects. The very rare purine nucleoside phosphorylase (PNP) defilow B cell counts. It has been found that the T cells of these patients ciency causes a profound although incomplete T cell deficiency that is exhibit a low TCR heterogeneity. This peculiar syndrome is the con-often associated with severe neurologic impairments. sequence of hypomorphic mutations in genes usually associated with Defective rearrangements of t anD b cell receptors A series of SCID SCID, i.e., RAG-1, RAG-2, or (less frequently) Artemis or IL-7Rα. conditions are characterized by a selective deficiency in T and B The impaired homeostasis of differentiating T cells thus causes this lymphocytes with autosomal recessive inheritance. These conditions immune system–associated disease.HSCT provides a curative approach.Functional T Cell Defects (Fig.374-2) AsubsetofTcellPIDswithautosomal inheritance is characterized by partially preserved T cell differentiation but defective activation resulting in abnormal effector function.

Environmental.Children with attention-deficit/hyperactivity disorder or conduct disorder, and adults with depressive, bipolar, anxiety, personality, psychotic, or other substance use disorders, are at higher risk of starting and continuing tobacco use and of to- bacco use disorder.Individuals with externalizing personality traits are more likely to initiate tobacco use.Temperamental.The prevalence of current nicotine dependence is greater among Native American and Alaska Natives (23%) than among whites (14%) but is less among African Americans (10%), Asian Amer- icans and Pacific Islanders (6%), and Hispanics (6%). The prevalence among current daily smokers is approximately 50%. In many developing nations, the prevalence of smoking is much greater in males than in females, but this is not the case in developed nations. However, there often is a lag in the demographic transition such that smoking increases in females at a later time. The majority of US. adolescents experiment with tobacco use, and by age 18 years, about 20% smoke at least monthly. Most of these individuals become daily tobacco users. Initi- ation of smoking after age 21 years is rare. In general, some of the tobacco use disorder cri- teria symptoms occur soon after beginning tobacco use, and many individuals’ pattern of use meets current tobacco use disorder criteria by late adolescence. More than 80% of in- dividuals who use tobacco attempt to quit at some time, but 60% relapse within 1 week and less than 5% remain abstinent for life. However, most individuals who use tobacco make multiple attempts such that one-half of tobacco users eventually abstain. Individuals who use tobacco who do quit usually do not do so until after age 30 years. Although non- daily smoking in the United States was previously rare, it has become more prevalent in the last decade, especially among younger individuals who use tobacco. Temperamental. Individuals with externalizing personality traits are more likely to initiate tobacco use. Children with attention-deficit/hyperactivity disorder or conduct disorder, and adults with depressive, bipolar, anxiety, personality, psychotic, or other substance use disorders, are at higher risk of starting and continuing tobacco use and of to- bacco use disorder. Environmental.Genetic and physiological.Genetic factors contribute to the onset of tobacco use, the continuation of tobacco use, and the development of tobacco use disorder, with a degree of heritability equivalent to that observed with other substance use disorders (i.e., about 50%).Some of this risk is specific to tobacco, and some is common with the vulnerability to developing any substance use disorder.

Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-γ.Different stimuli activate monocytes/macrophages to develop into functionally distinct populations.3.19 Classical and alternative macrophage activation.The half-life of blood monocytes is about 1 day, whereas the life span of tissue macrophages is several months or years. Thus, macrophages often become the dominant cell population in inflammatory reactions within 48 hours of onset. The macrophages that reside in tissues in the steady state (in the absence of tissue injury or inflammation), such as microglia, Kupffer cells, and alveolar macrophages, arise from the yolk sac or fetal liver very early in embryogenesis, populate the tissues, stay for long periods, and are replenished mainly by the proliferation of resident cells. There are two major pathways of macrophage activation, called classical andalternative ( Fig. 3.19 ). Which of these two pathways is taken by a given macrophage depends on the nature of the activating signals. • Classical macrophage activation may be induced by microbial products such as endotoxin, which engage TLRs and other sensors, and by T cell–derived signals, Activated macrophages in inflammation Macrophages in skin, intestinal tract Resident tissue macrophages Yolk (Kupffer cells, alveolar macrophages, sac microglia, etc.) Progenitor in yolk sac, fetal liver Fig. 3.18 Maturation of mononuclear phagocytes. (A) During inflammatory reactions, the majority of tissue macrophages are derived from hematopoietic precursors. Some long-lived resident tissue macrophages are derived from embryonic precursors that populate the tissues early in development. (B) The morphology of a monocyte and activated macrophage. TLR-ligands, ROS, NO, IL-10, lysosomal TGF-° enzymes IL-1, TNF, IL-12, IL-6, chemokines Anti-inflammatory effects, wound repair, fibrosis Fig. 3.19 Classical and alternative macrophage activation. Different stimuli activate monocytes/macrophages to develop into functionally distinct populations. Classically activated macrophages are induced by microbial products and cytokines, particularly IFN-γ.Alternatively activated macrophages are induced by other cytokines and are important in tissue repair and the resolution of inflammation.importantly the cytokine IFN-γ, in immune responses.

Varices can rupture, leading to massive upper gastrointestinal bleeding.Among the consequences of portal hypertension are ascites, hepatic encephalopathy, and the development of portosystemic collaterals—especially gastric or esophageal varices.Bile salt-induced diarrhea is uncommon. Unlike its predecessor, chenodeoxycholate, ursodiol has not been associated with hepatotoxicity. Obeticholic acid is a synthetic derivative of the naturally occurring bile acid chenodeoxycholate. Like ursodiol, it is a nontoxic bile acid and is believed to reduce liver injury by decreasing hepatic concentrations of more toxic endogenous bile acids. It also is a ligand for the nuclear farnesoid X receptor, which modulates hepatic inflammation, fibrosis, gluconeogenesis, lipid synthesis, and insulin sensitivity. Obeticholic acid was recently approved for the treatment of PBC at a dose of 5–10 mg/d orally in combination with ursodiol in patients who have had an inadequate response to ursodiol monotherapy. In a randomized, double-blind, placebo-controlled, 12-month trial, almost 50% of patients treated with combination therapy had a clinical response compared with 10% treated with ursodiol alone. Obeticholic acid causes severe pruritus in up to 25% of patients (especially at the 10 mg dose), leading to discontinuation in up to 10% of patients. Portal hypertension most commonly occurs as a consequence of chronic liver disease. Portal hypertension is caused by increased blood flow within the portal venous system and increased resistance to portal flow within the liver. Splanchnic blood flow is increased in patients with cirrhosis due to low arteriolar resistance that is mediated by increased circulating vasodilators and decreased vascular sensitivity to vasoconstrictors. Intrahepatic vascular resistance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins as well as reversible vasoconstriction of hepatic sinusoids and venules. Among the consequences of portal hypertension are ascites, hepatic encephalopathy, and the development of portosystemic collaterals—especially gastric or esophageal varices. Varices can rupture, leading to massive upper gastrointestinal bleeding.These may be used in the short term for the treatment of active variceal hemorrhage or long term to reduce the risk of hemorrhage.The pharmacology of octreotide is discussed above under Antidiarrheal Agents.

Each suture is passed first through the ingui-nal ligament, then the transversalis fascia, and then the EOA.37-18).The last suture is taken so as to sufficiently Brunicardi_Ch37_p1599-p1624.indd 161129/01/19 2:03 PM 1612SPECIFIC CONSIDERATIONSPART IInarrow the abdominal ring without constricting the spermatic cord (Fig.This incision is essential to reduce tension on the repair; however, it may result in increased postoperative pain and higher risk of ventral abdominal herniation. Using either interrupted or continuous suture, the superior transversalis flap is then fastened to Cooper’s ligament, and the repair is contin-ued laterally along Cooper’s ligament to occlude the femoral ring. Lateral to the femoral ring, a transition stitch is placed, affixing the transversalis fascia to the inguinal ligament. The transversalis is then sutured to the inguinal ligament laterally to the internal ring.Desarda Repair The Desarda hernia repair was recently described in 2001, and it consists of a mesh-free repair utilizing a strip of external oblique aponeurosis.An oblique skin incision is made, and dissection is carried down to the external oblique fascia. The integrity of the fascia is preserved as much as possible. The cremasteric muscle is then incised, and the spermatic cord along with the cremasteric muscle is separated from the inguinal floor. Excision of the sac is done in all cases except in small direct hernias, where it is inverted.The medial leaf of the external oblique aponeurosis is sutured to the inguinal ligament from the pubic tubercle to the abdominal ring using 1–0 Ethilon or Prolene interrupted sutures. The first two sutures are taken at the junction of the anterior rec-tus sheath and EOA. The last suture is taken so as to sufficiently Brunicardi_Ch37_p1599-p1624.indd 161129/01/19 2:03 PM 1612SPECIFIC CONSIDERATIONSPART IInarrow the abdominal ring without constricting the spermatic cord (Fig. 37-18). Each suture is passed first through the ingui-nal ligament, then the transversalis fascia, and then the EOA.A splitting incision is then taken in the EOA, partially separating a strip.This splitting incision is extended medially up to the pubic symphysis and laterally 1 to 2 cm beyond the reconstructed abdominal ring.The free border of the strip of the EOA is now sutured to the internal oblique or conjoined tendon lying close to it with 1–0 Ethilon or Prolene interrupted sutures.

Protamine administration should be performed judi-ciously and terminated if any side effects occur.In addition to hemorrhage, heparin also has other, unique, complications.Patients with prior exposure to protamine-containing insulin (NPH) and patients with allergy to fish may have an increased risk of hypersensitivity, although no direct relationship has been established.This should correspond with plasma heparin anti-Xa activity levels of 0.3 to 0.7 IU/mL.Initial anticoagulation with UFH may also be administered SC, although this route is less commonly used. Adjusted-dose therapeutic SC UFH is initiated with 17,500 units, followed by 250 units/kg twice daily, and dosing is adjusted to an aPTT goal range similar to that for IV UFH. Fixed-dose unmonitored SC UFH is started with a bolus of 333 units/kg, followed by 250 units/kg twice daily.30Hemorrhage is the primary complication of UFH therapy. The rate of major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion of >2 units of packed red blood cells) is approximately 5% in hospitalized patients undergoing UFH therapy (1% in medical patients and 8% in surgical patients).30 For patients with UFH-related bleeding complications, cessation of UFH is required, and anticoagulation may be reversed with protamine sulfate. Protamine sulfate binds to UFH and forms an inactive salt compound. Each milligram of protamine neutral-izes 90 to 115 units of heparin, and the dosage should not exceed 50 mg IV over any 10-minute period. Side effects of protamine sulfate include hypotension, pulmonary edema, and anaphylaxis. Patients with prior exposure to protamine-containing insulin (NPH) and patients with allergy to fish may have an increased risk of hypersensitivity, although no direct relationship has been established. Protamine administration should be performed judi-ciously and terminated if any side effects occur.In addition to hemorrhage, heparin also has other, unique, complications.Therefore, platelet counts should be monitored periodically in patients receiving continuous heparin therapy.HIT is diagnosed based on previous exposure to heparin, platelet count less than 100,000, and/or platelet count decline of 50% following exposure.

