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Clonal hematopoiesis.Excessive activation of thrombin, which you may recall can initiate inflammation through cleavage of protease-activated receptors (PARs; Chapter 4) on leukocytes, endothelium, and other cells, may be particularly atherogenic.Elevated levels of procoagulants are potent predictors of risk for major cardiovascular events including myocardial infarction and stroke.Homocystinuria, due to rare inborn errors of metabolism, causes elevated circulating homocysteine (greater than 100 µmol/L) and is associated with early-onset vascular disease. Although low folate and vitamin B12 levels can increase homocysteine levels, supplemental vitamin ingestion does not affect the incidence of cardiovascular disease. Metabolic syndrome. Associated with central obesity (Chapter 8), this clinical entity is characterized by insulin resistance, hypertension, dyslipidemia (elevated triglycerides and depressed HDL), hypercoagulability, and a pro-inflammatory state, which may be triggered by cytokines released from adipocytes. The dyslipidemia, hyperglycemia, and hypertension are all cardiac risk factors, while the systemic hypercoagulabgramle and pro-inflammatory state may contribute to endothelial dysfunction and/or thrombosis. Lipoprotein(a) levels. Lipoprotein(a) is an LDL-like particle that contains apolipoprotein B-100 linked to apolipoprotein(a). Lipoprotein(a) levels are correlated with risk of coronary and cerebrovascular disease, independent of total cholesterol or LDL levels. Apolipoprotein(a) is homologous to plasminogen, suggesting a potential link between thrombogenesis and circulating molecules that can drive atherosclerosis. Elevated levels of procoagulants are potent predictors of risk for major cardiovascular events including myocardial infarction and stroke. Excessive activation of thrombin, which you may recall can initiate inflammation through cleavage of protease-activated receptors (PARs; Chapter 4) on leukocytes, endothelium, and other cells, may be particularly atherogenic. Clonal hematopoiesis.Despite the presence of these mutations, such patients typically have normal blood counts.Unexpectedly, epidemiologic studies have found that clonal hematopoiesis is strongly associated with an increased risk of death from cardiovascular disease, possibly because of alterations in the function of innate immune cells derived from mutated hematopoietic stem cells.

Maternal Infection The association of infection with recurrent abortion is among the most controversial and poorly explored of the potential causes for pregnancy loss.At present, no consensus exists concerning this potential association.Although it has long been debated whether clinically euthyroid patients with antithyroid antibodies have higher rates of miscarriage and recurrent pregnancy loss, thyroid hormone supplementation was shown to reduce miscarriage in infertility patients with positive antithyroid antibodies undergoing IVF (100–106). The mechanism for an association between antithyroid antibody positivity and recurrent pregnancy loss remains unclear; however, these antibodies could be markers of more generalized autoimmunity or may predict an impaired ability of the thyroid gland to respond to the demands of pregnancy. Two additional endocrinologic abnormalities have been linked with recurrent pregnancy loss, although support for these associations and their mechanistic pathways remains shrouded in controversy. The relationship of hyperprolactinemia with recurrent pregnancy loss continues to be debated. Animal models suggest that elevated prolactin levels may adversely affect corpus luteal function; however, this concept is not well supported in humans (107,108). Some have suggested that elevated prolactin levels may promote pregnancy wastage via direct effects on the endometrium or indirect immunomodulatory mechanisms (88,109). Most recently, attempts have been made to correlate markers of ovarian reserve (day 3 follicle-stimulating hormone, day 3 estradiol, response to the clomiphene challenge test) with recurrent pregnancy loss (89,110,111). At present, no consensus exists concerning this potential association. Maternal Infection The association of infection with recurrent abortion is among the most controversial and poorly explored of the potential causes for pregnancy loss.More recent data have directly addressed the roles of some of these proposed organisms in recurrent pregnancy loss.One prospective comparison trial involving 70 recurrent pregnancy loss patients reported no elevations in any markers for present or past infection with Chlamydia trachomatis when compared with controls (114).

In some cases, both the anxiety about possible separation and the avoidance of situations involving separation from the home or nuclear family (e.g., going away to col- lege, moving away from attachment figures) may persist through adulthood.Typically there are periods of exacerbation and re- mission.When extremely upset at the prospect of separation, chil- dren may show anger or occasionally aggression toward someone who is forcing separa- tion. When alone, especially in the evening or the dark, young children may report unusual perceptual experiences (e.g., seeing people peering into their room, frightening creatures reaching for them, feeling eyes staring at them). Children with this disorder may be de- scribed as demanding, intrusive, and in need of constant attention, and, as adults, may ap- pear dependent and overprotective. The individual’s excessive demands often become a source of frustration for family members, leading to resentment and conflict in the family. The 12-month prevalence of separation anxiety disorder among adults in the United States is 0.9%—1.9%. In children, 6- to 12-month prevalence is estimated to be approximately 4%. In adolescents in the United States, the 12-month prevalence is 1.6%. Separation anxiety is the most prevalent anxiety disorder in children younger than 12 years. In clinical sam- ples of children, the disorder is equally common in males and females. In the community, the disorder is more frequent in females. Periods of heightened separation anxiety from attachment figures are part of normal early development and may indicate the development of secure attachment relationships (e.g., around 1 year of age, when infants may suffer from stranger anxiety). Onset of separation anxiety disorder may be as early as preschool age and may occur at any time during child- hood and more rarely in adolescence. Typically there are periods of exacerbation and re- mission. In some cases, both the anxiety about possible separation and the avoidance of situations involving separation from the home or nuclear family (e.g., going away to col- lege, moving away from attachment figures) may persist through adulthood.Many adults with separation anxiety disorder do not recall a childhood onset of separation anxiety disorder, although they may recall symptoms.The manifestations of separation anxiety disorder vary with age.Younger children are more reluctant to go to school or may avoid school altogether.

The patient should be placed in Trendelenburg and left lateral decubitus positions to prevent aspiration (even if an endotracheal tube is in place).Except in infants, for whom normal saline is recommended, tap water is acceptable.28 French tube for children).40 French orogastric tube (no.Palatability may be increased by adding a sweetener (sorbitol) or a flavoring agent (cherry, chocolate, or cola syrup) to the suspension. Charcoal adsorbs ingested poisons within the gut lumen, allowing the charcoal-toxin complex to be evacuated with stool. Charged (ionized) chemicals such as mineral acids, alkalis, and highly dissociated salts of cyanide, fluoride, iron, lithium, and other inorganic compounds are not well adsorbed by charcoal. In studies with animals and human volunteers, charcoal decreases the absorption of ingestants by an average of 73% when given within 5 min of ingestant administration, 51% when given at 30 min, and 36% when given at 60 min. For this reason, charcoal given before hospital arrival increases the potential clinical benefit. Side effects of charcoal include nausea, vomiting, and diarrhea or constipation. Charcoal may also prevent the absorption of orally administered therapeutic agents. Complications include mechanical obstruction of the airway, aspiration, vomiting, and bowel obstruction and infarction caused by inspissated charcoal. Charcoal is not recommended for patients who have ingested corrosives because it obscures endoscopy. Gastric lavage should be considered for life-threatening poisons that cannot be treated effectively with other decontamination, elimination, or antidotal therapies (e.g., colchicine). Gastric lavage is performed by sequentially administering and aspirating ~5 mL of fluid per kilogram of body weight through a no. 40 French orogastric tube (no. 28 French tube for children). Except in infants, for whom normal saline is recommended, tap water is acceptable. The patient should be placed in Trendelenburg and left lateral decubitus positions to prevent aspiration (even if an endotracheal tube is in place).Significant amounts of ingested drug are recovered from <10% of patients.Aspiration is a common complication (occurring in up to 10% of patients), especially when lavage is performed improperly.Serious complications (esophageal and gastric perforation, tube misplacement in the trachea) occur in ~1% of patients.

Clearly, the modern trend in peptic ulcer operation could be described as “less is more.”121,122Bleeding Peptic UlcerBleeding is the most common cause of ulcer-related death, but only rarely do patients with bleeding gastric or duodenal ulcer require operation today.The choice of opera-tion for the individual patient with PUD depends on a variety of factors, including the type of ulcer (duodenal, gastric, recurrent, or marginal), the indication for operation, and the condition of the patient. Other important considerations are intra-abdominal factors (duodenal scarring/inflammation, adhesions, or difficult exposure), the ulcer diathesis status of the patient, the surgeon’s experience and personal preference, whether H pylori infection is present, the need for NSAID therapy, previous treatment, and the likelihood of future compliance with treatment. Table 26-12 shows the surgical options for managing various aspects of PUD. Stomach Stom.AB DC Approximation suture PylorusInvertedincisionGallbladderDuodenumConnellthrough & throughsuture (1st ant. tier)Duod.Cushingseromuscularsuture (2nd ant. tier)Posteriorthrough &through sutureFigure 26-37. A through D. Finney pyloroplasty. ant. = anterior; Duod. = duodenum; Stom. = stomach. (Reproduced with permission from Zuidema GD: Shackelford’s Surgery of the Alimentary Tract, 4th ed. Philadelphia, PA: Elsevier/Saunders; 1996. )Brunicardi_Ch26_p1099-p1166.indd 113001/03/19 7:12 PM 1131STOMACHCHAPTER 26In general, resective procedures have a lower ulcer recurrence rate, but a higher morbidity and mortality rate (see Table 26-11) compared to nonresective ulcer operations. Because ulcer recur-rence often is related to H pylori and/or NSAIDs, it is usually managed adequately without reoperation. Thus, gastric resection to minimize recurrence in duodenal ulcer disease is usually not justified; resection for gastric ulcer remains the standard because of the risk of cancer. Clearly, the modern trend in peptic ulcer operation could be described as “less is more.”121,122Bleeding Peptic UlcerBleeding is the most common cause of ulcer-related death, but only rarely do patients with bleeding gastric or duodenal ulcer require operation today.It is likely that patients currently coming to operation for bleeding PUD are at higher risk for a poor outcome than ever before.The surgical options for treating bleeding PUD include suture ligation of the bleeder; suture ligation and definitive non-resective ulcer operation (HSV or V + D); and gastric resection (usually, including vagotomy and ulcer excision).

Testing for STDs may be performed as warranted on either a cervical or a urine specimen using DNA amplification techniques.Thyroid studies may be relevant.Management of Abnormal Bleeding von Willebrand factor (VWF) (measured with ristocetin cofactor activity and antigen, factor VIII), and fibrinogen to be assessed in collaboration with a hematologist (81).Am J Obstet Gynecol 2009;201:12e1–e8.Laboratory Testing Any adolescent with abnormal bleeding should undergo sensitive pregnancy testing, regardless of whether she states that she has had intercourse. The medical consequences of failing to diagnose a pregnancy are too severe to risk missing the diagnosis. Complications of pregnancy should be managed accordingly. In addition to a pregnancy test, laboratory testing should include a complete blood count with platelet count and screening tests for coagulopathies and platelet dysfunction. An international expert panel made recommendations about when a gynecologist should suspect a bleeding disorder and pursue a diagnosis (Table 14.8). The consensus report recommends measurement of complete blood cell count (CBC), platelet count and function, prothrombin time (PT), activated partial thromboplastin time (PTT), Table 14.8 When Should a Gynecologist Suspect a Bleeding Disorder Family history of bleeding disorder Personal history of any of the following: Epistaxis in the last year Postpartum hemorrhage, especially delayed >24 h Failure to respond to conventional management of menorrhagia From James AH, Kouides PA, Abdul-Kadir R, et al. Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel. Am J Obstet Gynecol 2009;201:12e1–e8. Management of Abnormal Bleeding von Willebrand factor (VWF) (measured with ristocetin cofactor activity and antigen, factor VIII), and fibrinogen to be assessed in collaboration with a hematologist (81). Thyroid studies may be relevant. Testing for STDs may be performed as warranted on either a cervical or a urine specimen using DNA amplification techniques.Imaging Studies If the pregnancy test results are positive, pelvic imaging using ultrasonography may be necessary to confirm a viable intrauterine pregnancy and rule out a spontaneous abortion or ectopic pregnancy.

This is a feature associated with the transport of fluid across the epithelium and, as noted above, commonly seen in intestinal absorptive cells.Lastly, with respect to its absorptive function, the epithelial cells frequently exhibit distended intercellular spaces at their basal aspect (see upper right figure arrows).The mucosa consists of a tall simple columnar absorptive epithelium (Ep) resting on a lamina propria of loose irregular connective tissue (CT). The epithelium has characteristics that distinguish it from the absorptive epithelium of other organs, such as the intestines. Only one cell type, tall columnar cells, is present in the epithelial layer (see upper right figure). The nuclei are in the basal portion of the cell. The cells possess a thin apical striated bor- Mucosa, gallbladder, human, H&E ×550. The smaller of the two gland-like structures is composed of mucous cells (MC) and represents a section through a mucous gland. This specimen was taken from a site near the neck of the gallbladder where mucous glands are often present. Note the characteristic flattened nuclei at the base of the cell and the lightly stained appearance of the cytoplasm, features characteristic The mucosa is thrown into numerous folds that are particularly pronounced when the muscularis is highly contracted. This is the usual histologic appearance of the gallbladder unless, of course, steps are taken to fix and preserve it in a distended state. Occasionally, the section cuts through a recess in a fold, and the recess may then resemble a gland (arrows). The mucosa, however, does not possess glands, except in the neck region, where some mucous glands are present (see lower right figure). der. However, this is not always evident in routine H&E–stained sections. The cytoplasm stains rather uniformly with eosin. This is related to its absorptive function and is in contrast to the staining of cells that are engaged in the production of protein. Lastly, with respect to its absorptive function, the epithelial cells frequently exhibit distended intercellular spaces at their basal aspect (see upper right figure arrows). This is a feature associated with the transport of fluid across the epithelium and, as noted above, commonly seen in intestinal absorptive cells.The lamina propria underlying the epithelium is usually very cellular.In this specimen, in addition to lymphocytes (L), a relatively common finding, a large number of plasma cells (PC) is also present within the lamina propria.(The high concentration of plasma cells suggests chronic inflammation.)

The patients described have had contusions of the C1-C2 region.The arm weakness may be asymmetrical or even unilateral and sensory loss is inconsistent.Central cord syndrome (“Schneider syndrome”) and cruciate paralysis A special from of acute cervical cord injury implicates mainly central cord damage, resulting in the loss of motor function solely or more severely in the upper limbs than in the lower ones, and it particularly affects the hands. Bladder dysfunction with urinary retention occurs in some cases and sensory loss is often slight (hyperpathia over the shoulders and arms may be the only sensory abnormality). Many of these instances are reversible but damage to the centrally situated gray matter may leave an atrophic, areflexic paralysis of the arms and hands and a segmental loss of pain and thermal sensation from interruption of crossing pain and thermal fibers. Retroflexion injuries of the head and neck are the ones most often associated with the central cord syndrome, but other causes include hematomyelia, fibrocartilaginous embolism, and infarction from dissection of the vertebral artery in the medullary-cervical region as mentioned earlier in the chapter. According to Dickman and colleagues, approximately 4 percent of patients who survive injuries of the very rostral cervical cord demonstrate a very limited form of the central cord syndrome, recognized by Nielson and named by Bell, “cruciate paralysis.” The weakness is very selective, being practically limited to the arms, a feature that is attributable to the segregation within the pyramidal decussation of corticospinal fibers to the arms (being rostral) and to the legs (more caudally situated). The arm weakness may be asymmetrical or even unilateral and sensory loss is inconsistent. The patients described have had contusions of the C1-C2 region.Management of Spinal Injury For some time, many centers administered methylprednisolone in high dosage (bolus of 30 mg/kg followed by 5.4 mg/kg every hour), beginning within 8 h of the injury and continued for 23 h. This measure, according to the multicenter National Acute Spinal Cord Study (Bracken et al, 1990) resulted in a slight improvement in both motor and sensory function.

Cells in the stratum granulosum exhibit typical apoptotic nuclear morphology, including fragmentation of their DNA.Terminal differentiation of the epidermal cells, which begins with the cell divisions in the stratum basale, is considered a specialized form of apoptosis.Differentiation of epithelial cells constitutes a specialized form of apoptosis.45.Beginning with the deepest layer, these are as follow:  the stratum basale, also called the stratum germina tivum because of the presence of mitotically active cells, the stem cells of the epidermis; the stratum spinosum, also called the spinous layer or prickle cell layer because of the characteristic light microscopic appearance of short processes extending from cell to cell; the stratum granulosum, which contains numerous in tensely staining granules; the stratum lucidum, which is limited to thick skin and considered a subdivision of the stratum corneum; and the stratum corneum, which is composed of keratinized cells. FIGURE 15.1 • Photomicrograph showing the layers of thin skin. This hematoxylin and eosin (H&E)–stained specimen from human skin shows the two chief layers of the skin—the epidermis (Epi) and dermis (Derm). The epidermis forms the surface; it consists of stratified squamous epithelium that is keratinized. The dermis consists of two layers: The papillary layer, which is the most superficial layer and is adjacent to the epidermis, and the more deeply positioned reticular layer. The boundary between these two layers is not conspicuous; the papillary layer is, however, more cellular than the reticular layer. In addition, the collagen fibers of the reticular layer are thick (clearly visible in the lower part of the figure); those of the papillary layer are thin. 45. Differentiation of epithelial cells constitutes a specialized form of apoptosis. Terminal differentiation of the epidermal cells, which begins with the cell divisions in the stratum basale, is considered a specialized form of apoptosis. Cells in the stratum granulosum exhibit typical apoptotic nuclear morphology, including fragmentation of their DNA.The stratum basale provides for epidermal cell renewal.The stratum basale is represented by a single layer of cells that rests on the basal lamina (Plate 42, page 515).It contains the stem cells from which new cells, the keratinocytes, arise by mitotic division.For this reason, the stratum basale is also called the stratum germinativum.The cells are small and cuboidal to low columnar.