Blood and other tissues are the most suitable samples for analysis.Primers for the spacer region between the genes encoding the 16S and 23S ribosomal RNAs (rrs-rrl), various outer-membrane protein–encoding genes, the insertion sequence IS711, and the protein BCSP31 are sensitive and specific.Concentration and lysis of buffy coat cells before culture may increase the isolation rate. Cultures in modern nonradiometric or similar signaling systems (e.g., Bactec) usually become positive within 7–10 days but should be maintained for at least 3 weeks before the results are declared negative. All cultures should be handled under containment conditions appropriate for dangerous pathogens. Brucella species may be misidentified as Agrobacterium, Ochrobactrum, or Psychrobacter (Moraxella) phenylpyruvicus by the gallery identification strips commonly used in the diagnostic laboratory. In recent years, matrix-assisted laser desorption ionization time-of-flight spectrometry (MALDI-TOF MS) has emerged as a powerful tool in bacterial identification. The relative homogeneity of classical Brucella species makes identification beyond the genus level by routine approaches challenging, although further improvements may facilitate discrimination at the species level. The place of this technique in routine diagnostic practice will depend on such refinements. Meanwhile, the authors are aware of cases in which blood culture isolates have been identified incorrectly using MALDI-TOF MS. The peripheral blood–based polymerase chain reaction has enormous potential to detect bacteremia, to predict relapse, and to exclude “chronic brucellosis.” This method is probably more sensitive and is certainly quicker than blood culture, and it does not carry the attendant biohazard risk posed by culture. Nucleic acid amplification techniques are now quite widely used, although no single standardized procedure has been adopted. Primers for the spacer region between the genes encoding the 16S and 23S ribosomal RNAs (rrs-rrl), various outer-membrane protein–encoding genes, the insertion sequence IS711, and the protein BCSP31 are sensitive and specific. Blood and other tissues are the most suitable samples for analysis.In acute infection, IgM antibodies appear early and are followed by IgG and IgA.All these antibodies are active in agglutination tests, whether performed by tube, plate, or microagglutination methods.The majority of patients have detectable agglutinins at this stage.As the disease progresses, IgM levels decline, and the avidity and subclass distribution of IgG and IgA change.

The same weak noncovalent bonds that enable a protein chain to fold into a specific conformation also allow proteins to bind to each other to produce larger structures in the cell.There are certainly enormous challenges ahead for the next generation of cell biologists, with no shortage of fascinating mysteries to solve.Based on this number alone, we would appear to be no more complex than the tiny mustard weed, Arabidopsis, and only about 1.3-fold more complex than a nematode worm. The genome sequences also reveal that vertebrates have inherited nearly all of their protein domains from invertebrates—with only 7% of identified human domains being vertebrate-specific. Each of our proteins is on average more complicated, however (Figure 3–17). Domain shuffling during vertebrate evolution has given rise to many novel Figure 3–17 Domain structure of a group of evolutionarily related proteins that are thought to have a similar function. In general, there is a tendency for the proteins in more complex organisms, such as humans, to contain additional domains—as is the case for the DNA-binding protein compared here. combinations of protein domains, with the result that there are nearly twice as many combinations of domains found in human proteins as in a worm or a fly. Thus, for example, the trypsinlike serine protease domain is linked to at least 18 other types of protein domains in human proteins, whereas it is found covalently joined to only 5 different domains in the worm. This extra variety in our proteins greatly increases the range of protein–protein interactions possible (see Figure 3–79), but how it contributes to making us human is not known. The complexity of living organisms is staggering, and it is quite sobering to note that we currently lack even the tiniest hint of what the function might be for more than 10,000 of the proteins that have thus far been identified through examining the human genome. There are certainly enormous challenges ahead for the next generation of cell biologists, with no shortage of fascinating mysteries to solve. The same weak noncovalent bonds that enable a protein chain to fold into a specific conformation also allow proteins to bind to each other to produce larger structures in the cell.A protein can contain binding sites for various large and small molecules.If a binding site recognizes the surface of a second protein, the tight binding of two folded polypeptide chains at this site creates a larger protein molecule with a precisely defined geometry.Each polypeptide chain in such a protein is called a protein subunit.

Preganglionic sympathetic fibers destined for the head are carried out of the spinal cord in spinal nerve T1.This means that sympathetic fibers found anywhere in the body ultimately emerge from the spinal cord as components of these spinal nerves.3.13).All preganglionic nerve fibers of the sympathetic system are carried out of the spinal cord in spinal nerves T1 to L2 (Fig.3.12C).Arteries to the wall arise from two sources: the thoracic aorta, which is in the posterior mediastinum, and a pair of vessels, the internal thoracic arteries, which run along the deep aspect of the anterior thoracic wall on either side of the sternum. the wall, mainly along the inferior margin of each rib (Fig. 3.12A). Running with these vessels are intercostal nerves (the anterior rami of thoracic spinal nerves), which innervate the wall, related parietal pleura, and associated skin. The position of these nerves and vessels relative to the ribs must be considered when passing objects, such as chest tubes, through the thoracic wall. Dermatomes of the thorax generally reflect the segmental organization of the thoracic spinal nerves (Fig. 3.12B). The exception occurs, anteriorly and superiorly, with the first thoracic dermatome, which is located mostly in the upper limb, and not on the trunk. The anterosuperior region of the trunk receives branches from the anterior ramus of C4 via supraclavicular branches of the cervical plexus. The highest thoracic dermatome on the anterior chest wall is T2, which also extends into the upper limb. In the midline, skin over the xiphoid process is innervated by T6. Dermatomes of T7 to T12 follow the contour of the ribs onto the anterior abdominal wall (Fig. 3.12C). All preganglionic nerve fibers of the sympathetic system are carried out of the spinal cord in spinal nerves T1 to L2 (Fig. 3.13). This means that sympathetic fibers found anywhere in the body ultimately emerge from the spinal cord as components of these spinal nerves. Preganglionic sympathetic fibers destined for the head are carried out of the spinal cord in spinal nerve T1.3.14).A rib’s posterior attachment is superior to its anterior attachment.Therefore, when a rib is elevated, it moves the anterior thoracic wall forward relative to the posterior wall, which is fixed.In addition, the middle part of each rib is inferior to its two ends, so that when this region of the rib is elevated, it expands the thoracic wall laterally.

The use of salicylates as a tonic against thrombosis in PV patients is not only potentially harmful if the red cell mass is not controlled by phlebotomy, but is also an unproven remedy.A “normal” hematocrit or hemoglobin level in a PV patient with massive splenomegaly should be considered indicative of an elevated red cell mass until proven otherwise. PV is generally an indolent disorder, the clinical course of which is measured in decades, and its management should reflect its tempo. Thrombosis due to erythrocytosis is the most significant complication and often the presenting manifestation, and maintenance of the hemoglobin level at ≤140 g/L (14 g/dL; hematocrit <45%) in men and ≤120 g/L (12 g/dL; hematocrit <42%) in women is mandatory to avoid thrombotic complications. Phlebotomy serves initially to reduce hyperviscosity by bringing the red cell mass into the normal range while further expanding the plasma volume. Periodic phlebotomies thereafter serve to maintain the red cell mass within the normal range and to induce a state of iron deficiency that prevents an accelerated reexpansion of the red cell mass. In most PV patients, once an iron-deficient state is achieved, phlebotomy is usually only required at 3-month intervals. Neither phlebotomy nor iron deficiency increases the platelet count relative to the effect of the disease itself, and thrombocytosis is not correlated with thrombosis in PV, in contrast to the strong correlation between erythrocytosis and thrombosis in this disease. The use of salicylates as a tonic against thrombosis in PV patients is not only potentially harmful if the red cell mass is not controlled by phlebotomy, but is also an unproven remedy.Asymptomatic hyperuricemia (<10 mg/dL) requires no therapy, but allopurinol should be administered to avoid further elevation of the uric acid when chemotherapy is used to reduce splenomegaly or leukocytosis or to treat pruritus.

33, p. 620).Aspiration of thick meconium may cause severe pulmonary dysfunction and neonatal death (Chap.The viscosity probably signiies the lack of liquid and thus oligohydramnios.Thick meconium in the amnionic luid is particularly worrisome.Amniotomy also aids identification of thick meconium.These usually provide more precise data concerning fetal heart rate and uterine contractions.It is our view that large, randomized trials should be performed before otherwise uncomplicated 41-week gestations are routinely considered pathologically prolonged. In women in whom a certain gestational age is known, labor is induced at the completion of 42 weeks. Almost 90 percent of such women are induced successfully or enter labor within 2 days of induction. For those who do not deliver with the first induction, a second induction is performed within 3 days. lmost all women are delivered using this management plan, but in the unusual few who are not delivered, management decisions involve a third-or even more-induction versus cesarean delivery. Women classiied as having uncertain postterm pregnancies are managed with weekly nonstress fetal testing and assessment ofamnionic luid volume. Women with an AFI ;5 cm or with reports ofdiminished fetal movement undergo labor induction. Labor is a particularly dangerous time for the postterm fetus. Therefore, women whose pregnancies are known or suspected to be postterm ideally come to the hospital as soon as they suspect labor. While being evaluated for active labor, we monitored electronically for variations consistent with fetal compromise. During labor, the decision to perform amniotomy is problematic. Further reduction in luid volume following amniotomy can enhance the possibility of cord compression. Conversely, after membrane rupture, a scalp electrode and an intrauterine pressure catheter can be placed. These usually provide more precise data concerning fetal heart rate and uterine contractions. Amniotomy also aids identification of thick meconium. Thick meconium in the amnionic luid is particularly worrisome. The viscosity probably signiies the lack of liquid and thus oligohydramnios. Aspiration of thick meconium may cause severe pulmonary dysfunction and neonatal death (Chap. 33, p. 620).As discussed in Chapter 24 (p. 475), the benefits of amnioinfusion remain controversial.In a large randomized trial by Fraser and colleagues (2005), amnioinfusion did not reduce the risk of meconium aspiration syndrome or perinatal death.

One potential conflict of interest is that physician-owners might lower their thresholds for intervention, exposing the patient and healthcare system to the harm and cost associated with unneces-sary treatment.They can also ensure that the facility has specialized equipment for their particular specialty and can design the facility to meet their specific needs.26 Furthermore, physicians who perform surgeries in their own ASCs receive a share of the ASC’s facility payment in addition to payment for their professional services. This could present a conflict of interest in terms of referring patients and lowering the threshold for surgery, as discussed further in the next section.Potential for Conflict of InterestApproximately 90% of ASCs nationwide have at least some physician ownership stake. Many are joint ventures between hospitals and physicians.27 Increasing investment in these cen-ters may be explained in a number of ways, including an attempt by providers to assert greater control over their professional lives, such as by having greater authority in scheduling sur-geries and in purchasing equipment. Alternatively, this invest-ment trend may be explained by declining reimbursements for physician services and rising practice costs. These economic pressures have intensified providers’ interest in nontraditional revenue sources, such as ASC investment, as a means of gen-erating income.Ownership entitles physicians to collect a share of the facil-ity’s profits from referrals, in addition to their professional fees. One potential conflict of interest is that physician-owners might lower their thresholds for intervention, exposing the patient and healthcare system to the harm and cost associated with unneces-sary treatment.There is some evidence that physi-cians with an ownership stake may refer well-insured patients to their own facilities while referring Medicare and Medicaid patients to hospital outpatient clinics.30-32Regardless of the reason for increasing investment in and utilization of ASCs, it is important to note that ASC owner-ship creates a potential conflict of interest for physicians.

grossappearances;theexceptionisfibrinoidnecrosis,whichis detectedonlybyhistologicexamination.Although the terms that describe these patterns do not reflect underlying mechanisms, such terms are commonly used and their implications are understood by pathologists and clinicians.There are several morphologically distinct patterns of tissue necrosis that may provide etiologic clues.Nuclear changes.Nuclearchangesassumeoneofthreepatterns,allresultingfromabreakdownofDNAandchromatin.Pyknosis ischaracterizedbynuclearshrinkageandincreasedbasophilia;theDNAcondensesintoadarkshrunkenmass.Thepyknoticnucleuscanundergofragmentation;thischangeiscalledkaryorrhexis.Ultimately,thenucleusmayundergokaryolysis,inwhichthebasophiliafadesbecauseofdigestionofDNAbydeoxyribonuclease(DNase)activity.In1to2days,thenucleusinadeadcellmaycompletelydisappear. Fates of necrotic cells.Necroticcellsmaypersistforsometimeormaybedigestedbyenzymesanddisappear.Deadcellsmaybereplacedbymyelinfigures,whichareeitherphagocytosedbyothercellsorfurtherdegradedintofattyacids.Thesefattyacidsbindcalciumsalts,whichmayresultinthedeadcellsultimatelybecomingcalcified. http://ebooksmedicine.net Fig. 2.6 Coagulativenecrosis. (A)Awedge-shapedkidneyinfarct(yellow) withpreservationoftheoutlines. (B)Microscopicviewoftheedgeoftheinfarct,withnormalkidney(N) andnecroticcellsintheinfarct(I).Thenecroticcellsshowpreservedoutlineswithlossofnuclei,andaninflammatoryinfiltrateis present(difficulttodiscernatthismagnification). Morphologic Patterns of Tissue Necrosis In severe pathologic conditions, large areas of a tissue or even entire orgrans may undergo necrosis. This may happen in association with marked ischemia, infections, and certain inflammatory reactions. There are several morphologically distinct patterns of tissue necrosis that may provide etiologic clues. Although the terms that describe these patterns do not reflect underlying mechanisms, such terms are commonly used and their implications are understood by pathologists and clinicians. grossappearances;theexceptionisfibrinoidnecrosis,whichis detectedonlybyhistologicexamination.

The understanding of the role of copy number variation in human disease is still in its infancy.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.Interestingly, the 16p deletion is also associated with epilepsy.As the complex architecture of the human genome becomes better defined, many disorders that result from alterations in copy numbers of genes (“gene-dosage” effects) resulting from unequal crossing-over are also likely to be identified. As much as 5–10% of the human genome consists of nonhomologous duplications and deletions, and these appear to occur with a much higher mutational rate than is the case for single base pair mutations. The first copy-number disorders to be recognized were Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication in the gene encoding the myelin protein PMP22, and the reciprocal deletion of the gene causing hereditary liability to pressure palsies (Chap. 459). 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.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.

Such a diagnosis requires demonstration of the absence of cerebral function (no response to any external stimulus) and brainstem functions (e.g., unreactive pupils, lack of ocular movement in response to head turning or ice-water irrigation of ear canals, positive apnea test [no drive to breathe]).Vasospasm can be detected by either transcranial Doppler assessment or cerebral angiography; it is typically treated with the calcium channel blocker nimodipine, aggressive IV fluid administration, and therapy aimed at increasing blood pressure, typically with vasoactive drugs such as phenylephrine. The IV fluids and vasoactive drugs (hypertensive hypervolemic therapy) are used to overcome the cerebral vasospasm. Early surgical clipping or endovascular coiling of aneurysms is advocated to prevent complications related to re-bleeding. Hydrocephalus, typically heralded by a decreased level of consciousness, may require ventriculostomy drainage. (See also Chap. 445) Recurrent or relentless seizure activity is a medical emergency. Cessation of seizure activity is required to prevent irreversible neurologic injury. Lorazepam is the most effective benzodiazepine for treating status epilepticus and is the treatment of choice for controlling seizures acutely. Phenytoin or fosphenytoin should be given concomitantly since lorazepam has a short half-life. Other drugs, such as gabapentin, carbamazepine, and phenobarbital, should be reserved for patients with contraindications to phenytoin (e.g., allergy or pregnancy) or ongoing seizures despite phenytoin. (See also Chap. 330) Although deaths of critically ill patients usually are attributable to irreversible cessation of circulatory and respiratory function, a diagnosis of death also may be established by irreversible cessation of all functions of the entire brain, including the brainstem, even if circulatory and respiratory functions remain intact on artificial life support. Such a diagnosis requires demonstration of the absence of cerebral function (no response to any external stimulus) and brainstem functions (e.g., unreactive pupils, lack of ocular movement in response to head turning or ice-water irrigation of ear canals, positive apnea test [no drive to breathe]).If there is uncertainty about the cause of coma, studies of cerebral blood flow and electroencephalography should be performed.(See also Chap.10) Withholding or withdrawal of care occurs commonly in the ICU setting.

However, with scar maturation and collagen remodeling, the content of proteoglycans gradually diminishes.Maturation and RemodelingThe maturation and remodeling of the scar begins during the fibroplastic phase and is characterized by a reorganization of previously synthesized collagen.As scar collagen is deposited, the proteoglycans are incorporated into the collagen scaffolding.C. The proliferative phase, with associated angiogenesis and collagen synthesis.Table 9-1Macrophage activities during wound healingACTIVITYMEDIATORSPhagocytosisReactive oxygen speciesNitric oxideDebridementCollagenase, elastaseCell recruitment and activationGrowth factors: PDGF, TGF-β, EGF, IGFCytokines: TNF-α, IL-1, IL-6FibronectinMatrix synthesisGrowth factors: TGF-β, EGF, PDGFCytokines: TNF-α, IL-1, IFN-γEnzymes: arginase, collagenaseProstaglandinsNitric oxideAngiogenesisGrowth factors: FGF, VEGFCytokines: TNF-αNitric oxideEGF = epithelial growth factor; FGF = fibroblast growth factor; IGF = insulin-like growth factor; IFN-γ = interferon-γ; IL = interleukin; PDGF = platelet-derived growth factor; TGF-β = transforming growth factor-β; TNF-α = tumor necrosis factor-α; VEGF = vascular endothelial growth factor.Brunicardi_Ch09_p0271-p0304.indd 27401/03/19 4:50 PM 275WOUND HEALINGCHAPTER 9composition of proteoglycans varies from about 10 units in the case of heparin sulfate to as much as 2000 units in the case of hyaluronic acid.The major glycosaminoglycans present in wounds are dermatan and chondroitin sulfate. Fibroblasts synthesize these compounds, increasing their concentration greatly during the first 3 weeks of healing. The interaction between collagen and proteoglycans is being actively studied. It is thought that the assembly of collagen subunits into fibrils and fibers is depen-dent upon the lattice provided by the sulfated proteoglycans. Furthermore, it appears that the extent of sulfation is critical in determining the configuration of the collagen fibrils. As scar collagen is deposited, the proteoglycans are incorporated into the collagen scaffolding. However, with scar maturation and collagen remodeling, the content of proteoglycans gradually diminishes.Maturation and RemodelingThe maturation and remodeling of the scar begins during the fibroplastic phase and is characterized by a reorganization of previously synthesized collagen.There is a net shift toward collagen synthesis and eventually the reestablishment of extracellular matrix com-posed of a relatively acellular collagen-rich scar.Wound strength and mechanical integrity in the fresh wound are determined by both the quantity and quality of the newly deposited collagen.

Just medial to the anterior scalene muscle, it courses inferiorly and drains into the union of the internal jugular and subclavian veins.As it exits the thoracic inlet, it passes to the left, just behind the carotid sheath and anterior to the inferior thyroid and vertebral bodies.If the mediastinal pleura are disrupted on both sides, bilateral chylothoraces may occur. Left-sided chylothoraces may develop after a left-sided neck dissection, especially in the region of the confluence of the subclavian and internal jugular veins. Chylothorax may also follow nonsurgical trauma, including penetrating or blunt inju-ries to the chest or neck area, central line placements, and other surgical misadventures. It may be seen in association with a variety of benign and malignant diseases that generally involve the lymphatic system of the mediastinum or neck.Pathophysiology. Most commonly, the thoracic duct origi-nates in the abdomen from the cisterna chyli, which is located in the midline, near the level of the second lumbar vertebra. From this origin, the thoracic duct ascends into the chest through the aortic hiatus at the level of T10 to T12, and courses just to the right of the aorta (see Fig. 19-52). As the thoracic duct courses cephalad above the diaphragm, it most commonly remains in the right chest, lying just behind the esophagus, between the aorta and azygos vein. The duct continues superiorly, lying just to the right of the vertebral column. Then, at the fourth thoracic ver-tebra, it crosses behind the aorta and the aortic arch into the left posterior mediastinum and travels superiorly, staying near the esophagus and mediastinal pleura as it exits the thoracic inlet. As it exits the thoracic inlet, it passes to the left, just behind the carotid sheath and anterior to the inferior thyroid and vertebral bodies. Just medial to the anterior scalene muscle, it courses inferiorly and drains into the union of the internal jugular and subclavian veins.Given the high volume of chyle that flows through the thoracic duct, signifi-cant injuries can cause leaks in excess of 2 L per day; if left untreated, protein, lymphocyte, and volume depletion can lead to serious metabolic effects and death.Thoracentesis is usually grossly suggestive, revealing milky, nonpurulent pleural fluid.