Why Do Mitochondria and Chloroplasts Maintain a Costly Separate System for DNa transcription and translation?Despite intensive research, the issue remains unresolved.However, there are many other processes that tend to go wrong as cells and tissues age, as one might expect given the incredible complexity of human cell biology.The less complex DNA replication and repair systems in mitochondria mean that accidents are corrected less efficiently. This results in a 100-fold higher occurrence of deletions and point mutations than in nuclear DNA. Mathematical modeling suggests that most of these mutations and lesions are acquired in childhood or early adult life, and then proliferate by clonal expansion in later life. Due to mitotic segregation, some cells will accumulate higher levels of faulty mitochondrial DNA than others. Above some threshold, serious deficiencies in respiratory-chain function will develop, producing cells that are senescent. In many organs of the human body, senescent cells with high levels of mitochondrial DNA damage are intermingled with normal cells, resulting in a mosaic of cells with and without respiratory-chain deficiency. The main role of mitochondrial fusion in cellular physiology is most likely to ensure an even distribution of mitochondrial DNA throughout the mitochondrial reticulum, and to prevent the accumulation of damaged DNA in one part of the network. When the fusion machinery is defective, DNA is lost from a subset of the mitochondria in the cell. Loss of mitochondrial DNA leads to a loss of respiratory-chain function, and it can cause disease. All of the considerations just discussed have suggested to some scientists that changes in our mitochondria are major contributors to human aging. However, there are many other processes that tend to go wrong as cells and tissues age, as one might expect given the incredible complexity of human cell biology. Despite intensive research, the issue remains unresolved. Why Do Mitochondria and Chloroplasts Maintain a Costly Separate System for DNa transcription and translation?The question is not trivial, because maintaining a separate genetic system is costly: more than 90 proteins—including many ribosomal proteins, aminoacyl-tRNA synthetases, DNA polymerase, RNA polymerase, and RNA-processing and RNA-modifying enzymes—must be encoded by nuclear genes specifically for this purpose.

Pneumocystosis—Pentamidine is a well-established alternative therapy for pulmonary and extrapulmonary disease caused by P jiroveci. The drug has somewhat lower efficacy and greater toxicity than trimethoprim-sulfamethoxazole. The standard dosage is 3 mg/kg/d intravenously for 21 days. Significant adverse reactions are common, and with multiple regimens now available to treat P jiroveci infection, pentamidine is best reserved for patients with severe disease who cannot tolerate or fail other drugs. Pentamidine is also an alternative agent for primary or secondary prophylaxis against pneumocystosis in immunocompromised individuals, including patients with advanced AIDS. For this indication, pentamidine is administered as an inhaled aerosol (300 mg inhaled monthly). The drug is well tolerated in this form. Its efficacy is good but less than that of daily trimethoprim-sulfamethoxazole. TABLE 52–6 Treatment of African trypanosomiasis. 1Available in the USA from the Drug Service, CDC, Atlanta, Georgia (phone: 404-639-3670; www.cdc.gov/laboratory/drugservice/). TABLE 52–7 Treatment of other protozoal infections. Not all preparations are available in the USA.1 Visceral (L donovani, L chagasi, L infantum) or mucosal (L braziliensis) Cutaneous (L major, L tropica, L mexicana, L braziliensis) Sodium stibogluconate, 20 mg/kg/d IV or IM for 28 days Amphotericin (liposomal preparations preferred (3 mg/kg/d IV on days 1–5, 14, and 21)); various other dosing regimens, including single dose Miltefosine, 2.5 mg/kg/d for 28 days Paromomycin,15 mg/kg for 21 days Sodium stibogluconate, 20 mg/kg/d IV or IM for 20 days Meglumine antimoniate Pentamidine, 2–4 mg/kg IM daily or every other day for up to 15 doses Combinations of listed drugs Pregnancy Spiramycin, 3 g daily until delivery TABLE 52–7 Treatment of other protozoal infections.2Established, relatively simple dosing regimens are provided.Route is oral unless otherwise indicated.See text for additional information, toxicities, cautions, and discussions of dosing for the more rarely used drugs, many of which are highly toxic.3Specific recommendations for leishmaniasis vary geographically.Combination regimens are increasingly used.

Each organelle membrane must also have a mechanism for importing, and incorporating into the organelle, the specific proteins that make the organelle unique.Because the lipid bilayer of cell membranes is impermeable to most hydrophilic molecules, the membrane of an organelle must contain membrane transport proteins to import and export specific metabolites.The ComparTmenTalizaTion of Cells In this brief overview of the compartments of the cell and the relationships between them, we organize the organelles conceptually into a small number of discrete families, discuss how proteins are directed to specific organelles, and explain how proteins cross organelle membranes. all eukaryotic Cells have the same Basic set of membrane-enclosed organelles Many vital biochemical processes take place in membranes or on their surfaces. Membrane-bound enzymes, for example, catalyze lipid metabolism; and oxidative phosphorylation and photosynthesis both require a membrane to couple the transport of H+ to the synthesis of ATP. In addition to providing increased membrane area to host biochemical reactions, intracellular membrane systems form enclosed compartments that are separate from the cytosol, thus creating functionally specialized aqueous spaces within the cell. In these spaces, subsets of molecules (proteins, reactants, ions) are concentrated to optimize the biochemical reactions in which they participate. Because the lipid bilayer of cell membranes is impermeable to most hydrophilic molecules, the membrane of an organelle must contain membrane transport proteins to import and export specific metabolites. Each organelle membrane must also have a mechanism for importing, and incorporating into the organelle, the specific proteins that make the organelle unique.The nucleus contains the genome (aside from mitochondrial and chloroplast DNA), and it is the principal site of DNA and RNA synthesis.The surrounding cytoplasm consists of the cytosol and the cytoplasmic organelles suspended in it.The cytosol constitutes a little more than half the total volume of the cell, and it is the main site of protein synthesis and degradation.

A small zygomaticofacial foramen on the lateral surface of the zygomatic bone transmits the zygomaticofacial nerve and vessels onto the cheek.A temporal process extends posteriorly to articulate with the zygomatic process of the temporal bone to complete the zygomatic arch.A frontal process extends superiorly to articulate with the zygomatic process of the frontal bone.In addition, one or more small sphenoidal emissary foramina penetrate the base of the greater wing anteromedial to the foramen ovale and allow emissary veins to pass between the pterygoid plexus of veins in the infratemporal fossa and the cavernous sinus in the middle cranial fossa. Projecting vertically downward from the greater wing immediately medial to the foramen spinosum is the irregularly shaped spine of the sphenoid, which is the attachment site for the cranial end of the sphenomandibular ligament. The lateral plate of the pterygoid process is a vertically oriented sheet of bone that projects posterolaterally from the pterygoid process (Fig. 8.136). Its lateral and medial surfaces provide attachment for the lateral and medial pterygoid muscles, respectively. The posterior surface of the maxilla contributes to the anterior wall of the infratemporal fossa (Fig. 8.136). This surface is marked by a foramen for the posterosuperior alveolar nerve and vessels. The superior margin forms the inferior border of the inferior orbital fissure. The zygomatic bone is a quadrangular-shaped bone that forms the palpable bony prominence of the cheek: A maxillary process extends anteromedially to articulate with the zygomatic process of the maxilla. A frontal process extends superiorly to articulate with the zygomatic process of the frontal bone. A temporal process extends posteriorly to articulate with the zygomatic process of the temporal bone to complete the zygomatic arch. A small zygomaticofacial foramen on the lateral surface of the zygomatic bone transmits the zygomaticofacial nerve and vessels onto the cheek.A zygomaticotemporal foramen on the temporal fossa surface of the plate where it attaches to the frontal process is for the zygomaticotemporal nerve.Ramus of mandible The ramus of the mandible is quadrangular in shape and has medial and lateral surfaces and condylar and coronoid processes (Fig.8.137).

There is increasing experience with the use of fosfomycin against UTIs (including complicated infections) caused by multidrugresistant E. coli.Single-dose fosfomycin treatment for acute cystitis is widely used in Europe but has produced mixed results in randomized trials.Second-line agents include fluoroquinolone and β-lactam compounds.Antibiotic resistance among uropathogens causing uncomplicated cystitis has since increased, appreciation of the importance of collateral damage (as defined below) has increased, and newer agents have been studied. Unfortunately, there is no longer a single best agent for acute uncomplicated cystitis. Collateral damage refers to the adverse ecologic effects of antimicrobial therapy, including killing of the normal flora and selection of drug-resistant organisms. Outbreaks of Clostridium difficile infection offer an example of collateral damage in the hospital environment. The implication of collateral damage in this context is that a drug that is highly efficacious for the treatment of UTI is not necessarily the optimal first-line agent if it also has pronounced secondary effects on the normal flora or is likely to change resistance patterns. Drugs used for UTI that have a minimal effect on fecal flora include pivmecillinam, fosfomycin, and nitrofurantoin. In contrast, trimethoprim, TMP-SMX, quinolones, and ampicillin affect the fecal flora more significantly; these drugs are notably the agents for which rising resistance levels have been documented. Several effective therapeutic regimens are available for acute uncomplicated cystitis in women (Table 162-1). Well- studied first-line agents include TMP-SMX and nitrofurantoin. Second-line agents include fluoroquinolone and β-lactam compounds. Single-dose fosfomycin treatment for acute cystitis is widely used in Europe but has produced mixed results in randomized trials. There is increasing experience with the use of fosfomycin against UTIs (including complicated infections) caused by multidrugresistant E. coli.The pros and cons of other therapies are discussed briefly below.Traditionally, TMP-SMX has been recommended as first-line treatment for acute cystitis, and it remains appropriate to consider the use of this drug in regions with resistance rates not exceeding 20%.

In the past two decades, there has been a revolution in our ability to determine the exact order of subunits in DNA molecules.And it must also allow access to chromosomal DNA, both for the enzymes that repair DNA damage and for the specialized proteins that direct the expression of its many genes.But still, as the 1950s began, both how proteins could be specified by instructions in the DNA and how this information might be copied for transmission from cell to cell seemed completely mysterious. The puzzle was suddenly solved in 1953, when James Watson and Francis Crick derived the mechanism from their model of DNA structure. As outlined in Chapter 1, the determination of the double-helical structure of DNA immediately solved the problem of how the information in this molecule might be copied, or replicated. It also provided the first clues as to how a molecule of DNA might use the sequence of its subunits to encode the instructions for making proteins. Today, the fact that DNA is the genetic material is so fundamental to biological thought that it is difficult to appreciate the enormous intellectual gap that was filled by this breakthrough discovery. We begin this chapter by describing the structure of DNA. We see how, despite its chemical simplicity, the structure and chemical properties of DNA make it ideally suited as the raw material of genes. We then consider how the many proteins in chromosomes arrange and package this DNA. The packing has to be done in an orderly fashion so that the chromosomes can be replicated and apportioned correctly between the two daughter cells at each cell division. And it must also allow access to chromosomal DNA, both for the enzymes that repair DNA damage and for the specialized proteins that direct the expression of its many genes. In the past two decades, there has been a revolution in our ability to determine the exact order of subunits in DNA molecules.is DNA.Figure 4–2 The first experimental demonstration that DNA is the genetic material.These experiments, carried out in the 1920s (A) and 1940s (b), showed that adding purified DNA to a bacterium changed the bacterium’s properties and that this change was faithfully passed on to subsequent generations.

This patient has had rheumatoid arthritis for decades.B.The scapholunate interval is widened (double arrow), and the radioscaphoid joint is degenerated (solid oval), but the radiolunate and lunocapitate joint spaces are well preserved (dashed ovals).This patient injured her scapholunate ligament years prior to presentation.A.Arthritis of the hand and wrist.Figure 44-17.However, since RA usually affects multiple joints, fusion is typically avoided due to impaired function of adjacent joints, which would leave a severe motion deficit to the finger.Failure of the support ligaments of the distal radioulnar joint (DRUJ) leads to the caput ulnae posture of the wrist with the ulnar head prominent dorsally. As this dorsal prominence becomes more advanced, the ulna head, denuded of its cartilage to act as a buffer, erodes into the overlying extensor tendons. Extensor tenosynovitis, followed ultimately by tendon rupture, begins ulnarly and proceeds radially. Rupture of the ECU ten-don may go unnoticed due to the intact ECRL and ECRB ten-dons to extend the wrist. EDQ rupture may go unnoticed if a sufficiently robust EDC tendon to the small finger exists. Once the fourth compartment (EDC) tendons begin to fail, the motion deficit is unable to be ignored by the patient.Surgical solutions must address the tendon ruptures as well as the DRUJ synovitis and instability and ulna head break-down that led to them.65 Excision of the ulna head removes the bony prominence. The DRUJ synovitis must also be resected. Figure 44-17. Arthritis of the hand and wrist. A. This patient injured her scapholunate ligament years prior to presentation. The scapholunate interval is widened (double arrow), and the radioscaphoid joint is degenerated (solid oval), but the radiolunate and lunocapitate joint spaces are well preserved (dashed ovals). B. This patient has had rheumatoid arthritis for decades.For both pro-cedures, the remaining distal ulna must be stabilized.Multiple techniques have been described using portions of FCU, ECU, wrist capsule, and combinations thereof.The ruptured extensor tendons are typically degenerated over a significant length.

Combination chemotherapy with doxorubicin and DTIC, or these two drugs plus vincristine and cyclophosphamide, was yielded somewhat higher response rates (478–480).Gemcitabine and liposomaldoxorubicin showed activity in leiomyosarcomas (476,477).Paclitaxel yielded an 18% response rate with carcinosarcoma, but had limited activity in leiomyosarcomas (474,475).Radiation Therapy Several studies showed that adjuvant preoperative or postoperative radiation therapy is beneficial in decreasing pelvic recurrences and increasing quality of life in patients with localized ESS and carcinosarcoma, but not with leiomyosarcoma (457–465). Radiation was not demonstrated to improve survival. One trial randomized patients with uterine sarcomas to pelvic radiotherapy versus observation. Althoughthe risk of local relapse significantly decreased from 24% to 14%, there was no difference in survival between groups (466). The GOG randomized patients to whole abdomen radiation versus three cycles of cisplatin, ifosfamide, and mesna in patients with less than 1 cm of residual disease (467). Whole-abdomen radiation was associated with significant toxicity and the chemotherapy regimen appeared to confer a nonsignificant survival advantage. Chemotherapy Several chemotherapeutic agents have activity in sarcomas, including vincristine, actinomycin D, cyclophosphamide, doxorubicin, dimethyl triazeno imidazole carboxamide (dacarbazine, DTIC), cisplatin, ifosfamide paclitaxel, gemcitabine, and liposomal doxorubicin (468). Doxorubicin appears to be the most active single agent in the treatment of leiomyosarcoma, producing a 25% response rate (469). Ifosfamide has a lesser degree of activity (470). Cisplatin and ifosfamide demonstrated clear activity in carcinosarcoma, with response rates of 18% to 42% and 32%, respectively (471–473). Doxorubicin demonstrated less than a 10% response rate in carcinosarcoma (469). Paclitaxel yielded an 18% response rate with carcinosarcoma, but had limited activity in leiomyosarcomas (474,475). Gemcitabine and liposomaldoxorubicin showed activity in leiomyosarcomas (476,477). Combination chemotherapy with doxorubicin and DTIC, or these two drugs plus vincristine and cyclophosphamide, was yielded somewhat higher response rates (478–480).Gemcitabine combined with docetaxel for treatment of metastatic leiomyosarcoma yielded an overall response rate of 53%, including patients previously treated with doxorubicin (482).Median time to progression was 5.6 months.Several retrospective investigations concluded that neither chemotherapy nor radiation impacts survival for patients with ESS or leiomyosarcoma (428,483,484).

In tissue, infections with rubella virus have diverse effects, ranging from no obvious impact to cell destruction.The pathology of CRS in the infected fetus is well defined, with almost all organs found to be infected; however, the pathogenesis of CRS is only poorly delineated.Placental virus replication may lead to infection of fetal organs.Despite enormous progress, measles remains a leading vaccine-preventable cause of childhood mortality worldwide and continues to cause outbreaks in communities with low vaccination coverage rates in industrialized nations. Laura A. Zimmerman, Susan E. Reef Rubella was historically viewed as a variant of measles or scarlet fever. Not until 1962 was a separate viral agent for rubella isolated. After an epidemic of rubella in Australia in the early 1940s, the ophthalmologist Norman Gregg noticed the occurrence of congenital cataracts among infants whose mothers had reported rubella infection during early pregnancy, and congenital rubella syndrome (CRS; see “Clinical Manifestations,” below) was first described. Rubella virus is a member of the Togaviridae family and the only member of the genus Rubivirus. This single-stranded RNA enveloped virus measures 50–70 nm in diameter. Its core protein is surrounded by a single-layer lipoprotein envelope with spike-like projections containing two glycoproteins, E1 and E2. There is only one antigenic type of rubella virus, and humans are its only known reservoir. Although the pathogenesis of postnatal (acquired) rubella has been well documented, data on pathology are limited because of the mildness of the disease. Rubella virus is spread from person to person via respiratory droplets. Primary implantation and replication in the nasopharynx are followed by spread to the lymph nodes. Subsequent viremia occurs, which in pregnant women often results in infection of the placenta. Placental virus replication may lead to infection of fetal organs. The pathology of CRS in the infected fetus is well defined, with almost all organs found to be infected; however, the pathogenesis of CRS is only poorly delineated. In tissue, infections with rubella virus have diverse effects, ranging from no obvious impact to cell destruction.Individuals with acquired rubella may shed virus from 7 days before rash onset to ~5–7 days thereafter.Both clinical and subclinical infections are considered contagious.Infants with CRS may shed large quantities of virus from bodily secretions, particularly from the throat and in the urine, up to 1 year of age.