2.4).Many of the most dangerous extracellular bacterial pathogens cause disease by releasing protein toxins; these secreted toxins are called exotoxins (see Fig.2.3).Pathogens that live inside macrophage vesicles may become more susceptible to being killed after activation of the macrophage as a result of NK-cell or T-cell actions (see Fig.Infectious diseases differ in their symptoms and outcome depending on where the causal pathogen replicates within the body—the intracellular or the extracellular compartment—and what damage it does to the tissues (Fig. 2.4). Pathogens that live intracellularly frequently cause disease by damaging or killing the cells they infect. Obligate intracellular pathogens, such as viruses, must invade host cells to replicate. Facultative intracellular pathogens, such as mycobacteria, can replicate either intracellularly or outside the cell. Two strategies of innate immunity defend against intracellular pathogens. One is to destroy pathogens before they infect cells. To this end, innate immunity includes soluble defenses such as antimicrobial peptides, as well as phagocytic cells that can engulf and destroy pathogens before they become intracellular. Alternatively, the innate immune system can recognize and kill cells infected by some pathogens. This is the role of the natural killer cells (NK cells), which are instrumental in keeping certain viral infections in check before cytotoxic T cells of the adaptive immune system become functional. Intracellular pathogens can be subdivided further into those that replicate freely in the cell, such as viruses and certain bacteria (for example, Chlamydia, Rickettsia, and Listeria), and those that replicate inside intracellular vesicles, such as mycobacteria. Pathogens that live inside macrophage vesicles may become more susceptible to being killed after activation of the macrophage as a result of NK-cell or T-cell actions (see Fig. 2.3). Many of the most dangerous extracellular bacterial pathogens cause disease by releasing protein toxins; these secreted toxins are called exotoxins (see Fig. 2.4).

The paracrine signaling molecule, Indian hedgehog (Ihh), also plays a critical role in osteoblast development, as evidenced by Ihh-deficient mice that lack osteoblasts in the type of bone formed on a cartilage mold (endochondral ossification).Remarkably, osteocytes also secrete fibroblast growth factor 23 (FGF23), a major regulator of phosphate metabolism (see below). Mineralization of the matrix, both in trabecular bone and in osteones of compact cortical bone (Haversian systems), begins soon after the matrix is secreted (primary mineralization) but is not completed for several weeks or even longer (secondary mineralization). Although this mineralization takes advantage of the high concentrations of calcium and phosphate, already near saturation in serum, mineralization is a carefully regulated process that is dependent on the activity of osteoblast-derived alkaline phosphatase, which probably works by hydrolyzing inhibitors of mineralization. Genetic studies in humans and mice have identified several key genes that control osteoblast development. Runx2 is a transcription factor expressed specifically in chondrocyte (cartilage cells) and osteoblast progenitors as well as in hypertrophic chondrocytes and mature osteoblasts. Runx2 regulates the expression of several important osteoblast proteins, including osterix (another transcription factor needed for osteoblast maturation), osteopontin, bone sialoprotein, type I collagen, osteocalcin, and receptor-activator of NFκB (RANK) ligand. Runx2 expression is regulated in part by bone morphogenic proteins (BMPs). Runx2-deficient mice are devoid of osteoblasts, whereas mice with a deletion of only one allele (Runx2 +/−) exhibit a delay in formation of the clavicles and some cranial bones. The latter abnormalities are similar to those in the human disorder cleidocranial dysplasia, which is also caused by heterozygous inactivating mutations in Runx2. The paracrine signaling molecule, Indian hedgehog (Ihh), also plays a critical role in osteoblast development, as evidenced by Ihh-deficient mice that lack osteoblasts in the type of bone formed on a cartilage mold (endochondral ossification).Numerous other growth-regulatory factors affect osteoblast function, including the three closely related transforming growth factor βs, fibroblast growth factors (FGFs) 2 and 18, platelet-derived growth factor, and insulin-like growth factors (IGFs) I and II.

The lifetimes of mRNA and protein molecules are enormously variable, from a few minutes or hours to days or more, explaining much of the variation we see in the tempo of developmental events.In all these cases, molecular lifetimes, along with gestation delays, play a key part in determining the pace of development.First, it takes time to make an mRNA molecule: the RNA polymerase must travel the length of the gene, the primary RNA transcript must be spliced and otherwise processed, and the resulting mRNA must be exported from the nucleus and delivered to the site where it will be translated. This adds up to what one might call the gestation time of the individual molecule. Second, it takes time for the individual mRNA molecules to accumulate to their fully effective concentration; as explained in Chapter 15, this accumulation time is dictated by the average lifetime of the molecules—the longer they last, the higher their ultimate concentration, and the longer the time taken to attain it. Similar delays occur at the next step, where the mRNA is translated into protein: synthesis of each individual protein molecule involves a gestation delay, and attainment of an effective concentration of protein molecules involves an accumulation delay that depends on the protein’s lifetime. The time for the whole gene switching process is just the sum of the gestation delays and the accumulation delays (basically, the molecular lifetimes) for both the mRNA and the protein molecules. Somewhat counterintuitively, it is the combined length of these delays, rather than the rate of molecular synthesis (the number of molecules synthesized per second), that chiefly determines the switching time. The same additive principle applies to long cascades of gene switching, where gene A activates gene B, and gene B activates gene C, and so on. It also applies in other circumstances, such as in signaling pathways where one protein directly regulates the activation of the next. In all these cases, molecular lifetimes, along with gestation delays, play a key part in determining the pace of development. The lifetimes of mRNA and protein molecules are enormously variable, from a few minutes or hours to days or more, explaining much of the variation we see in the tempo of developmental events.Development involves many other kinds of delay that contribute to timing.Chromatin structure takes time to remodel.Inductive signals take time to diffuse across a field of cells (see Figure 21–9).Cells take time to move and rearrange themselves in space.

Such decision-aids are used most commonly to identify patients with a low clinical probability of ACS who are candidates either for early provocative testing for ischemia or for discharge from the ED.In addition, observation of a change in cardiac troponin concentration between serial samples is useful in discriminating acute causes of myocardial injury from chronic elevation due to underlying structural heart disease, end-stage renal disease, or interfering antibodies. The diagnosis of MI is reserved for acute myocardial injury that is marked by a rising and/or falling pattern—with at least one value exceeding the 99th percentile reference limit—and that is caused by ischemia. Other non-ischemic insults, such as myocarditis, may result in myocardial injury but should not be labeled MI. Other laboratory assessments may include the D-dimer test to aid in exclusion of pulmonary embolism (Chap. 300). Measurement of a B-type natriuretic peptide is useful when considered in conjunction with the clinical history and exam for the diagnosis of heart failure. B-type natriuretic peptides also provide prognostic information regarding patients with ACS and those with pulmonary embolism. Other putative biomarkers of acute myocardial ischemia or ACS, such as myeloperoxidase, have not been adopted in routine use. Multiple clinical algorithms have been developed to aid in decision-making during the evaluation and disposition of patients with acute nontraumatic chest pain. Such decision-aids have been derived on the basis of their capacity to estimate either of two closely related but not identical probabilities: (1) the probability of a final diagnosis of ACS and (2) the probability of major cardiac events during short-term follow-up. Such decision-aids are used most commonly to identify patients with a low clinical probability of ACS who are candidates either for early provocative testing for ischemia or for discharge from the ED.The Acute Cardiac Ischemia Time-Insensitive Predictive Instrument (ACI-TIPI) combines age, sex, chest pain presence, and ST-segment abnormalities to define a probability of ACS.More recently developed decision-aids are shown in Fig.19-3.

The classic picture of malabsorption is rarely seen today in most parts of the United States.Similarly, the development of a pattern of bowel movements suggestive of steatorrhea in a patient with long-standing alcohol abuse and chronic pancreatitis should prompt an assessment of pancreatic exocrine function.The proenzymes pepsinogen and trypsinogen must be activated to pepsin (by pepsin at a pH <5) and to trypsin (by the intestinal brush border enzyme enterokinase and subsequently by trypsin), respectively. Proteins are absorbed by separate transport systems for diand tripeptides and for different types of amino acids—e.g., neutral and dibasic. Alterations in either protein or amino acid digestion and absorption are rarely observed clinically, even in the presence of extensive small-intestinal mucosal inflammation. However, three rare genetic disorders involve protein digestion/absorption: (1) Enterokinase deficiency is due to an absence of the brush border enzyme that converts the proenzyme trypsinogen to trypsin and is associated with diarrhea, growth retardation, and hypoproteinemia. (2) Hartnup’s syndrome, a defect in neutral amino acid transport, is characterized by a pellagra-like rash and neuropsychiatric symptoms. (3) Cystinuria, a defect in dibasic amino acid transport, is associated with renal calculi and chronic pancreatitis. APPROACH TO THE PATIENT: The clues provided by the history, symptoms, and initial preliminary observations will serve to limit extensive, ill-focused, and expensive laboratory and imaging studies. For example, a clinician evaluating a patient who has symptoms suggestive of malabsorption and who has recently undergone extensive small-intestinal resection for mesenteric ischemia should direct the initial assessment almost exclusively to defining whether a short-bowel syndrome might explain the entire clinical picture. Similarly, the development of a pattern of bowel movements suggestive of steatorrhea in a patient with long-standing alcohol abuse and chronic pancreatitis should prompt an assessment of pancreatic exocrine function. The classic picture of malabsorption is rarely seen today in most parts of the United States.Although diarrhea can be caused by changes in fluid and electrolyte movement in either the small or the large intestine, dietary nutrients are absorbed almost exclusively in the small intestine.

Bone marrow myeloid stem cells (CD34+) give rise to monocyte (CD14+, CD68+, CD11c+, CD1a–) and DC (CD14–, CD11c+/–, CD1a+/c) precursors.DCs are antigen-presenting cells, whereas histiocyte/ macrophages are antigen-processing cells.Dendritic cell (DC) and histiocyte/macrophage neoplasms are extremely rare.In contrast, imatinib is ineffective in the treatment of PDGFR-unmutated SM.Diagnosis of SM is based on bone marrow examination that shows clusters of morphologically abnormal, spindle-shaped mast cells that are best evaluated by the use of immunohistochemical stains that are specific to mast cells (tryptase, CD117). In addition, mast cell immunophenotyping reveals aberrant CD25 expression by neoplastic mast cells. Other laboratory findings in SM include increased levels of serum tryptase, histamine and urine histamine metabolites, and prostaglandins. SM is associated with KIT mutations, usually KIT D816V, in the majority of patients. Accordingly, mutation screening for KIT D816V is diagnostically useful. However, the ability to detect KIT D816V depends on assay sensitivity and mast cell content of the test sample. Both indolent and aggressive SM patients might experience mast cell mediator release symptoms, which are usually managed by both H1 and H2 histamine receptor blockers as well as cromolyn sodium. In addition, patients with propensity to vasodilatory shock should wear a medical alert bracelet and carry an Epi-Pen self-injector for self-administration of subcutaneous epinephrine. Urticaria pigmentosa shows variable response to both topical and systemic glucocorticoid therapy. Cytoreductive therapy is not recommended for indolent SM. In aggressive SM, either interferon α or cladribine is considered first-line therapy and benefits the majority of patients. In contrast, imatinib is ineffective in the treatment of PDGFR-unmutated SM. Dendritic cell (DC) and histiocyte/macrophage neoplasms are extremely rare. DCs are antigen-presenting cells, whereas histiocyte/ macrophages are antigen-processing cells. Bone marrow myeloid stem cells (CD34+) give rise to monocyte (CD14+, CD68+, CD11c+, CD1a–) and DC (CD14–, CD11c+/–, CD1a+/c) precursors.DC precursors give rise to Langerhans cell DCs (Birbeck granules, CD1a+, S100+, langerin+) and plasmacytoid DCs (CD68+, CD123+).Follicular DCs (CD21+, CD23+, CD35+) originate from mesenchymal stem cells.Dendritic and histiocytic neoplasms are operationally classified into macrophage/histiocyte-related and DC-related neoplasms.

In these instances, critical care personnel must decide whether and when to perform a tracheostomy.Prolonged Mechanical Ventilation and Tracheostomy From 5% to 13% of patients undergoing MV will go on to require prolonged MV (>21 days).The use of NIV to facilitate weaning in respiratory failure of other etiologies is not currently indicated.The clinical manifestations of shock are also the result, in part, of autonomic neuroendocrine responses to hypoperfusion as well as the break-down in organ function induced by severe cellular dysfunction (Fig. 324-1). When very severe and/or persistent, inadequate oxygen delivery leads to irreversible cell injury, only rapid restoration of oxygen 324 SEC TIon 2 SHoCK And CARdIAC ARREST delivery can reverse the progression of the shock state. The funda- 1744 Daily wean screen (resolving disease, adequate gas exchange, stable hemodynamics, spontaneous breathing ability) Pass Assess for extubation Fail NoYes SBT Pass Fail Continue MV Treat reversible elements Repeat daily screen Extubate Consider tracheostomy secretions, and is alert enough to follow commands. In addition, other factors must be taken into account, such as the possible difficulty of replacing the tube if that maneuver is required. If upper airway difficulty is suspected, an evaluation using a “cuff-leak” test (assessing the presence of air movement around a deflated endotracheal tube cuff) is supported by some internists. Despite all precautions, ~10–15% of extubated patients require reintubation. Several studies suggest that NIV can be used to obviate reintubation, particularly in patients with ventilatory failure secondary to COPD exacerbation; in this setting, earlier extubation with the use of prophylactic NIV has yielded good results. The use of NIV to facilitate weaning in respiratory failure of other etiologies is not currently indicated. Prolonged Mechanical Ventilation and Tracheostomy From 5% to 13% of patients undergoing MV will go on to require prolonged MV (>21 days). In these instances, critical care personnel must decide whether and when to perform a tracheostomy.A tracheostomy is thought to be more comfortable, to require less sedation, and to provide a more secure airway and may also reduce weaning time.However, tracheostomy carries the risk of complications, which occur in 5–40% of these procedures and include bleeding, cardiopulmonary arrest, hypoxia, structural damage, pneumothorax, pneumomediastinum, and wound infection.

2.8 Granulation tissue.(Courtesy of Aliya Fig.2.7 Myocardial scarring.Fig.2.6 Basal layer of skin.Infection (most common cause; S aureus is the most common offender) Fig.Delayed wound healing occurs in 1.B.Granulation tissue fills the defect; myofibroblasts then contract the wound, forming a scar.Secondary intention-Edges are not approximated.2.5 Intestinal crypts. syndrome. Inflammation, Inflammatory Disorders, and Wound Healing E. Permanent tissues lack significant regenerative potential (e.g., myocardium, skeletal muscle, and neurons). III. REPAIR A. Replacement of damaged tissue with fibrous scar B. Occurs when regenerative stem cells are lost (e.g., deep skin cut) or when a tissue lacks regenerative capacity (e.g., healing after a myocardial infarction, Fig. 2.7) C. Granulation tissue formation is the initial phase of repair (Fig. 2.8). 1. Consists of fibroblasts (deposit type III collagen), capillaries (provide nutrients), and myofibroblasts (contract wound) D. Eventually results in scar formation, in which type III collagen is replaced with type I collagen 1. Type III collagen is pliable and present in granulation tissue, embryonic tissue, uterus, and keloids. 2. Type I collagen has high tensile strength and is present in skin, bone, tendons, and most organs. 3. Collagenase removes type III collagen and requires zinc as a cofactor. IV. A. Mediated by paracrine signaling via growth factors (e.g., macrophages secrete growth factors that target fibroblasts) B. Interaction of growth factors with receptors (e.g., epidermal growth factor with growth factor receptor) results in gene expression and cellular growth. C. Examples of mediators include 1. 2. 3. Platelet-derived growth factor-growth factor for endothelium, smooth muscle, and fibroblasts 4. 5. V. A. Cutaneous healing occurs via primary or secondary intention. 1. Primary intention-Wound edges are brought together (e.g., suturing of a surgical incision); leads to minimal scar formation 2. Secondary intention-Edges are not approximated. Granulation tissue fills the defect; myofibroblasts then contract the wound, forming a scar. B. Delayed wound healing occurs in 1. Infection (most common cause; S aureus is the most common offender) Fig. 2.6 Basal layer of skin. Fig. 2.7 Myocardial scarring. (Courtesy of Aliya Fig. 2.8 Granulation tissue.Vitamin C, copper, or zinc deficiency i. Vitamin C is an important cofactor in the hydroxylation of proline and lysine procollagen residues; hydroxylation is necessary for eventual collagen cross-linking.ii.Copper is a cofactor for lysyl oxidase, which cross-links lysine and hydroxylysine to form stable collagen.iii.

Two classes of drugs are used in treatment of intractable and multiple tics; alpha agonists and antipsychosis medications.Isolated or infrequent nonintrusive, motor tics in males beyond adolescence, generally an inherited trait, is often aided by clonazepam but may require some of the more potent medications named above.Reassurance of the parents can be very helpful.There is no consistent association with infection, trauma, or other disease except the putative connection to streptococcal infections discussed further on. Hyperactive children who have been treated with stimulants appear to be at increased risk of developing or exacerbating tics (Price et al) but a causal relationship has not been established beyond doubt (see comments regarding treatment below). MRI has shown no uniform abnormalities; functional imaging has demonstrated numerous but inconsistent abnormalities. Histopathologic changes have not been discerned in the few brains examined by the usual methods. However, Singer and coworkers (1991), who analyzed preand postsynaptic dopamine markers in postmortem striatal tissue, found a significant alteration of dopamine uptake mechanisms; more recently, Wolf and colleagues, have found that differences in D2 dopamine receptor binding in the head of the caudate nucleus reflected differences in the phenotypic severity of Gilles de la Tourette syndrome. These observations, coupled with the facts that L-dopa exacerbates the symptoms of the syndrome and that haloperidol, which blocks dopamine (particularly D2) receptors, is an effective treatment, support a dopaminergic abnormality in the basal ganglia, more specifically in the caudate. In this respect, instances of compulsive behavior in relation to lesions in the head of the caudate nucleus and its projections from orbitofrontal and cingulate cortices may be pertinent. For delimited and benign tics, treatment is generally not necessary. Reassurance of the parents can be very helpful. Isolated or infrequent nonintrusive, motor tics in males beyond adolescence, generally an inherited trait, is often aided by clonazepam but may require some of the more potent medications named above. Two classes of drugs are used in treatment of intractable and multiple tics; alpha agonists and antipsychosis medications.These are not as potent as treatment with neuroleptic drugs, but their side effects are less severe and they are recommended as the first treatment.Guanfacine has the advantage over clonidine of daily dosing and less sedating effect.

As calcium flows into the terminal, the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane.A classic example of this type of action is provided by the β adrenoceptor, which generates cAMP via the activation of adenylyl cyclase (see Chapter 2). Whereas membrane-delimited actions occur within microdomains in the membrane, second messenger-mediated effects can occur over considerable distances. Finally, an important consequence of the involvement of G proteins in receptor signaling is that, in contrast to the brief effect of ionotropic receptors, the effects of metabotropic receptor activation can last tens of seconds to minutes. Metabotropic receptors predominate in the diffuse neuronal systems in the CNS (see below). The communication between neurons in the CNS occurs through chemical synapses in the majority of cases. (A few instances of electrical coupling between neurons have been documented, and such coupling may play a role in synchronizing neuronal discharge. However, it is unlikely that these electrical synapses are an important site of drug action.) The events involved in synaptic transmission can be summarized as follows. An action potential propagating down the axon of the presynaptic neuron enters the synaptic terminal and activates voltage-sensitive calcium channels in the membrane of the terminal (see Figure 6–3). The calcium channels responsible for the release of neurotransmitter are generally resistant to the calcium channel-blocking agents discussed in Chapter 12 (eg, verapamil) but are sensitive to blockade by certain marine toxins and metal ions (see Tables 21–1 and 12–4). As calcium flows into the terminal, the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane.The neurotransmitter binds to its receptor and opens channels (either directly or indirectly as described above) causing a brief change in membrane conductance (permeability to ions) of the postsynaptic cell.The time delay from the arrival of the presynaptic action potential to the onset of the postsynaptic response is approximately 0.5 ms.