Another important layer to reapproximate separately is the gray line (con-junctival margin) so as to avoid height mismatch or lid notching.OK-432 is lyophilized low virulence S pyogenes cultured in penicillin. It is used as a sclerotherapy agent for lymphatic malformations and has a 94% response rate in macrocystic lesions, a 63% response rate in mixed macromicrocystic lesions, and no response in micro-cystic lesions.60TRAUMA OF THE HEAD AND NECKSoft TissueSoft tissue trauma of the head and neck is managed with the same general surgical principles as any other body subsite with a few particularities. Most lacerations can be closed primarily if there is not soft tissue loss; even some devitalized soft tis-sue should be preserved because of the excellent blood sup-ply to head and neck tissue that allows it to recover at a higher rate. Thus, minimal debridement is usually required. Thor-ough irrigation to remove foreign bodies and clean the tissue is required. This is followed by a careful layered closure. On the face, the deep layers are usually closed with a 3-0 or 4-0 Vicryl/Polysorb after a minimal amount of undermining, and interrupted 5-0 or 6-0 Prolene or Nylon is used for the skin. These sutures are removed at 5 days on the face. Antibiotics are reserved for through-and-through mucosal lacerations, con-taminated wounds, bite injuries, and when delayed closure is performed (>72 hours). The chosen antibiotic should cover S aureus. Patients are instructed to avoid sunlight because this can cause pigmentary abnormalities in the suture line as it heals and matures over the first year.Eyelid lacerations are closed in layers with careful reap-proximation of the orbicularis oculi as a separate layer. Another important layer to reapproximate separately is the gray line (con-junctival margin) so as to avoid height mismatch or lid notching.18-16).Of course, a mucosal layer closure may also be required for through-and-through defects.Rarely, locoregional flaps or grafts are required for closure when greater than one-fourth of the eyelid width or one-third of the lip width is missing.

24.3, ).Increased fatty acid synthesis: Liver is the primary site of de novo synthesis of FA (see Fig.Fat metabolism 1.B.[Note: The increased uptake and decreased production of blood glucose in the absorptive period prevents hyperglycemia.]Glycogenolysis is inhibited by dephosphorylation of glycogen phosphorylase and phosphorylase kinase.8.17, p. 100).Increased glycolysis: In the liver, glycolysis is significant only during the absorptive period following a carbohydrate-rich meal. The conversion of glucose to pyruvate is stimulated by the elevated insulin/glucagon ratio that results in increased amounts of the regulated enzymes of glycolysis: glucokinase, PFK-1, and pyruvate kinase ([PK] see p. 105). Additionally, PFK-1 is allosterically activated by fructose 2,6bisphosphate generated by the active (dephosphorylated) kinase domain of bifunctional PFK-2. PK is dephosphorylated and active. Pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl CoA, is active (dephosphorylated) because pyruvate inhibits PDH kinase (see Fig. 24.3, ). The acetyl CoA either is used as a substrate for fatty acid (FA) synthesis or is oxidized for energy in the tricarboxylic acid (TCA) cycle. (See Fig. 24.4 for the central role of glucose 6-phosphate.) 5. Decreased glucose production: While glycolysis and glycogenesis (pathways that promote glucose storage) are being stimulated in the liver in the absorptive state, gluconeogenesis and glycogenolysis (pathways that generate glucose) are being inhibited. Pyruvate carboxylase (PC), which catalyzes the first step in gluconeogenesis, is largely inactive because of low levels of acetyl CoA, its allosteric activator (see p. 119). [Note: The acetyl CoA is being used for FA synthesis.] The high insulin/glucagon ratio also favors inactivation of other gluconeogenic enzymes such as fructose 1,6-bisphosphatase (see Fig. 8.17, p. 100). Glycogenolysis is inhibited by dephosphorylation of glycogen phosphorylase and phosphorylase kinase. [Note: The increased uptake and decreased production of blood glucose in the absorptive period prevents hyperglycemia.] B. Fat metabolism 1. Increased fatty acid synthesis: Liver is the primary site of de novo synthesis of FA (see Fig. 24.3, ).[Note: Inactivity of AMPK favors dephosphorylation.]ACC catalyzes the formation of malonyl CoA from acetyl CoA, the rate-limiting reaction for FA synthesis (see p. 183).[Note: Malonyl CoA inhibits carnitine palmitoyltransferase-I (CPT-I) of FA oxidation (see p. 191).Thus, citrate directly activates FA synthesis and indirectly inhibits FA degradation.]a.

The sections that follow review the normal anatomy of body fluids, electrolyte composition and concentration abnormalities and treatments, common metabolic derangements, and alternative resuscitative fluids.Changes in both fluid volume and electro-lyte composition occur preoperatively, intraoperatively, and postoperatively, as well as in response to trauma and sepsis.doi: 10.1097/01.CCM.0000260629.86351.A5Brunicardi_Ch02_p0027-p0082.indd 8201/03/19 6:50 PM Introduction 83Body Fluids 83Total Body Water / 83Fluid Compartments / 83Composition of Fluid Compartments / 83Osmotic Pressure / 84Body Fluid Changes 85Normal Exchange of Fluid and Electrolytes / 85Classification of Body Fluid Changes / 85Disturbances in Fluid Balance / 85Volume Control / 86Concentration Changes / 86Composition Changes: Etiology and Diagnosis / 88Acid-Base Balance / 91Metabolic Derangements / 91Fluid and Electrolyte Therapy 93Parenteral Solutions / 93Alternative Resuscitative Fluids / 94Correction of Life-Threatening Electrolyte Abnormalities / 94Preoperative Fluid Therapy / 96Intraoperative Fluid Therapy / 97Postoperative Fluid Therapy / 97Fluid Management in Enhanced Recovery After Surgery (ERAS) Pathways / 97Special Considerations for the Postoperative Patient / 98Electrolyte Abnormalities in Specific  Surgical Patients 98Neurologic Patients / 98Malnourished Patients: Refeeding Syndrome / 98Acute Renal Failure Patients / 99Cancer Patients / 99Fluid and Electrolyte Management of the Surgical PatientMatthew D. Neal 3chapterINTRODUCTIONFluid and electrolyte management is paramount to the care of the surgical patient. Changes in both fluid volume and electro-lyte composition occur preoperatively, intraoperatively, and postoperatively, as well as in response to trauma and sepsis. The sections that follow review the normal anatomy of body fluids, electrolyte composition and concentration abnormalities and treatments, common metabolic derangements, and alternative resuscitative fluids.The relationship between total body weight and total body water (TBW) is relatively constant for an individual and is primarily a reflection of body fat.Lean tissues such as muscle and solid organs have higher water content than fat and bone.As a result, young, lean males have a higher proportion of body weight as water than elderly or obese individuals.

Weakly self-reactive lymphocytes are not removed in the primary lymphoid tissues (thymus and bone marrow), as deletion of weakly autoreactive cells would impose too great a limitation on the immune repertoire, resulting in impaired immune responses to pathogens.The lower panel shows how regulatory T cells, both natural and induced, can inhibit other self‑reactive T cells. If regulatory T cells encounter their self antigen on an antigen‑presenting cell, they secrete inhibitory cytokines such as IL‑10 and TGF‑β that inhibit all surrounding autoreactive T cells, regardless of their precise autoantigen specificity. Summary. Discrimination between self and nonself is imperfect, partly because a proper balance must be struck between preventing autoimmune disease and preserving immune competence. Self-reactive lymphocytes always exist in the natural immune repertoire but are not often activated. In autoimmune diseases, however, these cells become activated by autoantigens. If activation persists, autoreactive effector lymphocytes are generated and cause disease. The immune system has a remarkable set of mechanisms that work together to prevent autoimmune disease (see Fig. 15.2). This collective action means that each mechanism need not work perfectly nor apply to every possible self-reactive cell. Self-tolerance begins during lymphocyte development, when autoreactive T cells in the thymus and B cells in the bone marrow are deleted or, in the case of CD4 T cells, give rise to a subpopulation of self antigen-reactive FoxP3+ ‘natural’ or ‘thymic’ Treg cells that suppress autoimmune responses after exiting the thymus. Mechanisms of peripheral tolerance, such as anergy and deletion, or the extrathymic production of ‘induced’ or ‘peripheral’ Treg cells, complement these central tolerance mechanisms for antigens that are not expressed in the thymus or bone marrow. Weakly self-reactive lymphocytes are not removed in the primary lymphoid tissues (thymus and bone marrow), as deletion of weakly autoreactive cells would impose too great a limitation on the immune repertoire, resulting in impaired immune responses to pathogens.T cells can inhibit self-reactive lymphocytes if the regulatory cells are targeting autoantigens located in the same vicinity as the autoantigens to which the self-reactive lymphocytes respond.This allows regulatory cells to home to and suppress sites of autoimmune inflammation.

This has sub-sequently created occasional confusion and uncertainty in the marketplace—simply because the generation of public reports are not necessarily always based upon solid scientific data or evidence.Additionally, different large medical societies, includ-ing the Society for Thoracic Surgery (STS), are encouraging and rewarding practitioners and hospitals that are transparent with their outcomes. Making hospital outcomes transparent makes hospitals accountable to the public for their outcomes and, in the case of New York, caused a radical improvement in the quality of care provided to patients. It also empowers patients by mak-ing them better informed about which hospital they choose for their care, which will further incentivize hospitals to improve.Public Reporting and Patient Assessment of CareThe epiphany moment in contemporary healthcare created by the Institute of Medicine report2 generated far-reaching effects. One important aspect has been development of a variety of ini-tiatives focused on the generation, endorsement, and reporting of numerous measures related to the safety and quality of health-care—primarily process and outcomes measures. However, the science of measure development is slow paced and, unfortu-nately, has difficulty evolving at the same pace of change as clinical medicine or healthcare delivery systems.Given the strong interest for improved knowledge and information by consumers of healthcare, the trend toward public reporting has rapidly gained momentum and outpaced report-ing from the measurement science community. This has sub-sequently created occasional confusion and uncertainty in the marketplace—simply because the generation of public reports are not necessarily always based upon solid scientific data or evidence.

IgG and IgM predominate in blood (shown here for simplicity by IgM and IgG in the heart), whereas IgG and monomeric IgA are the major antibodies in extracellular fluid within the body.10.30 Immunoglobulin classes are selectively distributed in the body.The ability of IgG antibodies to diffuse easily throughout the Fig.By means of these specialized transport systems, mammals are supplied from birth with antibodies against pathogens common in their environments. As they mature and make their own antibodies of all isotypes, these are distributed selectively to different sites in the body (Fig. 10.30). Thus, throughout life, class switching and the distribution of antibody classes throughout the body provide effective protection against infection in extracellular spaces. 10-18 High-affinity IgG and IgA antibodies can neutralize toxins and block the infectivity of viruses and bacteria. Pathogens can cause damage to a host by producing toxins or by infecting cells directly, and antibodies can protect by blocking both of these actions. Many bacteria cause disease by secreting toxins that damage or disrupt the function of the host’s cells (Fig. 10.31). To affect cells, many toxins consist of separate domains for exerting toxicity and for binding to specific cell-surface receptors by which they enter cells. Antibodies that bind a toxin’s receptor-binding site can prevent cell entry and protect cells from attack (Fig. 10.32). Antibodies that act in this way to neutralize toxins are referred to as neutralizing antibodies. Most toxins are active at nanomolar concentrations: a single molecule of diphtheria toxin can kill a cell. To neutralize toxins, therefore, antibodies must be able to diffuse into the tissues and bind the toxin rapidly and with high affinity. The ability of IgG antibodies to diffuse easily throughout the Fig. 10.30 Immunoglobulin classes are selectively distributed in the body. IgG and IgM predominate in blood (shown here for simplicity by IgM and IgG in the heart), whereas IgG and monomeric IgA are the major antibodies in extracellular fluid within the body.The fetus receives IgG from the mother by transplacental transport.IgE is found mainly associated with mast cells just beneath epithelial surfaces (especially of the respiratory tract, gastrointestinal tract, and skin).The brain is normally devoid of immunoglobulin.Fig.10.31 Many common diseases are caused by bacterial toxins.

Levels of mRNA for hPL in syncytiotrophoblast remain relatively con stant throughout pregnancy.Within 5 to 10 days after conception, hPL is demonstrable in the placenta and can be detected in maternal serum as early as 3 weeks.Relatively higher hCG levels may be found in women carrying a fetus with Down syndrome. This observation is used in biochemical screening tests (Chap. 14, p. 281). The reason for the elevation is not clear, but reduced placental maturity has been speculated. Various malignant tumors also produce hCG, sometimes in large amounts-especially trophoblastic neoplasms (Chaps. 9, p. 159 and 20, p. 391). Relatively lower hCG plasma levels are found in women with early pregnancy wastage, including ectopic pregnancy (Chap. 19, p. 373). hCG is produced in very small amounts in normal tissues of men and nonpregnant women, perhaps primarily in the anterior pituitary gland. Nonetheless, the detection of hCG in blood or urine almost always indicates pregnancy (Chap. 9, p. 158). This is a single, nonglycosylated polypeptide chain with a molecular weight of 22,279 Da. The sequences of hPL and of human growth hormone (hGH) are strikingly similar, with 96-percent homology. Also, hPL is structurally similar to human prolactin (hPRL), with a 67-percent amino acid sequence similarity. Because of these similarities, it was called human placental lactogen or chorionic growth hormone. Currently, human placental lactogen is used by most. here are ive genes in the growth hormone-placental lactogen gene cluster that are linked and located on chromosome 17. hPL is concentrated in syncytiotrophoblast, but similar to hCG, hPL is demonstrated in cytotrophoblasts before 6 weeks (Grumbach, 1964; Maruo, 1992). Within 5 to 10 days after conception, hPL is demonstrable in the placenta and can be detected in maternal serum as early as 3 weeks. Levels of mRNA for hPL in syncytiotrophoblast remain relatively con stant throughout pregnancy.Levels rise steadily until 34 to 36 weeks' gestation.The hPL produc tion rate near term-approximately 1 g/d-is by far the great est of aRY known hormone in humans.The hal-life of hPL in maternal plasma is between 10 and 30 minutes (Walker, 1991).In late pregnancy, maternal serum concentrations reach levels of5 to 15 �g/mL (see Fig.5-18).

Localized degradation of matrix components is also required wherever cells have to escape from confinement by a basal lamina.If a cell lacks the enzymes needed to degrade the surrounding matrix, it is strongly inhibited from dividing, as well as being hindered from migrating.Cells in connective tissues generally need to be able to stretch out in order to divide.shell of REGENERATED residual returns to site of original junction nerve cut new acetylcholine receptors become concentrated at site of originalDEGENERATED MUSCLE AND NERVE REGENERATED junctionMUSCLE FIBER with special isoforms of type IV collagen and laminin and a proteoglycan called agrin. After a nerve or muscle injury, the basal lamina at the synapse has a central role in reconstructing the synapse at the correct location (Figure 19–54). Defects in components of the basal lamina at the synapse are responsible for some forms of muscular dystrophy, in which muscles develop normally but then degenerate later in life. Cells have to Be able to Degrade Matrix, as Well as Make It The ability of cells to degrade and destroy extracellular matrix is as important as their ability to make it and bind to it. Rapid matrix degradation is required in processes such as tissue repair, and even in the seemingly static extracellular matrix of adult animals there is a slow, continuous turnover, with matrix macromolecules being degraded and resynthesized. This allows bone, for example, to be remodeled so as to adapt to changes in the stresses on it. From the point of view of individual cells, the ability to cut through matrix is crucial in two ways: it enables them to divide while embedded in matrix, and it enables them to travel through it. Cells in connective tissues generally need to be able to stretch out in order to divide. If a cell lacks the enzymes needed to degrade the surrounding matrix, it is strongly inhibited from dividing, as well as being hindered from migrating. Localized degradation of matrix components is also required wherever cells have to escape from confinement by a basal lamina.Matrix degradation is important both for the spread of cancer cells through the body and for their ability to proliferate in the tissues that they invade (discussed in Chapter 20).In general, matrix components are degraded by extracellular proteolytic enzymes (proteases) that act close to the cells that produce them.Many of these proteases belong to one of two general classes.