When the volume of interstitial fluid exceeds the drainage capacity of the lymphatic vessels, or when the lymphatic vessels become blocked, interstitial fluid accumulates and gives rise to clinical edema.It is increased by any mechanism that enhances the rate of blood capillary filtration; such mechanisms include increased capillary pressure or permeability and decreased plasma oncotic pressure.The lymphatic vessels return all of the proteins filtered back to the blood; these proteins account for approximately one fourth to half of the circulating plasma proteins in the blood. The lymphatic vessels are the only means by which the protein that leaves the vascular compartment can be returned to blood. Net backward diffusion of protein into the capillaries cannot occur against the large protein concentration gradient. If the protein were not removed by the lymph vessels, it would accumulate in interstitial fluid and act as an oncotic force that draws fluid from the blood capillaries and produces edema. In addition to returning fluid and protein to the vascular bed, the lymphatic system filters the lymph at the lymph nodes and removes foreign particles such as bacteria. The CHAPTER 17 Properties of the Vasculature largest lymphatic vessel, the thoracic duct, not only drains the lower extremities but also returns the protein lost through the permeable liver capillaries. Moreover, the thoracic duct carries substances absorbed from the gastrointestinal tract. The principal substance is fat, in the form of chylomicrons. Lymph flow varies considerably. The flow from resting skeletal muscle is almost nil, and it increases during exercise in proportion to the degree of muscular activity. It is increased by any mechanism that enhances the rate of blood capillary filtration; such mechanisms include increased capillary pressure or permeability and decreased plasma oncotic pressure. When the volume of interstitial fluid exceeds the drainage capacity of the lymphatic vessels, or when the lymphatic vessels become blocked, interstitial fluid accumulates and gives rise to clinical edema.These arteries provide the entire blood supply to the myocardium.The right coronary artery supplies mainly the right ventricle and atrium.The left coronary artery, which divides near its origin into the anterior descending and the circumflex branches, supplies mainly the left ventricle and atrium.There is some overlap between the regions supplied by the left and right arteries.

Disease often recurs at the site of anastomosis, and as many as 40% of patients require additional resections within 10 years.Fibrosing strictures, particularly of the terminal ileum, are common and require surgical resection.15.29C ).Granulomasalsomaybefoundinmesentericlymphnodes.Cutaneousgranulomasformnodulesthatarereferredto(misleadingly)asmetastatic Crohn disease.The absence of granulomas does not preclude a diagnosis of Crohn disease. http://ebooksmedicine.net Fig. 15.28 GrosspathologyofCrohndisease.(A)Small-intestinalstricture.(B)Linearmucosalulcersandthickenedintestinalwall.(C)Creepingfat. Fig. 15.29 MicroscopicpathologyofCrohndisease.(A)HaphazardcryptUlcerativecolitisalwaysinvolvestherectumandextendsproxiorganizationresultsfromrepeatedinjuryandregeneration.(B)Noncaseatingmallyinacontinuousfashiontoinvolvepartortheentirecolongranuloma. (C)TransmuralCrohndiseasewithsubmucosalandserosal The clinical manifestations of Crohn disease are extremely variable. In most patients, disease begins with intermittent attacks of relatively mild diarrhea, fever, and abdominal pain. Approximately 20% of patients present acutely with right lower-quadrant pain and fever, which may mimic acute appendicitis or bowel perforation. Patients with colonic involvement may present with bloody diarrhea and abdominal pain, creating a differential diagnosis with some colonic infections. Periods of disease activity typically are interrupted by asymptomatic intervals that last for weeks to many months. Disease reactivation can be associated with a variety of external triggers, including physical or emotional stress, specific dietary items, NSAID use, and cigarette smoking. Iron-deficiency anemia may develop in individuals with colonic disease, while extensive small-bowel disease may result in serum protein loss and hypoalbuminemia, generalized nutrient malabsorption, or malabsorption of vitamin B12 and bile salts. Fibrosing strictures, particularly of the terminal ileum, are common and require surgical resection. Disease often recurs at the site of anastomosis, and as many as 40% of patients require additional resections within 10 years.Perforations and peritoneal abscesses can also occur.Extraintestinal manifestations of Crohn disease include uveitis, migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, and clubbing of the fingertips, any of which may develop before intestinal disease is recognized.

Once macroalbuminuria develops, blood pressure rises slightly and the pathologic changes are likely irreversible.Once macroalbuminuria is present, there is a steady decline in GFR, and ~50% of individuals reach ESRD in 7–10 years.Microalbuminuria is also a risk factor for CVD.In some individuals with type 1 diabetes and microalbuminuria of short duration, the microalbuminuria regresses.During the first 5 years of DM, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to normal. After 5–10 years of type 1 DM, many individuals begin to excrete small amounts of albumin in the urine. The American Diabetes Association (ADA) recently suggested that the terms previously used to refer to increased urinary protein (microalbuminuria as defined as 30–299 mg/d in a 24-h collection or 30–299 μg/mg creatinine in a spot collection or macroalbuminuria as defined as >300 mg/24 h) be replaced by the phrases “persistent albuminuria (30–299 mg/24 h)” and “persistent albuminuria (≥300 mg/24 h)” to better reflect the continuous nature of albumin excretion in the urine as risk factor for nephropathy and cardiovascular disease (CVD). This chapter uses the terms microalbuminuria and macroalbuminuria. Although the appearance of microalbuminuria in type 1 DM is an important risk factor for progression to macroalbuminuria, only ~50% of individuals progress to macroalbuminuria over the next 10 years. In some individuals with type 1 diabetes and microalbuminuria of short duration, the microalbuminuria regresses. Microalbuminuria is also a risk factor for CVD. Once macroalbuminuria is present, there is a steady decline in GFR, and ~50% of individuals reach ESRD in 7–10 years. Once macroalbuminuria develops, blood pressure rises slightly and the pathologic changes are likely irreversible.Finally, it should be noted that albuminuria in type 2 DM may be secondary to factors unrelated to DM, such as hypertension, congestive heart failure (CHF), prostate disease, or infection.As part of comprehensive diabetes care (Chap.418), albuminuria should be detected at an early stage when effective therapies can be instituted.

These symptoms should not be attributed to schizophrenia with- out due consideration of the more common disorders of childhood.Disorganized speech occurs in many disorders with childhood onset (e.g., autism spectrum disorder), as does disorganized behavior (e.g., attention-deficit/ hyperactivity disorder).Impaired cognition is common, and alterations in cognition are present during de- velopment and precede the emergence of psychosis, taking the form of stable cognitive impairments during adulthood. Cognitive impairments may persist when other symptoms are in remission and contribute to the disability of the disease. The predictors of course and outcome are largely unexplained, and course and outcome may not be reliably predicted. The course appears to be favorable in about 20% of those with schizophrenia, and a small number of individuals are reported to recover completely. However, most individuals with schizophrenia still require formal or informal daily living supports, and many remain chronically ill, with exacerbations and remissions of active symptoms, while others have a course of progressive deterioration. Psychotic symptoms tend to diminish over the life course, perhaps in association with normal age-related declines in dopamine activity. Negative symptoms are more closely re- lated to prognosis than are positive symptoms and tend to be the most persistent. Further- more, cognitive deficits associated with the illness may not improve over the course of the illness. The essential features of schizophrenia are the same in childhood, but it is more diffi- cult to make the diagnosis. In children, delusions and hallucinations may be less elaborate than in adults, and visual hallucinations are more common and should be distinguished from normal fantasy play. Disorganized speech occurs in many disorders with childhood onset (e.g., autism spectrum disorder), as does disorganized behavior (e.g., attention-deficit/ hyperactivity disorder). These symptoms should not be attributed to schizophrenia with- out due consideration of the more common disorders of childhood.Children who later receive the diagnosis of schizophrenia are more likely to have experienced nonspecific emotional-behavioral disturbances and psychopathology, intellectual and language alterations, and subtle motor delays.Late-onset cases (i.e., onset after age 40 years) are overrepresented by females, who may have married.

Asherman’s syndrome presents as secondary amenorrhea or hypomenorrhea and results from partial or complete obliteration of the uterine cavity by adhesions that prevent normal growth and shedding of the endometrium.The absence of pubic and axillary hair distinguishes them clinically from patients with müllerian agenesis, as does an elevated testosterone level.This system is maintained by complex negative and positive feedback loops involving the ovarian steroids (estradiol and progesterone) and peptides (inhibin B and inhibin A) and the hypothalamic (gonadotropin-releasing hormone [GnRH]) and pituitary (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) components of this system (Fig. 69-1). Disorders of menstrual function can be thought of in two main categories: disorders of the uterus and outflow tract and disorders of ovulation. Many of the conditions that cause primary amenorrhea are congenital but go unrecognized until the time of normal puberty (e.g., genetic, chromosomal, and anatomic abnormalities). All causes of secondary amenorrhea also can cause primary amenorrhea. Disorders of the uterus or Outflow Tract Abnormalities of the uterus and outflow tract typically present as primary amenorrhea. In patients with normal pubertal development and a blind vagina, the differential diagnosis includes obstruction by a transverse vaginal septum or imperforate hymen; müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome), which has been associated with mutations in the WNT4 gene; and androgen insensitivity syndrome (AIS), which is an X-linked recessive disorder that accounts for ~10% of all cases of primary amenorrhea (Chap. 411). Patients with AIS have a 46,XY karyotype, but because of the lack of androgen receptor responsiveness, those with complete AIS have severe underandrogenization and female external genitalia. The absence of pubic and axillary hair distinguishes them clinically from patients with müllerian agenesis, as does an elevated testosterone level. Asherman’s syndrome presents as secondary amenorrhea or hypomenorrhea and results from partial or complete obliteration of the uterine cavity by adhesions that prevent normal growth and shedding of the endometrium.or secondary amenorrhea.They may occur in association with other features suggestive of hypothalamic or pituitary dysfunction, such as short stature, diabetes insipidus, galactorrhea, and headache.Hypogonadotropic hypogonadism also may be seen after cranial irradiation.In the postpartum period, it may be caused by pituitary necrosis (Sheehan’s syndrome) or lymphocytic hypophysitis.

Analogous "insight” specifiers have been included for body dysmorphic disorder and hoarding disorder.Panic disorder and agoraphobia are unlinked in DSM-S. Thus, the former DSM-IV diagnoses of panic disorder with agoraphobia, panic disorder without agoraphobia, and agoraphobia without history of panic disorder are now replaced by two diagnoses, panic disorder and ag- oraphobia, each with separate criteria. The ”generalized" specifier for social anxiety disor- der has been deleted and replaced with a ”performance only” specifier. Separation anxiety disorder and selective mutism are now classified as anxiety disorders. The wording of the criteria is modified to more adequately represent the expression of separation anxiety symp- toms in adulthood. Also, in contrast to DSM-IV, the diagnostic criteria no longer specify that onset must be before age 18 years, and a duration statement—"typically lasting for 6 months or more”—has been added for adults to minimize overdiagnosis of transient fears. The chapter ”Obsessive-Compulsive and Related Disorders" is new in DSM-S. New disor- ders include hoarding disorder, excoriation (skin-picking) disorder, substance/medica- tion-induced obsessive-compulsive and related disorder, and obsessive-compulsive and related disorder due to another medical condition. The DSM-IV diagnosis of trichotillo- mania is now termed trichotillomania (hair-pulling disorder) and has been moved from a DSM—IV classification of impulse—control disorders not elsewhere classified to obsessive- compulsive and related disorders in DSM-5. The DSM-IV ”with poor insight” specifier for obsessive-compulsive disorder has been refined to allow a distinction between individuals with good or fair insight, poor insight, and "absent insight/delusional” obsessive-compul- sive disorder beliefs (i.e., complete conviction that obsessive-compulsive disorder beliefs are true). Analogous "insight” specifiers have been included for body dysmorphic disorder and hoarding disorder.A ”muscle dysmorphia” specifier for body dysmorphic disorder is added to re- flect a growing literature on the diagnostic validity and clinical utility of making this 812 Highlights of Changes From DSM-IV to DSM-5 distinction in individuals with body dysmorphic disorder.

Intestinal-derived endotoxin initiates a pathogenic process through toll-like receptor 4 and tumor necrosis factor α (TNF-α) that facilitates hepatocyte apoptosis and necrosis.Steatosis from lipogenesis, fatty acid synthesis, and depression of fatty acid oxidation appears secondary to effects on sterol regulatory transcription factor and peroxisome proliferator-activated receptor α (PPAR-α).Gender-dependent differences result from poorly understood effects of estrogen, proportion of body fat, and the gastric metabolism of alcohol. Obesity, a high-fat diet, and the protective effect of coffee have been postulated to play a part in the development of the pathogenic process. Chronic infection with hepatitis C virus (HCV) (Chap. 362) is an important comorbidity in the progression of alcoholic liver disease to cirrhosis in chronic and excessive drinkers. Even moderate alcohol intake of 20–50 g/d increases the risk of cirrhosis and hepatocellular cancer in HCV-infected individuals. Patients with both alcoholic liver injury and HCV infection develop decompensated liver disease at a younger age and have poorer overall survival. Increased liver iron stores and, rarely, porphyria cutanea tarda can occur as a consequence of the overlapping injurious processes secondary to alcohol abuse and HCV infection. In addition, alcohol intake of >50 g/d by HCV-infected patients decreases the efficacy of interferon-based antiviral therapy. The pathogenesis of alcoholic liver injury is unclear. The present conceptual foundation is that alcohol acts as a direct hepatotoxin and that malnutrition does not have a major role. Ingestion of alcohol initiates an inflammatory cascade by its metabolism to acetaldehyde, resulting in a variety of metabolic responses. Steatosis from lipogenesis, fatty acid synthesis, and depression of fatty acid oxidation appears secondary to effects on sterol regulatory transcription factor and peroxisome proliferator-activated receptor α (PPAR-α). Intestinal-derived endotoxin initiates a pathogenic process through toll-like receptor 4 and tumor necrosis factor α (TNF-α) that facilitates hepatocyte apoptosis and necrosis.The production of toxic protein-aldehyde adducts, generation of reducing equivalents, and oxidative stress also contribute to the liver injury.Hepatocyte injury and impaired regeneration following chronic alcohol ingestion are ultimately associated with stellate cell activation and collagen production, which are key events in fibrogenesis.

Resolution depends not only on the optical system but also on the wavelength of the light source and other factors such as specimen thickness, quality of fixation, and staining intensity.Resolving power is the ability of a microscope lens or optical system to produce separate images of closely positioned objects.Table 1.3 compares the resolution of the eye with that of various instruments.For instance, after injection of an animal with tritiated thymidine, cells that have incorporated this nucleotide into their DNA before they divide will have approximately twice as many silver grains overlying their nuclei as will cells that have divided after incorporating the labeled nucleotide. Autoradiography can also be carried out by using thin plastic sections for examination with the EM. Essentially the same procedures are used, but as with all TEM preparation techniques, the processes are much more delicate and difficult; however, they also yield much greater resolution and more precise localization (Fig. 1.8b). A microscope, whether simple (one lens) or compound (multiple lenses), is an instrument that magnifies an image and allows visualization of greater detail than is possible with the unaided eye. The simplest microscope is a magnifying glass or a pair of reading glasses. TABLE Eye Versus Instrument Resolution1.3 Distance Between Resolvable Points Human eye 0.2 mm Bright-field microscope 0.2 m SEM 2.5 nm TEM Theoretical 0.05 nm Tissue section 1.0 nm Atomic force microscopy 50.0 pm The resolving power of the human eye—that is, the distance by which two objects must be separated to be seen as two objects (0.2 mm)—is determined by the spacing of the photoreceptor cells in the retina. The role of a microscope is to magnify an image to a level at which the retina can resolve the information that would otherwise be below its limit of resolution. Table 1.3 compares the resolution of the eye with that of various instruments. Resolving power is the ability of a microscope lens or optical system to produce separate images of closely positioned objects. Resolution depends not only on the optical system but also on the wavelength of the light source and other factors such as specimen thickness, quality of fixation, and staining intensity.This is the theoretical resolution and, as mentioned, depends on all conditions being optimal.The ocular or eyepiece lens magnifies the image produced by the objective lens, but it cannot increase resolution.Various light microscopes are available for general and specialized use in modern biologic research.

The boxes represent distinct functional features of cells in the myeloid (upper box) versus lymphoid (lower box) lineages.(2) Cord blood stem cells have a large number of T cells associated with them, but (paradoxically) they appear to be associated with a lower FIGURE 89e-3 Relative function of cells in the hematopoietic hierarchy.Lowering expression of p16INK4a in older animals improves stem cell cycling and capacity to reconstitute hematopoiesis in adoptive hosts, making them similar to younger animals. Mature cell numbers are unaffected. Therefore, molecular events governing the specific functions of stem cells are being gradually made clear and offer the potential of new approaches to changing stem cell function for therapy. One critical stem cell function that remains poorly defined is the molecular regulation of self-renewal. For medicine, self-renewal is perhaps the most important function of stem cells because it is critical in regulating the number of stem cells. Stem cell number is a key limiting parameter for both autologous and allogeneic stem cell transplantation. Were we to have the ability to use fewer stem cells or expand limited numbers of stem cells ex vivo, it might be possible to reduce the morbidity and expense of stem cell harvests and enable use of other stem cell sources. Specifically, umbilical cord blood is a rich source of stem cells. However, the volume of cord blood units is extremely small, and therefore, the total number of hematopoietic stem cells that can be obtained in any single cord blood unit is generally only sufficient to transplant an individual of <40 kg. This limitation restricts what would otherwise be an extremely promising source of stem cells. Two features of cord blood stem cells are particularly important. (1) They are derived from a diversity of individuals that far exceeds the adult donor pool and therefore can overcome the majority of immunologic cross-matching obstacles. (2) Cord blood stem cells have a large number of T cells associated with them, but (paradoxically) they appear to be associated with a lower FIGURE 89e-3 Relative function of cells in the hematopoietic hierarchy. The boxes represent distinct functional features of cells in the myeloid (upper box) versus lymphoid (lower box) lineages.If stem cell expansion by self-renewal could be achieved, the number of cells available might be sufficient for use in larger adults.An alternative approach to this problem is to improve the efficiency of engraftment of donor stem cells.Graft engineering is exploring methods of adding cell components that may enhance engraftment.

The lateral pathways can excite motor neurons directly, although interneurons are their main target.9.13 ).The lateral pathways terminate in the lateral portions of the spinal cord’s gray matter ( Fig.Another way of classifying the motor pathways is based on their sites of termination in the spinal cord and the consequent differences in their roles in the control of movement and posture.ThecircuitsshownmediategroupIareciprocalinhibitionofantagonistmuscles(inthiscase,anextensor)andinhibitionofthisreciprocalinhibitionbyRenshawcells.NotethatequivalentnumbersofRenshawcellsandgroupIainhibitoryinterneuronsareassociatedwithextensormotorneuronsandgroupIainputfromspindlesinextensormuscles,buttheyarenotshownforsimplicity.Orange cells areinhibitory,andblue andgreen cells areexcitatory. Classification of Descending Motor Pathways Descending motor pathways were traditionally subdivided into pyramidal and extrapyramidal pathways. This terminology reflects a clinical dichotomy between pyramidal tract disease and extrapyramidal disease. In pyramidal tract disease, the corticospinal (pyramidal) tract is interrupted. The signs of this disease were originally attributed to the loss of function of the pyramidal tract (so named because the corticospinal tract passes through the medullary pyramid). However, in many cases of pyramidal tract disease, the functions of other pathways are also altered, and most signs of pyramidal tract disease (see the later section “ Caused by Lesions of Descending Motor Pathways ”) are apparently not caused solely by loss of the corticospinal tract but also reflect damage to additional motor pathways. The CHAPTER 9 Organization of Motor Function term extrapyramidal is even more problematic. Thus this classification system is not used in this book. Another way of classifying the motor pathways is based on their sites of termination in the spinal cord and the consequent differences in their roles in the control of movement and posture. The lateral pathways terminate in the lateral portions of the spinal cord’s gray matter ( Fig. 9.13 ). The lateral pathways can excite motor neurons directly, although interneurons are their main target.The medial pathways end in the medial ventral horn on the medial group of interneurons (see Fig.9.13 ).These interneurons connect bilaterally with motor neurons that control the axial musculature and thereby contribute to balance and posture.They also contribute to the control of proximal limb muscles.In this book, the terms lateral and medial are used to classify the descending motor pathways.