The diuretic effect of thiazides is largely due to inhibition of the Na+-Cl– cotransporter NCC in DCT cells.Thiazides have a greater effect on plasma K+ concentration than loop diuretics, despite their lesser natriuretic effect.Apparent mineralocorticoid excess: genetic deficiency of 11β-dehydrogenase-2 (syndrome of apparent mineralocorticoid excess), inhibition of 11β-dehydrogenase-2 (glycyrrhetinic/ glycyrrhizinic acid and/or carbenoxolone; licorice, food products, drugs), Liddle’s syndrome (genetic activation of epithelial Na+ channels) c. Distal delivery of nonreabsorbed anions: vomiting, nasogastric suction, proximal renal tubular acidosis, diabetic ketoacidosis, glue-sniffing (toluene abuse), penicillin derivatives (penicillin, nafcillin, dicloxacillin, ticarcillin, oxacillin, and carbenicillin) 3. Magnesium deficiency of K+. Diarrhea is a globally important cause of hypokalemia, given the worldwide prevalence of infectious diarrheal disease. Noninfectious gastrointestinal processes such as celiac disease, ileostomy, villous adenomas, inflammatory bowel disease, colonic pseudo-obstruction (Ogilvie’s syndrome), VIPomas, and chronic laxative abuse can also cause significant hypokalemia; an exaggerated intestinal secretion of potassium by upregulated colonic BK channels has been directly implicated in the pathogenesis of hypokalemia in many of these disorders. Renal Loss of Potassium Drugs can increase renal K+ excretion by a variety of different mechanisms. Diuretics are a particularly common cause, due to associated increases in distal tubular Na+ delivery and 306 distal tubular flow rate, in addition to secondary hyperaldosteronism. Thiazides have a greater effect on plasma K+ concentration than loop diuretics, despite their lesser natriuretic effect. The diuretic effect of thiazides is largely due to inhibition of the Na+-Cl– cotransporter NCC in DCT cells.The higher propensity of thiazides to cause hypokalemia may also be secondary to thiazide-associated hypocalciuria, versus the hypercalciuria seen with loop diuretics; the increases in downstream luminal calcium in response to loop diuretics inhibit ENaC in principal cells, thus reducing the lumen-negative potential difference and attenuating distal K+ excretion.

Certain other complement proteins also enhance the phagocytes’ bactericidal capacity.Most phagocytes express receptors that bind certain complement proteins; called complement receptors, these receptors bind to the complement proteins deposited onto the bacterial surface and thus facilitate bacterial phagocytosis.Antibodies coating an antigen render it recognizable as foreign by phagocytes (macrophages and neutrophils), which then ingest and destroy it; this is called opsonization. the center panels show opsonization and phagocytosis of a bacterial cell. Antibody first binds to antigens (red) on the bacterial cell through the variable regions. then the antibody’s Fc region binds to Fc receptors (yellow) expressed by macrophages and other phagocytes, facilitating phagocytosis. the right panels show activation of the complement system by antibodies coating a bacterial cell. Bound antibodies form a platform that activates the first protein in the complement system, which deposits complement proteins (blue) on the surface of the bacterium. this can lead in some cases to formation of a pore that lyses the bacterium directly. more generally, complement proteins on the bacterium can be recognized by complement receptors on phagocytes; this stimulates the phagocytes to ingest and destroy the bacterium. thus, antibodies target pathogens and their toxic products for disposal by phagocytes. microbial activation alone. Thus, once antibodies are produced, complement activation against a pathogen can be substantially increased. Certain complement components that are deposited on the bacterial surface can directly lyse the membranes of some bacteria, and this is important in a few bacterial infections (see Fig. 1.28, right panels). The major function of complement, however, is to enable phagocytes to engulf and destroy bacteria that the phagocytes would not otherwise recognize. Most phagocytes express receptors that bind certain complement proteins; called complement receptors, these receptors bind to the complement proteins deposited onto the bacterial surface and thus facilitate bacterial phagocytosis. Certain other complement proteins also enhance the phagocytes’ bactericidal capacity.1.28, bottom panels).The complement system and the phagocytes that antibodies recruit are not themselves antigen-specific; they depend upon antibody molecules to mark the particles as foreign.the effector mechanisms of immunity.1-21 T cells orchestrate cell-mediated immunity and regulate B-cell responses to most antigens.

Therefore, for women who are mildly or moderately symptomatic with fibroids, watchful waiting may allow treatment to be deferred, perhaps indefinitely.Of the 106 women who initially chose watchful waiting, 23% opted for hysterectomy during the course of the year.Furthermore, mental health, general health, and activity indexes were also unchanged.This may lead physicians to underestimate the true impact of the condition, despite the fact that women who have hysterectomies as a result of fibroid-related symptoms have significantly worse scores on SF-36 quality-of-life questionnaires than women diagnosed with hypertension, heart disease, chronic lung disease, or arthritis (44). After an exhaustive review of the medical literature published between 1975 and 2000, with evaluation of 637 relevant articles and careful study of 200 articles, the authors found no satisfactory answers to fundamental question about fibroid treatments (83). Women and their physicians need information on which to base decisions regarding possible treatments. This section summarizes the literature regarding the management of fibroids. Treatment options include observation, medical therapy, hysteroscopic myomectomy, laparoscopic myomectomy, hysterectomy, uterine artery embolization, and focused ultrasound. Watchful Waiting Not having treatment for fibroids rarely results in harm, except for women with severe anemia from fibroid-related menorrhagia or hydronephrosis from ureteric obstruction from an massively enlarged fibroid uterus. Predicting future fibroid growth or onset of new symptoms is not possible (84). During observation, the average fibroid volume increases 9% per year with a range of −25% to +138% (84). A nonrandomized study of women with uterine size 8 weeks or greater who chose watchful waiting found that 77% of women had no significant changes in the self-reported amount of bleeding, pain, or degree of bothersome symptoms at the end of 1 year (85). Furthermore, mental health, general health, and activity indexes were also unchanged. Of the 106 women who initially chose watchful waiting, 23% opted for hysterectomy during the course of the year. Therefore, for women who are mildly or moderately symptomatic with fibroids, watchful waiting may allow treatment to be deferred, perhaps indefinitely.Although not specifically studied, the incidence of hysterectomy for fibroids declines considerably after menopause, suggesting that there is a significant decline in symptoms.Nonsteroidal anti-inflammatory drugs (NSAIDs) were not shown to be effective for the treatment of menorrhagia in women with fibroids.

The ATP synthase functions like a miniature turbine, and it is a reversible device that can couple proton flow to either ATP synthesis or ATP hydrolysis.The large amount of free energy released when H+ flows back into the matrix from the cristae provides the basis for ATP production on the matrix side of mitochondrial cristae membranes by a remarkable protein machine—the ATP synthase.a proton-motive force generated across the plasma membrane pumps nutrients into the cell and expels Na+. (a) In an aerobic bacterium, a respiratory chain fed by the oxidation of substrates produces an electrochemical proton gradient across the plasma membrane. this gradient is then harnessed to make atp, as well as to transport nutrients (proline, succinate, lactose, and lysine) into the cell and to pump Na+ out of the cell. (B) When the same bacterium grows under anaerobic conditions, it derives its atp from glycolysis. as indicated, the atp synthase in the plasma membrane then hydrolyzes some of this atp to establish an electrochemical proton gradient that drives the same transport processes that depend on respiratory chain proton-pumping in (a). Figure 14–35 The rotation of the bacterial flagellum driven by H+ flow. the flagellum is attached to a series of protein rings (pink), which are embedded in the outer and inner membranes and rotate with the flagellum. the rotation is driven by a flow of protons through an outer ring of proteins (the stator) by mechanisms that may resemble those used by the atp synthase. however, the flow of protons in the flagellar motor is always toward the cytosol, both during clockwise and counterclockwise rotation, whereas in atp synthase this flow reverses with the direction of rotation (Movie 14.8). The large amount of free energy released when H+ flows back into the matrix from the cristae provides the basis for ATP production on the matrix side of mitochondrial cristae membranes by a remarkable protein machine—the ATP synthase. The ATP synthase functions like a miniature turbine, and it is a reversible device that can couple proton flow to either ATP synthesis or ATP hydrolysis.The resulting high cellular concentration of ATP makes the free-energy change for ATP hydrolysis extremely favorable, allowing this hydrolysis reaction to drive a very large number of energy-requiring processes throughout the cell.The universal presence of ATP synthase in bacteria, mitochondria, and chloroplasts testifies to the central importance of chemiosmotic mechanisms in cells.

Hypertension increases the relative risk of intracranial hemorrhage by approximately fourfold, likely due to chronic degenerative vasculopathy.Table 42-3 pro-vides a listing of relative incidences of intracranial hemorrhage by anatomic distribution.Hypertension.AVM or aneurysm rupture (along with trauma, discussed previously in this chapter) result in subarachnoid hemorrhage (SAH) because the major cerebral and cortical blood vessels travel in the sub-arachnoid space, between the pia and the arachnoid membranes. SAH can cause immediate concussive-like neuronal dysfunc-tion by exposure of the brain to intra-arterial pressure pulsa-tions during the hemorrhage. Moreover, it can cause delayed ischemia from cerebral arterial vasospasm, which can present as acute worsening of the patient’s neurological status days to weeks after the injury. Patients presenting with intracranial hemorrhages that do not follow typical patterns should undergo cerebral angiography or MRI to evaluate for possible underlying lesions, such as AVM or tumor.Hemorrhagic stroke most commonly occurs within the basal ganglia or cerebellum. The patient is usually hypertensive on admission and has a history of poorly controlled hyperten-sion. Such patients are more likely to present with lethargy or obtundation compared to those who suffer an ischemic stroke. Depressed mental status results from mass effect from the hema-toma in deep structures, which can produce midline shift or herniation. Ischemic stroke does not cause mass effect acutely. Therefore, patients are more likely to present with normal con-sciousness and a focal neurologic deficit. Hemorrhagic strokes tend to present with a relatively gradual decline in neurologic function as the hematoma expands, rather than the immediately maximal symptoms caused by ischemic stroke. Table 42-3 pro-vides a listing of relative incidences of intracranial hemorrhage by anatomic distribution.Hypertension. Hypertension increases the relative risk of intracranial hemorrhage by approximately fourfold, likely due to chronic degenerative vasculopathy.42-16).Most hypertensive hemorrhages should be medically man-aged.The hematoma often contains intact, salvageable axons because the blood dissects through and along neural tracts, and surgical clot evacuation destroys these axons.

This revolution-ary technique enabled the modern methods for the isolation of genes, construction of a DNA vector, introduction of alterations into DNA, and quantitation of gene expression, making it a fun-damental cornerstone of genetic and molecular analysis.Immunoblotting and Immunoprecipitation.As a recombinant DNA tool, it underlies almost all of molecular biology.Because the primer extension products synthesized in one cycle can serve as a template in the next, the number of target DNA copies nearly doubles at each cycle. Thus, a repeated series of cycles result in the exponential accumulation of a specific fragment in which the termini are sharply defined by the 5′ ends of the primers. The introduction of the thermostable DNA polymerase (e.g., Taq polymerase) transforms the PCR into a simple and robust reaction. The reaction components (e.g., template, primers, Taq polymerase, 2′-deoxynucleoside 5′-triphosphates, and buffer) could all be assembled and the amplification reaction carried out by simply cycling the temperatures within the reaction tube. The specificity and yield in amplifying a particular DNA frag-ment by PCR reaction are affected by the proper setting of the reaction parameters (e.g., enzyme, primer, and Mg2+ concen-tration, as well as the temperature cycling profile). Modifying various PCR parameters to optimize the specificity of amplifi-cation yields more homogenous products, even in rare template reactions.The emergence of the PCR technique has dramatically altered the approach to both fundamental and applied bio-logic problems. The capability of amplifying a specific DNA fragment from a gene or the whole genome greatly advances the study of the gene and its function. It is simple, yet robust, speedy, and most of all, flexible. As a recombinant DNA tool, it underlies almost all of molecular biology. This revolution-ary technique enabled the modern methods for the isolation of genes, construction of a DNA vector, introduction of alterations into DNA, and quantitation of gene expression, making it a fun-damental cornerstone of genetic and molecular analysis.Immunoblotting and Immunoprecipitation.For example, Western blotting, also called immunoblotting, is performed to detect protein levels in a popu-lation of cells or tissues, whereas immunoprecipitation is used to concentrate proteins from a larger pool.

Because EF rises in severe MR in the presence of normal LV function, even a modest reduction in this parameter (<60%) reflects significant dysfunction.The regurgitant volume varies directly with the LV systolic pressure and the size of the regurgitant orifice; the latter, in turn, is influenced by the extent of LV and mitral annular dilation.A cleft anterior mitral valve leaflet accompanies primum atrial septal defect. Chronic MR is frequently secondary to ischemia and may occur as a consequence of ventricular remodeling, papillary muscle displacement, and leaflet tethering, or with fibrosis of a papillary muscle, in patients with healed MI(s) and ischemic cardiomyopathy. Similar mechanisms of annular dilation and ventricular remodeling contribute to the MR that occurs among patients with nonischemic forms of dilated cardiomyopathy once the LV end-diastolic dimension reaches 6 cm. Irrespective of cause, chronic severe MR is often progressive, because enlargement of the LA places tension on the posterior mitral leaflet, pulling it away from the mitral orifice and thereby aggravating the valvular dysfunction. Similarly, LV dilation increases the regurgitation, which, in turn, enlarges the LA and LV further, resulting in a vicious circle; hence the aphorism, “mitral regurgitation begets mitral regurgitation.” The resistance to LV emptying (LV afterload) is reduced in patients with MR. As a consequence, the LV is decompressed into the LA during ejection, and with the reduction in LV size during systole, there is a rapid decline in LV tension. The initial compensation to MR is more complete LV emptying. However, LV volume increases progressively with time as the severity of the regurgitation increases and as LV contractile function deteriorates. This increase in LV volume is often accompanied by a reduced forward CO. LV compliance is often increased, and thus, LV diastolic pressure does not increase until late in the course. The regurgitant volume varies directly with the LV systolic pressure and the size of the regurgitant orifice; the latter, in turn, is influenced by the extent of LV and mitral annular dilation. Because EF rises in severe MR in the presence of normal LV function, even a modest reduction in this parameter (<60%) reflects significant dysfunction.Semiquantitative estimates of LV ejection fraction (LVEF), CO, PA systolic pressure, regurgitant volume, regurgitant fraction (RF), and the effective regurgitant orifice area can be obtained during a careful Doppler echocardiographic examination.These measurements can also be obtained accurately with cardiac magnetic resonance (CMR) imaging, although this technology is not widely available.

As will become clear, it is much more useful for the clinician to consider TLC and RV individually.Thus, although VC is easy to measure (see below), it provides little information about the intrinsic properties of the respiratory system.As these recoils are transmitted through the pleural fluid, the lung is pulled both outward and inward simultaneously at FRC, and thus its pressure falls below atmospheric pressure (typically, −5 cmH2O). The normal passive respiratory system would equilibrate at the FRC and remain there were it not for the actions of respiratory muscles. The inspiratory muscles act on the chest wall to generate the equivalent of positive pressure across the lungs and passive chest wall, while the expiratory muscles generate the equivalent of negative transrespiratory pressure. The maximal pressures these sets of muscles can generate vary with the lung volume at which they operate. This variation is due to length-tension relationships in striated muscle sarcomeres and to changes in mechanical advantage as the angles of insertion change with lung volume (Fig. 306e-1). Nonetheless, under normal conditions, the respiratory muscles are substantially “overpowered” for their roles and generate more than adequate force to drive the respiratory system to its stiffness extremes, as determined by the lung (total lung capacity [TLC]) or by chest wall or airway closure (residual volume [RV]); the airway closure always prevents the adult lung from emptying completely under normal circumstances. The excursion between full and minimal lung inflation is called vital capacity (VC; Fig. 306e-2) and is readily seen to be the difference between volumes at two unrelated stiffness extremes—one determined by the lung (TLC) and the other by the chest wall or airways (RV). Thus, although VC is easy to measure (see below), it provides little information about the intrinsic properties of the respiratory system. As will become clear, it is much more useful for the clinician to consider TLC and RV individually.In contrast, the dynamic airflow properties of the lung substantially affect its ability to ventilate and contribute importantly to the work of breathing, and these properties are often deranged by disease.Understanding dynamic airflow properties is therefore worthwhile.

834 Glossary of Cultural Concepts of Distress Although dhat syndrome was formulated as a cultural guide to local clinical practice, related ideas about the harmful effects of semen loss have been shown to be widespread in the general population, suggesting a cultural disposition for explaining health problems and symptoms with reference to dhat syndrome.Related conditions in other cultural contexts: Indisposition in Haiti, blacking out in the Southern United States, and falling out in the West Indies. Related conditions in DSM-S: Panic attack, panic disorder, other specified or unspec- ified dissociative disorder, conversion (functional neurologic symptom) disorder, inter- mittent explosive disorder, other specified or unspecified anxiety disorder, other specified or unspecified trauma and stressor-related disorder. Dhat syndrome is a term that was coined in South Asia little more than half a century ago to account for common clinical presentations of young male patients who attributed their various symptoms to semen loss. Despite the name, it is not a discrete syndrome but rather a cultural explanation of distress for patients who refer to diverse symptoms, such as anx- iety, fatigue, weakness, weight loss, impotence, other multiple somatic complaints, and depressive mood. The cardinal feature is anxiety and distress about the loss of dhat in the absence of any identifiable physiological dysfunction. Dhat was identified by patients as a white discharge that was noted on defecation or urination. Ideas about this substance are related to the concept of dhatu (semen) described in the Hindu system of medicine, Ayurveda, as one of seven essential bodily fluids whose balance is necessary to maintain health. 834 Glossary of Cultural Concepts of Distress Although dhat syndrome was formulated as a cultural guide to local clinical practice, related ideas about the harmful effects of semen loss have been shown to be widespread in the general population, suggesting a cultural disposition for explaining health problems and symptoms with reference to dhat syndrome.Although dhat syndrome is most commonly identified with young men from lower socioeconomic backgrounds, mid- dle-aged men may also be affected.Comparable concerns about white vaginal discharge (leu— korrhea) have been associated with a variant of the concept for women.

Although most cases are idiopathic, in about half there is an associated connective tissue disease, scleroderma being the main one (Porter et al).It is a disease of early onset, the mean age in idiopathic cases being 14 years; it occurs in a number of clinical settings.Numbness, paresthesia, and burning often accompany the color changes.The Effects of Thoracolumbar Sympathectomy Surgical resection of the thoracolumbar sympathetic trunk, widely used in the 1940s in the treatment of hypertension but now of historical interest, provided the clinician with the clearest examples of extensive injury to the peripheral sympathetic nervous system, though a similar defect had long been suspected in one type of primary orthostatic hypotension (see earlier). In general, bilateral thoracolumbar sympathectomy results in surprisingly few disturbances. Aside from loss of sweating over the denervated areas of the body, the most pronounced abnormality is an impairment of vasomotor reflexes. In the upright posture, faintness and syncope are frequent because of pooling of blood in the splanchnic bed and lower extremities. Although the blood pressure may fall steadily to shock levels, there is little or no pallor, nausea, vomiting, or sweating—the usual accompaniments of syncope. Bladder, bowel, and sexual function are preserved, though semen is sometimes ejaculated into the posterior urethra and bladder (retrograde ejaculation). This disorder, characterized by episodic, painful blanching of the fingers and presumably caused by digital artery spasm, was first described by Raynaud in 1862. The appearance is of a triphasic sequence of color change of pallor, cyanosis, and subsequent rubor of the affected fingers or toes, but about one-third of such patients have no cyanosis. The episodes are brought on by cold or emotional stress and are usually followed by redness on rewarming. Numbness, paresthesia, and burning often accompany the color changes. It is a disease of early onset, the mean age in idiopathic cases being 14 years; it occurs in a number of clinical settings. Although most cases are idiopathic, in about half there is an associated connective tissue disease, scleroderma being the main one (Porter et al).In a small group, predominantly men, the syndrome is induced by local trauma, such as prolonged sculling on a cold day, and particularly by vibratory injury incurred by the sustained use of a pneumatic drill or hammer (a syndrome well known in quarry workers).

MTX is metabolized to a less active hydroxylated product.Although variable, bioavailability decreased further in one study when more than 25 mg weekly MTX was used.The drug is approximately 70% absorbed after oral administration (see Chapter 54).Pharmacokinetics: Methotrexate can be administered either orally or parentally (SC or IM).2.Other adverse effects associated with leflunomide are mild alopecia, weight gain, and increased blood pressure. Leukopenia and thrombocytopenia occur rarely. This drug is contraindicated in pregnancy. Methotrexate, a synthetic nonbiologic antimetabolite, is the first-line csDMARD for treating RA and is used in 50–70% of patients. It is active in this condition at much lower doses than those needed in cancer chemotherapy (see Chapter 54). 1. Mechanism of Action: Methotrexate’s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of amino-imidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase. AICAR, which accumulates intracellularly, competitively inhibits AMP deaminase, leading to an accumulation of AMP. The AMP is released and converted extracellularly to adenosine, which is a potent inhibitor of inflammation. As a result, the inflammatory functions of neutrophils, macrophages, dendritic cells, and lymphocytes are suppressed. Methotrexate has secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, it inhibits proinflammatory cytokines linked to rheumatoid synovitis. 2. Pharmacokinetics: Methotrexate can be administered either orally or parentally (SC or IM). The drug is approximately 70% absorbed after oral administration (see Chapter 54). Although variable, bioavailability decreased further in one study when more than 25 mg weekly MTX was used. MTX is metabolized to a less active hydroxylated product.Methotrexate’s serum half-life is usually only 6–9 hours.Hydroxychloroquine can reduce the clearance or increase the tubular reabsorption of methotrexate.Methotrexate is excreted principally in the urine, but up to 30% may be excreted in bile.3.Dosage and Indications: It is recommended to start treatment with 7.5 mg weekly.

172-2).MRI most reliably establishes the diagnosis (Fig.Surgical intervention in this setting often constitutes a medical emergency.Patients complain of difficulty voiding or walking and of radicular pain in addition to the symptoms associated with their osteomyelitis.S. aureus is the most common cause of epidural abscess, a complication that can result in neurologic compromise.This infection of the breast, which generally presents within 2–3 weeks after delivery, is characterized by findings that range from cellulitis to abscess formation. Systemic signs, such as fever and chills, are often present in more severe cases. Musculoskeletal Infections S. aureus is among the most common 957 causes of bone infections—both those resulting from hematogenous dissemination and those arising from contiguous spread from a soft tissue site. Hematogenous osteomyelitis in children most often involves the long bones. Infections present as fever and bone pain or with a child’s reluctance to bear weight. The white blood cell count and erythrocyte sedimentation rate are often elevated. Blood cultures are positive in ~50% of cases. When necessary, bone biopsies for culture and histopathologic examination are usually diagnostic. Routine x-rays may be normal for up to 14 days after the onset of symptoms. 99mTc-phosphonate scanning often detects early evidence of infection. MRI is more sensitive than other techniques in establishing a radiologic diagnosis. In adults, hematogenous osteomyelitis involving the long bones is less common. However, vertebral osteomyelitis is among the more common clinical presentations. Vertebral bone infections are most often seen in patients with endocarditis, those undergoing hemodialysis, diabetics, and injection drug users. These infections may present as intense back pain and fever but may also be clinically occult, presenting as chronic back pain and low-grade fever. S. aureus is the most common cause of epidural abscess, a complication that can result in neurologic compromise. Patients complain of difficulty voiding or walking and of radicular pain in addition to the symptoms associated with their osteomyelitis. Surgical intervention in this setting often constitutes a medical emergency. MRI most reliably establishes the diagnosis (Fig. 172-2).Exposure of bone, a draining fistulous tract, failure to heal, or continued drainage suggests involvement of underlying bone.Bone involvement is established by bone culture and histopathologic examination (revealing evidence of PMN infiltration).Contamination of culture material from adjacent tissue can make the diagnosis of osteomyelitis difficult in the absence of pathologic confirmation.

Also, there may be a special form of chronic relapsing optic neuritis that is the result of an undefined granulomatous process such as sarcoid, as suggested by Kidd and colleagues.The risk is much lower if the initial attack of optic neuritis occurs in childhood (26 percent developed after 40 years of followup [Lucchinetti et al, 1997]), suggesting that some instances of the childhood disease may be of a different type, perhaps viral or postinfectious. The longer the period of observation and the greater the care given to detection of mild cases, the greater the proportion of patients who are found to develop signs of MS; however, most do so within 5 years of the original attack (Ebers, 1985; Hely et al). In fact, in many patients with clinically isolated optic neuritis, MRI has disclosed lesions of the cerebral white matter—suggesting that dissemination, albeit asymptomatic, had already occurred and thereby establishing the diagnosis of MS (Jacobs et al, 1986; Ormerod et al). The Optic Neuritis Study Group has made the point, well known to neurologists, that the recurrence of optic neuritis greatly increases the chances of developing MS. Of practical value is the observation, in the study by Beck and colleagues (2003), that the risk of relapsing-remitting MS is also considerably lower (22 percent at 10 years) if the initial brain MRI fails to reveal other demyelinating lesions. It is unclear whether optic neuritis that occurs alone and is not followed by other evidence of demyelinating disease is simply a restricted form of MS or a manifestation of some other disease process, such as postinfectious encephalomyelitis. By far the most common pathologic basis for optic neuropathy is demyelinating disease, although it is known that a vascular lesion or compression of an optic nerve by a tumor or mucocele may cause a central or cecocentral scotoma that is indistinguishable from the defect of optic neuritis. Also, there may be a special form of chronic relapsing optic neuritis that is the result of an undefined granulomatous process such as sarcoid, as suggested by Kidd and colleagues.The retinal vascular sheathing is caused by T-cell infiltration, identical to that in typical plaques, but this is an infrequent finding, because the retina usually contains no myelinated fibers (Lightman et al).Optic neuritis is, of course, a common feature in neuromyelitis optica (Devic disease), discussed in a later section.Acute Myelitis (Transverse Myelitis) (See Chap.

Evasion of the immune system: Downregulation of MHC class I and II molecules; induction of T cell tolerance; inhibition of normal dendritic cell and/ or T cell function; antigenic loss variants and clonal heterogeneity; increase in regulatory T cells.Limited by the ability of tumor cells to survive in a foreign environment.Metastasis: Spread of tumor cells to lymph nodes or distant tissue sites.Genetic instability: Defects in DNA repair pathways leading to either single-nucleotide or oligonucleotide mutations (as in microsatellite instability, MIN) or more commonly chromosomal instability (CIN) leading to aneuploidy. Caused by loss of function of p53, BRCA1/2, mismatch repair genes, DNA repair enzymes, and the spindle checkpoint. Leads to accumulation of a variety of mutations in different cells within the tumor and heterogeneity. Loss of replicative senescence: Normal cells stop dividing in vitro after 25–50 population doublings. Arrest is mediated by the Rb, p16INK4a, and p53 pathways. Further replication leads to telomere loss, with crisis. Surviving cells often harbor gross chromosomal abnormalities. Relevance to human in vivo cancer remains uncertain. Many human cancers express telomerase. Nonresponsiveness to external growth-inhibiting signals: Cancer cells have lost responsiveness to signals normally present to stop proliferating when they have overgrown the niche normally occupied by the organ from which they are derived. We know very little about this mechanism of growth regulation. Increased angiogenesis: Due to increased gene expression of proangiogenic factors (VEGF, FGF, IL-8) by tumor or stromal cells, or loss of negative regulators (endostatin, tumstatin, thrombospondin). Invasion: Loss of cell-cell contacts (gap junctions, cadherins) and increased production of matrix metalloproteinases (MMPs). Often takes the form of epithelial-to-mesenchymal transition (EMT), with anchored epithelial cells becoming more like motile fibroblasts. Metastasis: Spread of tumor cells to lymph nodes or distant tissue sites. Limited by the ability of tumor cells to survive in a foreign environment. Evasion of the immune system: Downregulation of MHC class I and II molecules; induction of T cell tolerance; inhibition of normal dendritic cell and/ or T cell function; antigenic loss variants and clonal heterogeneity; increase in regulatory T cells.Abbreviations: FGF, fibroblast growth factor; IL, interleukin; MHC, major histocompatibility complex; VEGF, vascular endothelial growth factor.and Rb (discussed below).The progression of a cell through the cell division cycle is regulated at a number of checkpoints by a wide array of genes.In the first phase, G1, preparations are made to replicate the genetic material.

Finally, in contrast to acute GBS, many cases of CIDP respond favorably to the administration of prednisone.Furthermore, CIDP may be distinct immunologically from GBS, insofar as certain HLA antigens occur with greater frequency in patients with CIDP than they do in the normal population, whereas there are no clear HLA propensities in patients with GBS.Both are widespread polyradiculoneuropathies, usually with cytoalbuminologic dissociation of the CSF (raised protein concentration with few or no cells); both exhibit nerve conduction abnormalities characteristic of a demyelinating neuropathy (reduced conduction velocity and partial conduction block in motor nerves), and pathologically, both show similar multifocal perivenous inflammatory infiltrates. But there are also important differences, the most evident of which are the modes of evolution, responses to treatment, and prognosis. As a rule, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) begins insidiously and evolves slowly, either in a steadily progressive or stepwise manner, attaining its maximum severity after several months. From the beginning it may be asymmetrical or involve the arms predominantly. However, in a small proportion of patients (16 percent in the series of McCombe et al [1987b] and a smaller proportion in our own series) the disease at first emerges from a mild or moderate case of GBS, in which case the illness becomes relapsing or simply worsens slowly and progressively. An antecedent infection is usually not identified in patients with CIDP as it is in GBS. Furthermore, CIDP may be distinct immunologically from GBS, insofar as certain HLA antigens occur with greater frequency in patients with CIDP than they do in the normal population, whereas there are no clear HLA propensities in patients with GBS. Finally, in contrast to acute GBS, many cases of CIDP respond favorably to the administration of prednisone.Chronic symmetric sensorimotor loss and areflexia coupled with nerve conduction findings of demyelination essentially defines the illness.Elevated spinal fluid protein concentration is so frequent that it might be added as a diagnostic criterion.The typical findings in nerve conduction studies are of multifocal conduction block as described in Chap.

As a result, an EPSP FIGURE 21–3 Postsynaptic potentials and action potential generation.This shunting effect decreases the change in membrane potential during the excitatory postsynaptic potential.The opening of the chloride channel during the inhibitory postsynaptic potential makes the neuron “leaky” so that changes in membrane potential are more difficult to achieve.When a microelectrode enters a cell, there is a sudden change in the potential recorded by the electrode, which is typically about −60 mV (Figure 21–3A). This is the resting membrane potential of the neuron. Two types of pathways—excitatory and inhibitory—impinge on the motor neuron. When an excitatory pathway is stimulated, a small depolarization or excitatory postsynaptic potential (EPSP) is recorded. This potential is due to the excitatory transmitter acting on an ionotropic receptor, causing an increase in cation permeability. As additional excitatory synapses are activated, there is a graded summation of the EPSPs to increase the size of the depolarization (Figure 21–3A, spatial summation, middle). When a sufficient number of excitatory synapses are activated, the excitatory post-synaptic potential depolarizes the postsynaptic cell to threshold, and an all-or-none action potential is generated. Alternatively, if there is a repetitive firing of an excitatory input, the temporal summation of the EPSPs may also reach the action potential threshold (Figure 21–3A, right). When an inhibitory pathway is stimulated, the postsynaptic membrane is hyperpolarized owing to the selective opening of chloride channels, producing an inhibitory postsynaptic potential (IPSP) (Figure 21–3B, middle). However, because the equilibrium potential for chloride (see Chapter 14) is only slightly more negative than the resting potential (~ −65 mV), the hyperpolarization is small and contributes only modestly to the inhibitory action. The opening of the chloride channel during the inhibitory postsynaptic potential makes the neuron “leaky” so that changes in membrane potential are more difficult to achieve. This shunting effect decreases the change in membrane potential during the excitatory postsynaptic potential. As a result, an EPSP FIGURE 21–3 Postsynaptic potentials and action potential generation.Stimulation of an excitatory pathway (E1, left) generates transient depolarization called an excitatory postsynaptic potential (EPSP).Simultaneous activation of multiple excitatory synapses (E1 + E2, middle) increases the size of the depolarization, so that the threshold for action potential generation is reached.

Sometimes these cause small bowel obstruction, known as meconium ileus. Fig. 7.6). These changes stem from obstruc tion of the air passages by the viscous mucus secretions of submucosal glands and superimposed infections. The bronchioles often are distended with thick mucus, associated with marked hyperplasia and hypertrophy of the mucus-secreting cells. Superimposed infections give rise to severe chronic bronchitis and Fig. 7.5 Mild to moderate changes of CF in the pancreas. The ducts are dilated and plugged with eosinophilic mucin, and the parenchymal glands are atrophic and replaced by fibrous tissue. Fig. 7.6 Lungsofapatientwhodiedofcysticfibrosis.Extensivemucousplugginganddilationofthetracheobronchialtreeareapparent.Thepulmonaryparenchymaisconsolidatedbyacombinationofbothsecretionsandpneumonia;thegreenishdiscolorationistheproductofPseudomonas infections. (Courtesy of Dr. Eduardo Yunis: Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania.) bronchiectasis.Developmentoflungabscessesiscommon.Staphylococcus aureus, Haemophilus influenzae, andPseudomonas aeruginosa arethethreemostcommonorganismsresponsibleforlunginfections.Evenmoresinisteristheincreasingfrequencyofinfectionwithanotherpseudomonad,Burkholderia cepacia.Thisopportunisticbacteriumisparticularlyhardy,andinfectionwiththisorganismhasbeenassociatedwithfulminantillness(“cepaciasyndrome”).Theliver involvement followsthesamebasicpattern.Bilecanaliculiarepluggedbymucinousmaterial,accompaniedbyductularproliferationandportalinflammation.Hepaticsteatosis (“fattyliver”)isacommonfindinginliverbiopsies.Withtime,cirrhosisdevelops,resultingindiffusehepaticnodularity.Suchseverehepaticinvolvementisencounteredinlessthan10%ofpatients.Azoospermia andinfertility arefoundin95%oftheaffectedmaleswhosurvivetoadulthood;bilateral absence of the vas deferens isafrequentfindinginthesepatients.Insomemales,thismaybetheonlyfeaturesuggestinganunderlyingCFTRmutation.7.4 ).Approximately 5% to 10% of the cases come to clinical attention at birth or soon after because of an attack of meconium ileus.Exocrine pancreatic insufficiency occurs in a majority (85% to 90%) of patients and is associated with “severe” CFTR mutations on both alleles (e.g., ΔF508/ΔF508).