A summary of the various acid-base abnormalities and associated therapies is shown in Table 22.5.Treatment of the acidosis without potassium replacement will result in severe hypokalemia with its associated risks.The patient with a normal potassium concentration and metabolic acidosis is actually depleted of intracellular potassium.The treatment of metabolic acidosis depends on the cause. In patients with lactic acidosis, restoration of tissue perfusion is imperative. This state can be accomplished through cardiovascular and pulmonary support as needed, oxygen therapy, and aggressive treatment of systemic Table 22.4 Causes of Metabolic Acidosis Adapted from Narins RG, Lazarus MJ. Renal system. In: Vandam LD, ed. To make the patient ready for anesthesia: medical care of the surgical patient, 2nd ed. Menlo Park, CA: Addison Wesley, 1984:67–114. Table 22.5 Acid-Base Disorders and Their Treatment NaHCl, sodium hydrochloride. infection wherever appropriate. Ketosis from diabetes can be corrected gradually with insulin therapy. Ketosis resulting from chronic starvation or from lack of caloric support postoperatively can be corrected with nutrition. In patients with normal anion gap acidosis, bicarbonate lost from the gastrointestinal tract should be replaced, excess chloride administration can be curtailed, and, where necessary, a loop diuretic can be used to induce renal clearance of chloride. Dilutional acidosis can be corrected with mild fluid restriction. Bicarbonates should not be given unless serum pH is lower than 7.2 or severe cardiac complications secondary to acidosis are present. Close monitoring of serum potassium levels is mandatory. Under states of acidosis, potassium will exit the cell and enter the circulation. The patient with a normal potassium concentration and metabolic acidosis is actually depleted of intracellular potassium. Treatment of the acidosis without potassium replacement will result in severe hypokalemia with its associated risks. A summary of the various acid-base abnormalities and associated therapies is shown in Table 22.5.Studies consistently show that 25% to 50% of patients suffer moderate to severe pain in the postoperative period (38,39).There are several reasons for the existing inadequacies in pain management.First, patient expectations of pain relief are low and they are not aware of the extent of analgesia that they should expect.

same range of pressures and because RBF is an important determinant of GFR, it is not surprising that the same mechanisms regulate both flows.Autoregulation maintains GFR and RBF relatively constant as blood pressure changes from 90 to 180 mm Hg.33.18 Relationship between arterial blood pressure and RBF and between arterial blood pressure and GFR.In addition the protein loss in urine caused by some renal diseases can lead to a decrease in the plasma protein concentration and thus in πGC. 4. Changes in PBS: Increased PBS reduces GFR, whereas decreased PBS enhances GFR. Acute obstruction of the urinary tract (e.g., a kidney stone occluding the ureter) increases PBS. Equation 33.11 organ R = resistance to flow through that organ Accordingly, RBF is equal to the pressure difference between the renal artery and the renal vein divided by renal vascular resistance: Equation 33.12 The afferent arteriole, efferent arteriole, and interlobular artery are the major resistance vessels in the kidneys and thereby determine renal vascular resistance. Like most other organs, the kidneys regulate their blood flow by adjusting vascular resistance in response to changes in arterial pressure. As shown in Fig. 33.18 these adjustments are so precise that blood flow remains relatively constant as arterial blood pressure changes between 90 and 180 mm Hg. GFR is also regulated over the same range of arterial pressures. The phenomenon whereby RBF and GFR are maintained relatively constant between blood pressures of 90 and 180 mm Hg, namely autoregulation, is achieved by changes in vascular resistance, mainly through the afferent arterioles of the kidneys. Because both RBF and GFR are regulated over the • Fig. 33.18 Relationship between arterial blood pressure and RBF and between arterial blood pressure and GFR. Autoregulation maintains GFR and RBF relatively constant as blood pressure changes from 90 to 180 mm Hg. same range of pressures and because RBF is an important determinant of GFR, it is not surprising that the same mechanisms regulate both flows.Both regulate the tone of the afferent arteriole.The pressure-sensitive mechanism, the so-called myogenic mechanism, is related to an intrinsic property of vascular smooth muscle: the tendency to contract when stretched.Accordingly, when arterial pressure rises and the renal afferent arteriole is stretched, the smooth muscle contracts in response.

Macrophages phagocytize oxidized LDL, slowly transforming themselves into foam cells with a characteristic spongy appearance of the cytoplasm loaded with lipid-containing vesicles.In response to this injury, monocytes from the bloodstream enter the tunica intima and differentiate into macrophages.Endothelial cells function in the conversion of angiotensin I to angiotensin II in the renin–angiotensin system that controls blood pressure, as well as in the inactivation or conversion of a several compounds conveyed in the blood (norepinephrine, thrombin, prostaglandins, bradykinin, and serotonin) to inactive forms.  Modification of the lipoproteins occurs by oxidation. Lipoproteins, mainly LDLs with a high cholesterol content and very low-density lipoproteins (VLDLs), are oxidized by chapter 13 Cardiovascular System GENERAL FEATURES OF ARTERIES AND VEINS 411 Atherosclerotic lesions are the most common acquired abnormality of blood vessels. More than half of the annual deaths in the United States are related to complications of atherosclerotic disease, which includes ischemic heart disease (see Folder 13.3), myocardial infarction, stroke, and gangrene of the limbs. Lesions develop pri-marily in the tunica intima of large elastic arteries follow-ing endothelial injury, which leads to endothelial dysfunction. Factors that predispose to endothelial in-juries include low-LDL cholesterol hyperlipidemia, hyper-glycemia (in diabetes), hypertension, increased toxin levels associated with cigarette smoking, and certain viral and bacterial infections caused by cytomegalovirus (CMV) or Chlamydia pneumoniae, respectively. Altered function of vascular endothelium leads to increased per-meability to LDL cholesterol and increased adherence of white blood cells to the endothelium. Endothelial injury in-creases the production of reactive oxygen species such as O2 , H2O2, OH, and ONOO, which in turn oxidize LDL in the tunica intima of the artery. In response to this injury, monocytes from the bloodstream enter the tunica intima and differentiate into macrophages. Macrophages phagocytize oxidized LDL, slowly transforming themselves into foam cells with a characteristic spongy appearance of the cytoplasm loaded with lipid-containing vesicles.This lesion under-goes further remodeling and growth into fibrofatty plaque as smooth muscle cells migrate from the media and fibrob-lasts form a protective capsule of connective tissue (Fig.F13.1.1).A thick layer of fibrous connective tissue con-taining scattered smooth muscle cells, macrophages, foam cells, T lymphocytes, cholesterol crystals, and cell debris is known as an atheromatous plaque.

Right atrial reentry parallel to the tricuspid annulus and dependent on conduction through the isthmus between the inferior vena cava and tricuspid annulus 1.Atrial flutter – macroreentrant atrial tachycardia Defining feature: organized reentry creates organized atrial activity, commonly seen as sawtooth flutter waves at rates typically faster than 200 beats/min a. i.Sinus tachycardia can be difficult to distinguish from focal atrial tachycardia (see below) that originates from a focus near the sinus node. A causative factor (such as exertion) and a gradual increase and decrease in rate favors sinus tachycardia, whereas an abrupt onset and offset favor atrial tachycardia. The distinction can be difficult and occasionally requires extended ECG monitoring or even invasive electrophysiology study. Treatment for physiologic sinus tachycardia is aimed at the underlying condition (Table 276-2). Nonphysiologic Sinus Tachycardia Inappropriate sinus tachycardia is an uncommon condition in which the sinus rate increases spontaneously at rest or out of proportion to physiologic stress or exertion. I. Physiologic sinus tachycardia Defining feature: normal sinus mechanism precipitated by exertion, stress, concurrent illness (Table 276-2) II. A. Tachycardia originating from the atrium Defining feature: tachycardia may continue despite beats that fail to conduct to the ventricles, indicating that the AV node is not participating in the tachycardia circuit 1. Inappropriate sinus tachycardia Defining feature: tachycardia from the normal sinus node area that occurs without an identifiable precipitating factor as a result of dysfunctional autonomic regulation 2. Focal atrial tachycardia Defining feature: Regular atrial tachycardia with defined p wave; may be sustained, nonsustained, paroxysmal, or incessant. Frequent sites of origin occur along the valve annuli of left or right atrium, pulmonary veins, coronary sinus musculature, superior vena cava 3. Atrial flutter – macroreentrant atrial tachycardia Defining feature: organized reentry creates organized atrial activity, commonly seen as sawtooth flutter waves at rates typically faster than 200 beats/min a. i. Right atrial reentry parallel to the tricuspid annulus and dependent on conduction through the isthmus between the inferior vena cava and tricuspid annulus 1.Usually due to reentry in left or right atrium associated with scars usually from prior surgery or catheter ablation for atrial fibrillation, but may be idiopathic 4.Atrial fibrillation Defining feature: chaotic rapid atrial electrical activity with variable ventricular rate; the most common sustained cardiac arrhythmia in older adults 5.

The f rst step in the diagnosis of hyperemesis gravidarum is to rule out molar pregnancy with ultrasound +/– β-hCG.Measure liver enzymes, serum bilirubin, and serum amylase/lipase.Determine severity: Evaluate for ketonemia, ketonuria, hyponatremia, and hypokalemic, hypochloremic metabolic alkalosis.Rule out molar pregnancy: Check β-hCG level and ultrasound.Local block (lidocaine) Excellent anesthesia before episiotomy and during repair of lacerations; can be used to perform a pudendal block. Rarely, may cause seizures, hypotension, and cardiac arrhythmias. Epidural The most effective form of pain relief; can also be used for cesarean delivery or postpartum tubal ligation. Can result in pruritus, fever, hypotension, and transient FHR deceleration. Spinal Rapid-onset analgesia that provides excellent pain relief for procedures of limited duration (30–250 minutes). Limited duration; puts patients at risk for hypotension, postdural puncture headache, and transient neurologic symptoms. Combined spinal epidural General Offers rapid onset of spinal analgesia combined with the ability to prolong the duration of analgesia with continuous epidural infusion. Used in emergent cesarean delivery and indicated in some cases of FHR abnormality; can be useful in cases where regional anesthesia is absolutely contraindicated or fails. The sedative effect of opioids ↓ FHR variability and ↑ the possible need for neonatal naloxone administration and f ve-minute Apgar scores < 7. Carries the risks of both procedures; may ↑ the risk of bradycardia and emergent cesarean delivery over epidural analgesia alone. Requires airway control; carries a signif cant risk of maternal aspiration and neonatal depression (inhaled anesthetic agents readily cross the placenta); associated with higher maternal morbidity rates than epidural anesthesia. Distinguish from “morning sickness,” acid refux, gastroenteritis, hyperthyroidism, and neurologic conditions. Rule out molar pregnancy: Check β-hCG level and ultrasound. Determine severity: Evaluate for ketonemia, ketonuria, hyponatremia, and hypokalemic, hypochloremic metabolic alkalosis. Measure liver enzymes, serum bilirubin, and serum amylase/lipase. The f rst step in the diagnosis of hyperemesis gravidarum is to rule out molar pregnancy with ultrasound +/– β-hCG.Gestational diabetes is typically asymptomatic, so the f rst step in diagnosis is a one-hour glucose challenge at 24–28 weeks.If ≥ 140 mg/dL, perform a three-hour glucose challenge test.Keys to the management of gestational diabetes: (1) the ADA diet; (2) insulin if needed; (3) ultrasound for fetal growth; and (4) NST beginning at 30–32 weeks.First step: Administer vitamin B6.