Ostium secundum ASDs are the most common cause of these shunts in adults.attributed to increased flow rates across the pulmonic valve with fixed splitting of S2.Copyright, American Heart Association.)Dallas, American Heart Association, 1990, p 45.(From JA Shaver, JJ Leonard, DF Leon: Examination of the Heart, Part IV, Auscultation of the Heart.51e-4 Pulmonic stenosis Tetralogy of Fallot P.Ej S1 S2S1 S2 PART 2 Cardinal Manifestations and Presentation of Diseases P.Ej A2 P2 A.Ej A2P.Ej P.Ej = Pulmonary ejection (valvular) A.Ej = Aortic ejection (root) FIguRe 51e-4 Left. In valvular pulmonic stenosis with intact ventricular septum, right ventricular systolic ejection becomes progressively longer, with increasing obstruction to flow. As a result, the murmur becomes longer and louder, enveloping the aortic component of the second heart sound (A2). The pulmonic component (P2) occurs later, and splitting becomes wider but more difficult to hear because A2 is lost in the murmur and P2 becomes progressively fainter and lower pitched. As the pulmonic gradient increases, the isometric contraction phase shortens until the pulmonic valve ejection sound fuses with the first heart sound (S1). In severe pulmonic stenosis with concentric hypertrophy and decreasing right ventricular compliance, a fourth heart sound appears. Right. In tetralogy of Fallot with increasing obstruction at the pulmonic infundibular area, an increasing amount of right ventricular blood is shunted across the silent ventricular septal defect and flow across the obstructed outflow tract decreases. Therefore, with increasing obstruction the murmur becomes shorter, earlier, and fainter. P2 is absent in severe tetralogy of Fallot. A large aortic root receives almost all cardiac output from both ventricular chambers, and the aorta dilates and is accompanied by a root ejection sound that does not vary with respiration. (From JA Shaver, JJ Leonard, DF Leon: Examination of the Heart, Part IV, Auscultation of the Heart. Dallas, American Heart Association, 1990, p 45. Copyright, American Heart Association.) attributed to increased flow rates across the pulmonic valve with fixed splitting of S2. Ostium secundum ASDs are the most common cause of these shunts in adults.With sinus venosus ASDs, the left-to-right shunt is usually not large enough to result in a systolic murmur, although the ECG may show abnormalities of sinus node function.A grade 2 or 3 mid-systolic murmur may also be heard best at the upper left sternal border in patients with idiopathic dilation of the pulmonary artery; a pulmonary ejection sound is also present in these patients.

Insomnia is often associated with physiological and cognitive arousal and conditioning factors that interfere with sleep.A diagnosis of insomnia disorder should be reserved for those individuals with significant daytime distress or impairment related to their nighttime sleep difficulties.For instance, difficulty initiating sleep is defined by a subjective sleep latency greater than 20—30 minutes, and difficulty maintain~ ing sleep is defined by a subjective time awake after sleep onset greater than 20—30 min- utes. Although there is no standard definition of early-morning awakening, this symptom involves awakening at least 30 minutes before the scheduled time and before total sleep time reaches 61/2 hours. It is essential to take into account not only the final awakening time but also the bedtime on the previous evening. Awakening at 4:00 A.M. does not have the same clinical significance in those who go to bed at 9:00 PM. as in those who go to bed at 1 1:00 PM. Such a symptom may also reflect an age-dependent decrease in the ability to sus- tain sleep or an age-dependent shift in the timing of the main sleep period. Insomnia disorder involves daytime impairments as well as nighttime sleep difficulties. These include fatigue or, less commonly, daytime sleepiness; the latter is more common among older individuals and when insomnia is comorbid with another medical condition (e.g., chronic pain) or sleep disorder (e.g., sleep apnea). Impairment in cognitive performance may include difficulties with attention, concentration and memory, and even with performing simple manual skills. Associated mood disturbances are typically described as irritability or mood lability and less commonly as depressive or anxiety symptoms. Not all individuals with nighttime sleep disturbances are distressed or have functional impairment. For example, sleep continuity is often interrupted in healthy older adults who nevertheless identify themselves as good sleepers. A diagnosis of insomnia disorder should be reserved for those individuals with significant daytime distress or impairment related to their nighttime sleep difficulties. Insomnia is often associated with physiological and cognitive arousal and conditioning factors that interfere with sleep.Thus, excessive attention and efforts to sleep, which override normal sleep-onset mechanisms, may contribute to the development of in- somnia.

349-4.With the increase in the number of patients diagnosed with celiac disease (mostly by serologic studies), the spectrum of histologic changes seen on duodenal biopsy has increased and includes findings that are not as severe as the classic changes shown in Fig.Absence of DQ2/DQ8 excludes the diagnosis of celiac disease. Diagnosis A small-intestinal biopsy is required to establish a diagnosis of celiac disease (Fig. 349-4). A biopsy should be performed when patients have symptoms and laboratory findings suggestive of nutrient malabsorption and/or deficiency as well as a positive tTG antibody test. Since the presentation of celiac disease is often subtle, without overt evidence of malabsorption or nutrient deficiency, a relatively low threshold for biopsy performance is important. It is more prudent to perform a biopsy than another test of intestinal absorption that can never completely exclude or establish this diagnosis. The diagnosis of celiac disease requires the detection of characteristic histologic changes on small-intestinal biopsy together with a prompt clinical and histologic response after the institution of a gluten-free diet. If IgA antiendomysial or tTG antibodies have been detected in serologic studies, they too should disappear after a gluten-free diet is started. With the increase in the number of patients diagnosed with celiac disease (mostly by serologic studies), the spectrum of histologic changes seen on duodenal biopsy has increased and includes findings that are not as severe as the classic changes shown in Fig. 349-4.349-4B).Although these features are characteristic of celiac disease, they are not diagnostic because a similar appearance can develop in tropical sprue, eosinophilic enteritis, and milk-protein intolerance in children and occasionally in lymphoma, bacterial overgrowth, Crohn’s disease, and gastrinoma with acid hypersecretion.

Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose utilization in skeletal muscle (see above discussion of DKA).Pathophysiology Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS.During illness or when oral intake is compromised, patients should (1) frequently measure the capillary blood glucose; (2) measure urinary ketones when the serum glucose is >16.5 mmol/L (300 mg/dL); (3) drink fluids to maintain hydration; (4) continue or increase insulin; and (5) seek medical attention if dehydration, persistent vomiting, or uncontrolled hyperglycemia develop. Using these strategies, early DKA can be prevented or detected and treated appropriately on an outpatient basis. HYPERGLYCEMIC HYPEROSMOLAR STATE Clinical Features The prototypical patient with HHS is an elderly individual with type 2 DM, with a several-week history of polyuria, weight loss, and diminished oral intake that culminates in mental confusion, lethargy, or coma. The physical examination reflects profound dehydration and hyperosmolality and reveals hypotension, tachycardia, and altered mental status. Notably absent are symptoms of nausea, vomiting, and abdominal pain and the Kussmaul respirations characteristic of DKA. HHS is often precipitated by a serious, concurrent illness such as myocardial infarction or stroke. Sepsis, pneumonia, and other serious infections are frequent precipitants and should be sought. In addition, a debilitating condition (prior stroke or dementia) or social situation that compromises water intake usually contributes to the development of the disorder. Pathophysiology Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS. Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose utilization in skeletal muscle (see above discussion of DKA).The absence of ketosis in HHS is not understood.Presumably, the insulin deficiency is only relative and less severe than in DKA.Lower levels of counterregulatory hormones and free fatty acids have been found in HHS than in DKA in some studies.It is also possible that the liver is less capable of ketone body synthesis or that the insulin/glucagon ratio does not favor ketogenesis.

In healthy individuals, this process usually takes from 6 to 12 weeks, depending on the severity of the break and the particular bone that is broken.While compact bone is being formed, the bony callus is removed by the action of osteoclasts, and gradual remodeling restores the bone to its original shape.As in normal bone formation, the spongy bone is gradually replaced by compact bone.The early bone is deposited as an immature bone, which is later replaced by mature compact bone. 300. c. Higher magnification of the callus from the area indicated by the lower rectangle in panel a. A fragment of old bone pulled away from the fracture site by the periosteum is now adjacent to the cartilage. It will be removed by osteoclast activity. The cartilage will calcify and be replaced by new bone spicules as seen in panel b. 300. While the callus is forming, osteoprogenitor cells of the periosteum divide and differentiate into osteoblasts. The newly formed osteoblasts begin to deposit new bone on the outer surface of the bone at some distance from the fracture. This new formation of bone progresses toward the fracture site until new bone forms a bony sheath over the fibrocartilaginous callus. Osteogenic buds from the new bone invade the callus and begin to deposit new bone within the callus, gradually replacing the original fibrous and cartilaginous callus with a bony callus. The cartilage in the original callus calcifies and is replaced by bone as in endochondral ossification. Endosteal proliferation and differentiation also occur in the marrow cavity, and medullary bone grows from both ends of the fracture toward the center. When this bone unites, the bony union of the fractured bone produced by the osteoblasts derived from both the periosteum and endosteum consists of spongy bone. As in normal bone formation, the spongy bone is gradually replaced by compact bone. While compact bone is being formed, the bony callus is removed by the action of osteoclasts, and gradual remodeling restores the bone to its original shape. In healthy individuals, this process usually takes from 6 to 12 weeks, depending on the severity of the break and the particular bone that is broken.PLATE 11 Bone, Ground Section Bone is a specialized connective tissue characterized by a mineralized extracellular matrix.Calcium phosphate, in the form of hydroxyapatite crystals (Ca10(PO4)6OH2), is deposited along the collagen fibrils and in the proteoglycan ground substance.

For this reason, many pharmacologic agents are used with varying degrees of success to treat stress incontinence.The tone of the urethra and bladder neck is maintained in large part by α-adrenergic activity from the sympathetic nervous system.Urethral inserts have not developed a widespread acceptance but may offer a viable treatment option for some select patients.Such inserts are appropriate for women with Figure 26.9 Vaginal incontinence pessaries: (clockwise from top): A: Suarez ring (Cook Urological, Spencer, IN), B: PelvX ring (DesChutes Medical Products, Bend, OR), C: Incontinence dish (Milex Inc., Chicago, IL), D: Incontinence dish with support (Mentor Corp., Santa Barbara, CA), E: Introl prosthesis (was Johnson and Johnson; currently not available), F: Incontinence ring with support (Milex Inc., Chicago, IL), (middle): G: Incontinence dish with support (Milex Inc., Chicago, IL). relatively pure stress incontinence, no history of recurrent urinary tract infections, and no serious contraindications to bacteriuria (e.g., artificial heart valves). The FemSoft device was U.S. Food and Drug Administration (FDA) approved in 1997 and is the only urethral insert that is available in the United States. Several other urethral inserts and urethral occlusion devices were marketed with good effectiveness but were withdrawn from the market. In a 5-year, multicenter trial involving 150 women with a mean follow-up of 15 months, a statistically significant reduction in incontinence episodes and pad weight were observed with 93% of the women having a negative pad test at 12 months. However, urinary tract infections were common and found in 31.3% of the subjects (56). Urethral inserts have not developed a widespread acceptance but may offer a viable treatment option for some select patients. The tone of the urethra and bladder neck is maintained in large part by α-adrenergic activity from the sympathetic nervous system. For this reason, many pharmacologic agents are used with varying degrees of success to treat stress incontinence.Many of these compounds increase vascular tone and may, therefore, lead to problems with hypertension, a condition that afflicts many postmenopausal women with stress incontinence.There is an increased risk for hemorrhagic cerebral vascular accident in women taking phenylpropanolamine, and while the risk is very low, it is not possible to predict who is at risk for this complication (57).

True capillaries lack smooth muscle and are therefore incapable of active constriction.When metabolic activity increases in these tissues, more precapillary vessels open to allow capillary perfusion.In tissues with metarterioles, nonnutritional flow may be continuous from arteriole to venule during low metabolic activity, when many precapillary vessels are closed.This effect is accomplished by metabolic (humoral) factors when the O2 supply becomes too low for the requirements of parenchymal tissue, as occurs in skeletal muscle during exercise. Although a reduction in transmural pressure relaxes the terminal arterioles, blood flow through the capillaries cannot increase if the reduction in intravascular pressure is caused by severe constriction of the upstream microvessels. Large arterioles and metarterioles also exhibit vasomotion. However, their contraction usually does not completely occlude the lumen of the vessel and arrest blood flow, whereas contraction of the terminal arterioles may arrest blood flow. Thus the flow rate in capillaries may be altered by contraction and relaxation of small arteries, arterioles, and metarterioles. Blood flow through the capillaries has been called nutritional flow because it provides for exchange of gases and solutes between blood and tissue. Conversely, blood flow that bypasses the capillaries as it passes from the arterial to the venous side of the circulation via metarterioles has been termed nonnutritional, or shunt, flow (see Fig. 17.22 ). In some areas of the body (e.g., fingertips, ears), true AV shunts exist (see Fig. 17.37 ). However, in many tissues, such as muscle, anatomical shunts are lacking. Even in the absence of these shunts, nonnutritional flow can occur. In tissues with metarterioles, nonnutritional flow may be continuous from arteriole to venule during low metabolic activity, when many precapillary vessels are closed. When metabolic activity increases in these tissues, more precapillary vessels open to allow capillary perfusion. True capillaries lack smooth muscle and are therefore incapable of active constriction.Because of its narrow lumen (i.e., small radius), a thin-walled capillary can withstand high internal pressures without bursting.This property can be explained in terms of the law of Pierre-Simon Laplace: Equation 17.16 T = tension in the vessel wall r = radius of the vessel Laplace’s equation applies to very thin-walled vessels, such as capillaries.

Despite higher preva- lence among older females, polysomnographic studies suggest better preservation of sleep continuity and slow-wave sleep in older females than in older males.Insomnia is a more prevalent complaint among females than among males, with first onset often associated with the birth of a new child or with menopause.Most individuals resume normal sleep patterns after the initial triggering event has disappeared, but others—perhaps those more vulnerable to insomnla—continue experiencing persistent sleep difficulties. Perpetuating factors such as poor sleep habits, irregular sleep scheduling, and the fear of not sleeping feed into the in- somnia problem and may contribute to a Vicious cycle that may induce persistent insomnia. Temperamental. Anxiety or worry-prone personality or cognitive styles, increased arousal predisposition, and tendency to repress emotions can increase vulnerability to insomnia. Environmental. Noise, light, uncomfortably high or low temperature, and high altitude may also increase vulnerability to insomnia. Genetic and physiological. Female gender and advancing age are associated with in- creased vulnerability to insomnia. Disrupted sleep and insomnia display a familial dispo- sition. The prevalence of insomnia is higher among monozygotic twins relative to dizygotic twins; it is also higher in first-degree family members compared with the general population. The extent to which this link is inherited through a genetic predisposition, learned by observations of parental models, or established as a by-product of another psy- chopathology remains undetermined. Course modifiers. Deleterious course modifiers include poor sleep hygiene practices (e.g., excessive caffeine use, irregular sleep schedules). Insomnia is a more prevalent complaint among females than among males, with first onset often associated with the birth of a new child or with menopause. Despite higher preva- lence among older females, polysomnographic studies suggest better preservation of sleep continuity and slow-wave sleep in older females than in older males.The severity of these sleep impairments does not always match the individual’s clinical presentation or subjective complaint of poor sleep, as individuals with insomnia often un- derestimate sleep duration and overestimate wakefulness relative to polysomnography.

The transient receptor potential cation subfamily M member 8 (TRPM8) channel, a known cold temperature sensor, may be a mediator of this syndrome.Although cold may be uncomfortable at some level for many people, it is the reliable, severe, and somewhat prolonged nature of these pains that set them apart.It is best recognized as “brain-freeze” headache or ice-cream headache when due to ingestion.In one study of patients whose computed tomography (CT) scans and CSF findings were negative, ~15% had recurrent episodes of thunderclap headache, and nearly half subsequently developed migraine or TTH. The first presentation of any sudden-onset severe headache should be diligently investigated with neuroimaging (CT or, when possible, MRI with MR angiography) and CSF examination. Formal cerebral angiography should be reserved for those cases in which no primary diagnosis is forthcoming and for clinical situations that are particularly suggestive of intracranial aneurysm. Reversible segmental cerebral vasoconstriction may be seen in primary thunderclap headache without an intracranial aneurysm. In the presence of posterior leukoencephalopathy, the differential diagnosis includes cerebral angiitis, drug toxicity (cyclosporine, intrathecal methotrexate/cytarabine, pseudoephedrine, or cocaine), posttransfusion effects, and postpartum angiopathy. Treatment with nimodipine may be helpful, although by definition, the vasoconstriction of primary thunderclap headache resolves spontaneously. Cold-Stimulus Headache This refers to head pain triggered by application or ingestion/inhalation of something cold. It is bought on quickly and typically resolves within 10–30 min of the stimulus being removed. It is best recognized as “brain-freeze” headache or ice-cream headache when due to ingestion. Although cold may be uncomfortable at some level for many people, it is the reliable, severe, and somewhat prolonged nature of these pains that set them apart. The transient receptor potential cation subfamily M member 8 (TRPM8) channel, a known cold temperature sensor, may be a mediator of this syndrome.It typically resolves within an hour of the stimulus being removed.Examples of stimuli include helmets, swimming goggles, or very long ponytails.Treatment is to recognize the problem and remove the stimulus.

Further, these results were independent of the degree of pancreatic fibrosis.Of patients with “toxic” etiologies of acquired disease (i.e., a history of alcohol or tobacco abuse), 89% experienced prolonged pain relief, whereas only 39% of those with hereditary or idiopathic disease achieved this result.Acute exacerbations of pain in the setting of chronic pain may be due to acute increases in duct pressure or recurrent episodes of acute inflammation in the set-ting of chronic parenchymal disease. Nealon and Matin have described these various pain syndromes as being predictive of the response to various surgical procedures.162 Pain that is found in association with ductal hypertension is most readily relieved by pancreatic duct decompression, through endoscopic stenting or surgical decompression.The surgical relief of pain due to obstructive pancreatopa-thy may be dependent on the degree of underlying fibrosis and the etiology of the disease rather than the presence of ductal obstruction, per se, according to a recent studies from Johns Hopkins. Cooper et al studied 35 patients with chronic pain associated with evidence of duct obstruction who were treated with local resection of the pancreatic head and longitudinal pan-creaticojejunostomy (LR-LPJ), or Frey procedure.163 The degree of pain resolution after surgery was compared to the degree of underlying parenchymal fibrosis. After a follow-up that averaged 22 months, patients with more than 80% fibrosis had 100% pain relief, whereas only 60% patients with less than 10% fibrosis experienced substantial or complete pain relief. Subsequently, this group studied 60 patients who had undergone either the Frey procedure or the Whipple procedure for refractory pain due to chronic pancreatitis.145 In addition to histopathologic findings, they also analyzed the etiology of the disease. Of patients with “toxic” etiologies of acquired disease (i.e., a history of alcohol or tobacco abuse), 89% experienced prolonged pain relief, whereas only 39% of those with hereditary or idiopathic disease achieved this result. Further, these results were independent of the degree of pancreatic fibrosis.

Individuals with behavioral—variant major or mild frontotemporal NCD present with varying degrees of apathy or disinhibition.The criteria must be met for either the behavioral or the lan- guage variant to make the diagnosis, but many individuals present with features of both.Coding note: For probable major neurocognitive disorder due to frontotemporal lobar de- generation, with behavioral disturbance, code first 331.19 (631.09) frontotemporal dis- ease, followed by 294.11 (F02.81) probable major neurocognitive disorder due to frontotemporal lobar degeneration, with behavioral disturbance. For probable major neu- rocognitive disorder due to frontotemporal lobar degeneration, without behavioral distur- bance, code first 331.19 (631.09) frontotemporal disease, followed by 294.10 (F02.80) probable major neurocognitive disorder due to frontotemporal lobar degeneration, without behavioral disturbance. For possible major neurocognitive disorder due to frontotemporal lobar degeneration, code 331.9 (631.9) possible major neurocognitive disorder due to frontotemporal lobar degen— eration. (Note: Do not use the additional code for frontotemporal disease. Behavioral distur- bance cannot be coded but should still be indicated in writing.) For mild neurocognitive disorder due to frontotemporal lobar degeneration, code 331.83 (631.84). (Note: Do not use the additional code for frontotemporal disease. Behavioral disturbance cannot be coded but should still be indicated in writing.) Major or mild frontotemporal neurocognitive disorder (NCD) comprises a number of syn- dromic variants characterized by the progressive development of behavioral and personality change and/ or language impairment. The behavioral variant and three language variants (se- mantic, agrammatic/nonfluent, and logopenic) exhibit distinct patterns of brain atrophy and some distinctive neuropathology. The criteria must be met for either the behavioral or the lan- guage variant to make the diagnosis, but many individuals present with features of both. Individuals with behavioral—variant major or mild frontotemporal NCD present with varying degrees of apathy or disinhibition.Insight is usually impaired, and this often delays medical consultation.The first referral is often to a psychiatrist.Individuals may develop changes in social style, and in religious and political beliefs, with repetitive movements, hoarding, changes in eating behavior, and hyperoral- ity.In later stages, loss of sphincter control may occur.

Insights gained by a wealth of basic and clinical research over the past two decades have revolutionized the contemporary paradigms for the diagnosis and management of RA.Patients with aPL in the absence of any clinical event who are simultaneously positive for aCL, anti-β2GPI, and LA or have SLE are at risk to develop thrombotic events and can be protected by aspirin 80 mg daily. Some patients with APS and patients with CAPS have recurrent thrombotic events despite appropriate anticoagulation. In these cases, IVIg 400 mg/kg every day for 5 days may be of benefit. Patients with CAPS, who are treated in the intensive care unit, are unable to receive warfarin; in this situation, therapeutic doses of low-molecular-weight heparin should be administered. In cases of heparin-induced thrombocytopenia and thrombosis syndrome, inhibitors of phospholipid-bound activated factor X (FXa), such as fondaparinux 7.5 mg SC daily or rivaroxaban 10 mg PO daily, are effective. The above drugs are administered by fixed doses and do not require close monitoring; their safety during the first trimester of pregnancy has not been clearly established. Ankoor Shah, E. William St. Clair Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis. It is the most common form of chronic inflammatory arthritis and often results in joint damage and physical disability. Because it is a systemic disease, RA may result in a variety of extraarticular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities. Insights gained by a wealth of basic and clinical research over the past two decades have revolutionized the contemporary paradigms for the diagnosis and management of RA.Advances in imaging modalities have improved our ability to detect jointinflammationanddestructioninRA.ThescienceofRAhastaken a major leap forward with the identification of new disease-related genes and further deciphering of the molecular pathways of disease pathogenesis.

However, in up to 90% of cases, cough eventually develops—often initially nonproductive and limited to the morning and subsequently accompanied by the production of purulent sputum, sometimes with blood streaking.It is usually localized to the apical and posterior segments of the upper lobes, where the substantially higher mean oxygen tension (compared with that in the lower zones) favors mycobacterial growth. The superior segments of the lower lobes are also more frequently involved. The extent of lung parenchymal involvement varies greatly, from small infiltrates to extensive cavitary disease. With cavity formation, liquefied necrotic contents are ultimately discharged into the airways and may undergo bronchogenic spread, resulting in satellite lesions within the lungs that may in turn undergo cavitation (Figs. 202-6 and 202-7). Massive involvement of pulmonary segments or lobes, with coalescence of lesions, produces caseating pneumonia. While up to one-third of untreated patients reportedly succumb to severe pulmonary TB within a few months after onset (the classic “galloping consumption” of the past), others may undergo a process of spontaneous remission or proceed along a chronic, progressively debilitating course (“consumption” or phthisis). Under these circumstances, some pulmonary lesions become fibrotic and may later calcify, but cavities persist in other parts of the lungs. Individuals with such chronic disease continue to discharge tubercle bacilli into the environment. Most patients respond to treatment, with defervescence, decreasing cough, weight gain, and a general improvement in well-being within several weeks. Early in the course of disease, symptoms and signs are often nonspecific and insidious, consisting mainly of diurnal fever and night sweats due to defervescence, weight loss, anorexia, general malaise, and weakness. However, in up to 90% of cases, cough eventually develops—often initially nonproductive and limited to the morning and subsequently accompanied by the production of purulent sputum, sometimes with blood streaking.Hemoptysis, however, may also result from rupture of a dilated vessel in a cavity (Rasmussen’s aneurysm) or from aspergilloma formation in an old cavity.Pleuritic chest pain sometimes develops in patients with subpleural parenchymal lesions or pleural disease.Extensive disease may produce dyspnea and, in rare instances, adult respiratory distress syndrome.

Recognition of these factors and understanding of this disease entity will enable phy-sicians to prescribe the appropriate treatment strategy, which may alleviate symptoms and improve quality of life.Diagnostic EvaluationOn clinical examination patients often have weakened femoral pulses and a reduced ABI.A similar analysis was reported by Leer-touwer and colleagues who performed a meta-analysis of 14 studies comparing patients with renal arterial stent placement to those who underwent balloon angioplasty alone for renal arterial stenosis.114 The study found that stent placement proved highly successful, with an initial technical success of 98%. The overall cure rate for hypertension was 20%, whereas hypertension was improved in 49%. Renal function improved in 30% of patients and stabilized in 38% of patients. The restenosis rate at follow-up of 6 to 29 months was 17%. Renal stenting resulted in a higher technical success rate and a lower restenosis rate when compared to balloon angioplasty alone.AORTOILIAC OCCLUSIVE DISEASEThe distal abdominal aorta and the iliac arteries are common sites affected by atherosclerosis. The symptoms and natural history of the atherosclerotic process affecting the aortoiliac Brunicardi_Ch23_p0897-p0980.indd 94027/02/19 4:14 PM 941ARTERIAL DISEASECHAPTER 23arterial segment are influenced by the disease distribution and extent. Atherosclerotic plaques may cause clinical symptoms by restricting blood flow due to luminal obstruction or by embo-lizing atherosclerotic debris to the lower extremity circulation. If the aortoiliac plaques reach sufficient mass and impinge on the arterial lumen, obstruction of blood flow to lower extremi-ties occurs. Various risk factors exist that can lead to the devel-opment of aortoiliac occlusive disease. Recognition of these factors and understanding of this disease entity will enable phy-sicians to prescribe the appropriate treatment strategy, which may alleviate symptoms and improve quality of life.Diagnostic EvaluationOn clinical examination patients often have weakened femoral pulses and a reduced ABI.Noninvasive tests such as pulse volume recordings (PVRs) of the lower extremity with estima-tion of the thigh-brachial pressure index may be suggestive of aortoiliac disease.MRA and multidetector CTA are increasingly being used to determine the extent and type of obstruction.

Larger abscesses are generally amenable to percutaneous drainage, with parameters for antibiotic therapy and drain removal similar to those men-tioned previously.Small (<1 cm), multiple abscesses should be sampled and treated with a 4to 6-week course of antibiotics.C albicans and other related yeast cause the majority of fungal hepatic abscesses.The necessity of antimicrobial agent therapy and precise guidelines that dictate duration of catheter drainage have not been estab-lished. A short course (3 to 5 days) of antibiotics that possess aerobic and anaerobic activity seems reasonable so long as the patient has good clinical response to therapy, and most practi-tioners leave the drainage catheter in situ until it is clear that cavity collapse has occurred, output is less than 10 to 20 mL/d, no evidence of an ongoing source of contamination is present, and the patient’s clinical condition has improved.33Organ-Specific InfectionsHepatic abscesses are rare, currently accounting for approximately 15 per 100,000 hospital admissions in the United States. Pyogenic abscesses account for approximately 80% of cases, the remaining 20% being equally divided among parasitic and fungal forms.65 Formerly, pyogenic liver abscesses mainly were caused by pyle-phlebitis due to neglected appendicitis or diverticulitis. Today, manipulation of the biliary tract to treat a variety of diseases has become a more common cause, although in nearly 50% of patients no cause is identified. The most common aerobic bacteria iden-tified in recent series include E coli, K pneumoniae, and other enteric bacilli, enterococci, and Pseudomonas spp., while the most common anaerobic bacteria are Bacteroides spp., anaero-bic streptococci, and Fusobacterium spp. C albicans and other related yeast cause the majority of fungal hepatic abscesses. Small (<1 cm), multiple abscesses should be sampled and treated with a 4to 6-week course of antibiotics. Larger abscesses are generally amenable to percutaneous drainage, with parameters for antibiotic therapy and drain removal similar to those men-tioned previously.Recurrent hepatic or splenic abscesses may require operative intervention—unroofing and marsupialization or splenectomy, respectively.Secondary pancreatic infections (e.g., infected pancreatic necrosis or pancreatic abscess) occur in approximately 10% to 15% of patients who develop severe pancreatitis with necro-sis.

activation of the N-methyl-d-aspartate (NMDA) subtype of the excitatory amino acid receptor, which causes additional Ca2+ influx and neuronal activation; and (4) ephaptic interactions related to changes in tissue osmolarity and cell swelling.The hallmark of an established seizure is typically an electrographic “spike” due to intense near-simultaneous firing of a large number of local excitatory neurons, resulting in an apparent hypersynchronization of the excitatory bursts across a relatively large cortical region. The bursting activity in individual neurons (the “paroxysmal depolarization shift”) is caused by a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca2+), which leads to the opening of voltage-dependent sodium (Na+) channels, influx of Na+, and generation of repetitive action potentials. This is followed by a hyper-polarizing afterpotential mediated by γ-aminobutyric acid (GABA) receptors or potassium (K+) channels, depending on the cell type. The synchronized bursts from a sufficient number of neurons result in a so-called spike discharge on the EEG. The spreading seizure wavefront is slowed and ultimately halted by intact hyperpolarization and a “surround” inhibition created by feed-forward activation of inhibitory neurons. With sufficient activation, there is a recruitment of surrounding neurons via a number of synaptic and nonsynaptic mechanisms, including: (1) an increase in extracellular K+, which blunts hyperpolarization and depolarizes neighboring neurons; (2) accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release; (3) depolarization-induced Alkylating agents (e.g., busulfan, chlorambucil) Antimalarials (chloroquine, mefloquine) Cyclosporine OKT3 (monoclonal antibodies to T cells) Tacrolimus Interferons Antidepressants (e.g., bupropion) Antipsychotics (e.g., clozapine) Lithium Drugs of abuse aIn benzodiazepine-dependent patients. activation of the N-methyl-d-aspartate (NMDA) subtype of the excitatory amino acid receptor, which causes additional Ca2+ influx and neuronal activation; and (4) ephaptic interactions related to changes in tissue osmolarity and cell swelling.Many factors control neuronal excitability, and thus there are many potential mechanisms for altering a neuron’s propensity to have bursting activity.

1.8 Movementofsmallmoleculesandlargerstructuresacrossmembranes.Thelipidbilayerisrelativelyimpermeabletoallbutthesmallestand/ormosthydrophobicmolecules.Thus,theimportorexportofchargedspeciesrequiresspecifictransmembranetransporterproteins;theinternalizationorexternalizationoflargeproteins,complexparticles,orevencellsrequiresencirclingthemwithsegmentsofthemembrane.Smallchargedsolutescanmoveacrossthemembraneusingeitherchannelsorcarriers;ingeneral,eachmoleculerequiresauniquetransporter.Channels areusedwhenconcentrationgradientscandrivethesolutemovement.Carriers arerequiredwhensoluteismovedagainst aconcentrationgradient.Receptor-mediatedandfluid-phaseuptakeofmaterialinvolvesmembrane-boundvacuoles.Caveolae endocytoseextracellularfluid,membraneproteins,andsomereceptor-boundmolecules(e.g.,folate)inaprocessdrivenbycaveolinproteinsconcentratedwithinlipidrafts.Pinocytosis ofextracellularfluidandmostsurfacereceptor–ligandpairsinvolvesclathrincoated pits and vesicles.Afterinternalization,theclathrindissociatesandcanbereused,whereastheresultingvesicleprogressivelymaturesandacidifies.Intheearlyand/orlateendosome,ligandcanbereleasedfromitsreceptor(e.g.,ironreleasedfromtransferrinboundtothetransferrinreceptor)withreceptorrecyclingtothecellsurfaceforanotherround.Alternatively,receptorandligandwithinendosomescanbetargetedtofusewithlysosomes(e.g.,epidermalgrowthfactorboundtoitsreceptor);aftercompletedegradation,thelateendosome–lysosomefusionvesiclecanreconstitutelysosomes.Phagocytosis involvesthenon–clathrin-mediatedmembraneinvaginationoflargeparticles—typicallybyspecializedphagocytes(e.g.,macrophagesorneutrophils).Theresultingphagosomeseventuallyfusewithlysosomestofacilitatethedegradationoftheinternalizedmaterial.Transcytosis involvesthetranscellularendocytotictransportofsoluteand/orboundligandfromonefaceofacelltoanother.Exocytosis istheprocessbywhichmembrane-boundvesiclesfusewiththeplasmamembraneanddischargetheircontentstotheextracellularspace.Transcytosis is the movement of endocytosed vesicles between the apical and basolateral compartments of cells; this is a mechanism for transferring large amounts of intact proteins across epithelial barriers (e.g., ingested antibodies in maternal milk across intestinal epithelia) or for the rapid movement of large volumes of solute.

Inherited deiciencies of these inhibitory proteins are caused by gene mutations.Several important regulatory proteins act as inhibitors at strategic sites in the coagulation cascade to maintain blood fluidity.Nine received neuraxial analgesia without complications, but only after fresh-frozen plasma was transfused to most to correct the activated partial thromboplastin time.Familial hypoibrinogenemia and sometimes aibrinogenemia are infrequent recessive disorders. In some cases, both are found-hypodysibrinogenemia (Deering, 2003). Our experience suggests that hypoibrinogenemia represents a heterozygous autosomal dominant state. he thrombinclottable protein level in these patients typically ranges from 80 to 110 mg/ dL when nonpregnant, and this increases by 40 or 50 percent in normal pregnancy. Those pregnancy complications that give rise to acquired hypoibrinogenemia, such as placental abruption, are more common with ibrinogen deiciency. Trehan and Fergusson (1991) and Funai and coworkers (1997) described successful outcomes in two afected women in whom ibrinogen or plasma inusions were given throughout pregnancy. Conduction Analgesia with Bleeding Disorders Most serious bleeding disorders would logically preclude the use of epidural or spinal analgesia for labor or delivery. If the bleeding disorder is controlled, however, conduction analgesia may be considered. Chi and colleagues (2009) reviewed intrapartum outcomes in 80 pregnancies in 63 women with an inherited bleeding disorder. These included those with factor XI deiciency, hemophilia carrier status, vWD, platelet disorders, or a deiciency of factor VII, Xl, or X. Regional block was used in 41. Of these, 35 had spontaneously normalized hemostatic dysfunction, and others were given prophylactic replacement therapy. The reviewers reported no unusual complications. Singh and associates (2009) reviewed 13 women with factor XI deiciency. Nine received neuraxial analgesia without complications, but only after fresh-frozen plasma was transfused to most to correct the activated partial thromboplastin time. Several important regulatory proteins act as inhibitors at strategic sites in the coagulation cascade to maintain blood fluidity. Inherited deiciencies of these inhibitory proteins are caused by gene mutations.These are discussed in Chapter 52 (p. 1005) and reviewed by the American College of Obstetricians and Gynecologists (2017b).Aessopos A, Karabatsos F, Farmakis D, et al: Pregnancy in patients with welltreated 3-thalassemia: outcome for mothers and newborn infants.Am J Obstet Gynecol 180:360, 1999 American College of Obstetricians and Gynecologists: Hemoglobinopathies in pregnancy.

Patients who respond can develop bowel perforation from responding tumor.The prognosis of this form of lymphoma is typically (median survival is 7 months) poor, but some patients have a good response to CHOP chemotherapy.Most patients have the HLA genotype associated with celiac disease, HLA DQA1*0501 or DQB1*0201.Many patients with extranodal NK/T-cell lymphoma, nasal type have excellent antitumor responses with combination chemotherapy regimens, particularly those with localized disease. Radiation therapy is often used after completion of chemotherapy. Four risk factors have been defined, including B symptoms, advanced stage, elevated LDH, and regional lymph node involvement. Patient survival is linked to the number of risk factors: 5-year survival is 81% for zero risk factors, 64% for one risk factor, 32% for two risk factors, and 7% for three or four risk factors. Combination regimens without anthracyclines have been touted as superior to CHOP, but data are sparse. High-dose therapy with stem cell transplantation has been used, but its role is unclear. Enteropathy-Type T-Cell Lymphoma Enteropathy-type T-cell lymphoma is a rare complication of longstanding celiac disease. It most commonly occurs in the jejunum or the ileum. In adults, the lymphoma may be diagnosed at the same time as celiac disease, but the suspicion is that the celiac disease was a longstanding precursor to the development of lymphoma. The tumor usually presents as multiple ulcerating mucosal masses, but may also produce a dominant exophytic mass or multiple ulcerations. The tumor expresses CD3 and CD7 nearly always and may or may not express CD8. The normal-appearing lymphocytes in the adjacent mucosa often have a similar phenotype to the tumor. Most patients have the HLA genotype associated with celiac disease, HLA DQA1*0501 or DQB1*0201. The prognosis of this form of lymphoma is typically (median survival is 7 months) poor, but some patients have a good response to CHOP chemotherapy. Patients who respond can develop bowel perforation from responding tumor.Hepatosplenic T-Cell Lymphoma Hepatosplenic T-cell lymphoma is a malignancy derived from T cells expressing the gamma/delta T-cell antigen receptor that affects mainly the liver and fills the sinusoids with medium-size lymphoid cells.When the spleen is involved, dominantly the red pulp is infiltrated.

The prevertebral fascia passing between the attachment points on the transverse processes is unique.Anteriorly, the prevertebral fascia is attached to the anterior surfaces of the transverse processes and bodies of vertebrae CI to CVII.Attaching posteriorly to the ligamentum nuchae and the spinous process of the CVII vertebra, this fascial layer splits as it passes forward to enclose the trapezius muscle, reunites into a single layer as it forms the roof of the posterior triangle, splits again to surround the sternocleidomastoid muscle, and reunites again to join its twin from the other side. Anteriorly, the investing fascia merges with fascia surrounding the infrahyoid muscles. The investing fascia is attached: superiorly to the external occipital protuberance and the superior nuchal line, laterally to the mastoid process and zygomatic arch, and inferiorly to the spine of the scapula, the acromion, the clavicle, and the manubrium of the sternum. The external and anterior jugular veins, and the lesser occipital, great auricular, transverse cervical, and supraclavicular nerves, all branches of the cervical plexus, pierce the investing fascia. The prevertebral layer is a cylindrical layer of fascia that surrounds the vertebral column and the muscles associated with it (Fig. 8.162). Muscles in this group include the prevertebral muscles, the anterior, middle, and posterior scalene muscles, and the deep muscles of the back. The prevertebral fascia is attached posteriorly along the length of the ligamentum nuchae, and superiorly forms a continuous circular line attaching to the base of the skull. This circle begins: anteriorly as the fascia attaches to the basilar part of the occipital bone, the area of the jugular foramen, and the carotid canal; continues laterally, attaching to the mastoid process; and continues posteriorly along the superior nuchal line ending at the external occipital protuberance, where it associates with its partner from the opposite side. Anteriorly, the prevertebral fascia is attached to the anterior surfaces of the transverse processes and bodies of vertebrae CI to CVII. The prevertebral fascia passing between the attachment points on the transverse processes is unique.8.162 and 8.163).There is one additional specialization of the prevertebral fascia in the lower region of the neck.The prevertebral fascia in an anterolateral position extends from the anterior and middle scalene muscles to surround the brachial plexus and subclavian artery as these structures pass into the axilla.This fascial extension is the axillary sheath.

4.21).The abdomen is the part of the trunk inferior to the thorax (Fig.Visceral sensory fibers generally parallel the motor pathways.Parasympathetic components are from the vagus nerve [X] and spinal cord levels S2 to S4.The prevertebral plexus contains sympathetic, parasympathetic, and visceral sensory components: Sympathetic components originate from spinal cord levels T5 to L2.Other regions where portal and caval systems interconnect include: where the liver is in direct contact with the diaphragm (the bare area of the liver); where the wall of the gastrointestinal tract is in direct contact with the posterior abdominal wall (retroperitoneal areas of the large and small intestine); and the posterior surface of the pancreas (much of the pancreas is secondarily retroperitoneal). Blockage of the hepatic portal vein or of vascular channels in the liver Blockage of the hepatic portal vein or of vascular channels in the liver can affect the pattern of venous return from abdominal parts of the gastrointestinal system. Vessels that interconnect the portal and caval systems can become greatly enlarged and tortuous, allowing blood in tributaries of the portal system to bypass the liver, enter the caval system, and thereby return to the heart. Portal hypertension can result in esophageal and rectal varices and in caput medusae in which systemic vessels that radiate from para-umbilical veins enlarge and become visible on the abdominal wall. Abdominal viscera are supplied by a large prevertebral plexus Innervation of the abdominal viscera is derived from a large prevertebral plexus associated mainly with the anterior and lateral surfaces of the aorta (Fig. 4.20). Branches are distributed to target tissues along vessels that originate from the abdominal aorta. The prevertebral plexus contains sympathetic, parasympathetic, and visceral sensory components: Sympathetic components originate from spinal cord levels T5 to L2. Parasympathetic components are from the vagus nerve [X] and spinal cord levels S2 to S4. Visceral sensory fibers generally parallel the motor pathways. The abdomen is the part of the trunk inferior to the thorax (Fig. 4.21).The abdominal cavity may extend superiorly as high as the fourth intercostal space, and is continuous inferiorly with the pelvic cavity.It contains the peritoneal cavity and the abdominal viscera.Topographical divisions of the abdomen are used to describe the location of abdominal organs and the pain associated with abdominal problems.

Abnormalities in Amplitude, Duration, and Shape of Motor Unit Potentials Figure 2-20 depicts the ways in which disease processes affect the motor unit and the appearance of the MUP in the EMG.In the stiff man syndrome, painful muscle spasms and stiffness are generated by a spinal mechanism; the EMG potentials resemble normal motor units but are abnormal by virtue of continuous firing at rest.2-19B), as the patient becomes able to relax the exercised muscle (“warmup” effect). In paradoxical myotonia the myotonia worsens after each of a succession of voluntary contractions. This is the converse of what happens in myotonia congenita (Thomsen disease). As shown by single-fiber EMG studies, myotonia is generated by single muscle fibers and the mechanism of the membrane instability, at least in some forms, seems to involve changes in the chloride conductance. These disorders are discussed in subsequent chapters. The cramp-like contracture of McArdle disease and phosphofructokinase deficiency is associated with electrical silence of contracting muscle. This feature is an important part of the definition of true physiologic muscle contracture (as distinguished from chronic shortening of a muscle and its tendon which, strictly speaking, is a pseudocontracture). In the syndrome of continuous muscle fiber activity or Isaacs syndrome (see Chap. 46), which is a generalized form of myokymia, the EMG discloses high-frequency (up to 300-Hz) repetitive discharges of varying waveforms. In the stiff man syndrome, painful muscle spasms and stiffness are generated by a spinal mechanism; the EMG potentials resemble normal motor units but are abnormal by virtue of continuous firing at rest. Abnormalities in Amplitude, Duration, and Shape of Motor Unit Potentials Figure 2-20 depicts the ways in which disease processes affect the motor unit and the appearance of the MUP in the EMG.In time, the remaining MUPs often increase in size and in electrical amplitude, perhaps two to three times normal, and become longer in duration and sometimes polyphasic (more than four phases).Such large and sometimes giant polyphasic potentials (Fig.

Previous studies have compared several cardiac risk indices.Preoperative laboratory testing should be carried out only for specific clinical conditions, as noted during clinical examination. Thus, healthy patients of any age who are undergoing elective surgical procedures without coexisting medical conditions should not require any testing unless the degree of surgical stress may result in unusual changes from the baseline state. A stepwise approach to cardiac risk assessment and stratification in patients undergoing noncardiac surgery is illustrated in Fig. 9-1. Assessment of exercise tolerance in the prediction of in-hospital perioperative risk is most helpful in patients who self-report worsening exercise-induced cardiopulmonary symptoms; those who may benefit from noninvasive or invasive cardiac testing regardless of a scheduled surgical procedure; and those with known coronary artery disease (CAD) or with multiple risk factors who are able to exercise. For predicting perioperative events, poor exercise tolerance has been defined as the inability to walk four blocks or climb two flights of stairs at a normal pace or to meet a metabolic equivalent (MET) level of 4 (e.g., carrying objects of 15–20 lb or playing golf or doubles tennis) because of the development of dyspnea, angina, or excessive fatigue (Table 9-2). Previous studies have compared several cardiac risk indices.Stepwise clinical evaluation: [1] emergency surgery; [2] prior coronary revascularization; [3] prior coronary evaluation; [4] clinical assessment; [5] RCRI; [6] risk modification strategies.Preventive medical therapy = beta blocker and statin therapy.RCRI, revised cardiac risk index.(Adapted from LA Fleisher et al: Circulation 116:1971, 2007, with permission.)

Renal lesions include membranoproliferative glomerulonephritis (MPGN), diffuse proliferative and exudative glomerulonephritis (DPGN), or mesangioproliferative glomerulonephritis, sometimes leading to RPGN.Serum complement levels are low, and there may be elevated levels of C-reactive proteins, rheumatoid factor, antinuclear antibodies, and cryoglobulins.Embolic infarcts or septic abscesses may also be present. The pathogenesis hinges on the renal deposition of circulating immune complexes in the kidney with complement activation. Patients present with gross or microscopic hematuria, pyuria, and mild proteinuria or, less commonly, RPGN with rapid loss of renal function. A normocytic anemia, elevated erythrocyte sedimentation rate, hypocomplementemia, high titers of rheumatoid factor, type III cryoglobulins, circulating immune complexes, and ANCAs may be present. Levels of serum creatinine may be elevated at diagnosis, but with modern therapy there is little progression to chronic renal failure. Primary treatment is eradication of the infection with 4–6 weeks of antibiotics, and if accomplished expeditiously, the prognosis for renal recovery is good. ANCA-associated vasculitis sometimes accompanies or is confused 1838 with subacute bacterial endocarditis (SBE) and should be ruled out, as the treatment is different. As variants of persistent bacterial infection in blood-associated glomerulonephritis, postinfectious glomerulonephritis can occur in patients with ventriculoatrial and ventriculoperitoneal shunts; pulmonary, intraabdominal, pelvic, or cutaneous infections; and infected vascular prostheses. In developed countries, a significant proportion of cases afflict adults, especially the immunocompromised, and the predominant organism is Staphylococcus. The clinical presentation of these conditions is variable and includes proteinuria, microscopic hematuria, acute renal failure, and hypertension. Serum complement levels are low, and there may be elevated levels of C-reactive proteins, rheumatoid factor, antinuclear antibodies, and cryoglobulins. Renal lesions include membranoproliferative glomerulonephritis (MPGN), diffuse proliferative and exudative glomerulonephritis (DPGN), or mesangioproliferative glomerulonephritis, sometimes leading to RPGN.The prognosis is guarded.Lupus nephritis is a common and serious complication of systemic lupus erythematosus (SLE) and most severe in African-American female adolescents.Thirty to 50% of patients will have clinical manifestations of renal disease at the time of diagnosis, and 60% of adults and 80% of children develop renal abnormalities at some point in the course of their disease.

self-management skills.In Schidlow DV, Smith DS, editors: A Practical Guide to Pediatric Disease, Philadelphia, 1994, Hanley & Belfus.In vitro serum tests, such as radioallergosorbent test (also known as RAST), fluorescent enzyme immunoassay (also known as FEIA), or enzyme-linked immunosorbent assay, are generally less sensitive in defining clinically pertinent allergens, are more expensive, and require several days for results compared to several minutes for skin testing (see Table 77-4). A chest radiograph should be performed with the first episode of asthma or with recurrent episodes of undiagnosed cough or wheeze to exclude anatomic abnormalities. Repeat chest radiographs are not needed with new episodes unless there is fever (suggesting pneumonia) or localized findings on physical examination. Two novel forms of monitoring asthma and airway inflammation directly include exhaled nitric oxide analysis and quantitative analysis of expectorated sputum for eosinophilia. Many childhood conditions can cause wheezing and coughingof asthma (Table 78-1) but not all cough and wheeze is asthma. Misdiagnosis delays correcting the underlying cause andexposes children to inappropriate asthma therapy (Table 78-2). Allergic bronchopulmonary aspergillosis is a hypersensitivity type of reaction to antigens of the mold Aspergillus fumigatus. It occurs primarily in patients with steroid-dependent asthma and in patients with cystic fibrosis. Optimal medical treatment of asthma includes several key components: environmental control, pharmacologic therapy, and patient education, including attainment of C—Cystic fibrosis R—Respiratory tract infections A—Aspiration (swallowing dysfunction, gastroesophageal reflux, tracheoesophageal fistula, foreign body) D—Dyskinetic cilia L—Lung and airway malformations (laryngeal webs, laryngotracheomalacia, tracheal stenosis, vascular rings and slings) E—Edema (heart failure, congenital heart disease) From Schidlow DV: Cough. In Schidlow DV, Smith DS, editors: A Practical Guide to Pediatric Disease, Philadelphia, 1994, Hanley & Belfus. self-management skills.For all children with asthma, exposures to tobacco and wood smoke and to persons with viral infections should be minimized.Influenza immunizations are indicated.Asthma medications can be divided into long-term control medications and quick-relief medications.

For convenience, the steps in this figure are depicted as occurring one at a time; in reality, many occur concurrently.Before it can be translated into protein, the two ends of the RNA are modified, the introns are removed by an enzymatically catalyzed RNA splicing reaction, and the resulting mRNA is transported from the nucleus to the cytoplasm.DNA gyrase therefore makes the opening of the DNA helix in bacteria energetically favorable compared with helix opening in DNA that is not supercoiled. For this reason, it facilitates those genetic processes in bacteria, such as the initiation of transcription by bacterial RNA polymerase, that require helix opening (see Figure 6–11). Transcription Elongation in Eukaryotes Is Tightly Coupled to RNA Processing We have seen that bacterial mRNAs are synthesized by the RNA polymerase starting and stopping at specific spots on the genome. The situation in eukaryotes is substantially different. In particular, transcription is only the first of several steps needed to produce a mature mRNA molecule. Other critical steps are the covalent modification of the ends of the RNA and the removal of intron sequences that are discarded from the middle of the RNA transcript by the process of RNA splicing (Figure 6–20). Both ends of eukaryotic mRNAs are modified: by capping on the 5ʹ end and by polyadenylation of the 3ʹ end (Figure 6–21). These special ends allow the cell to assess whether both ends of an mRNA molecule are present (and if the message is therefore intact) before it exports the RNA from the nucleus and translates it Figure 6–20 Comparison of the steps leading from gene to protein in eukaryotes and bacteria. The final level of a protein in the cell depends on the efficiency of each step and on the rates of degradation of the RNA and protein molecules. (A) In eukaryotic cells, the mRNA molecule resulting from transcription contains both coding (exon) and noncoding (intron) sequences. Before it can be translated into protein, the two ends of the RNA are modified, the introns are removed by an enzymatically catalyzed RNA splicing reaction, and the resulting mRNA is transported from the nucleus to the cytoplasm. For convenience, the steps in this figure are depicted as occurring one at a time; in reality, many occur concurrently.Because of the coupling between transcription and RNA processing, intact primary transcripts—the full-length RNAs that would, in theory, be produced if no processing had occurred—are found only rarely.(B) In prokaryotes, the production of mRNA is much simpler.

In the first phase of development, progenitor B cells in the bone marrow rearrange their immunoglobulin genes.8.1 B cells develop in the bone marrow and migrate to peripheral lymphoid organs, where they can be activated by antigens.Fig.Positive and negative selection of T cells.Development of T lymphocytes.Given the incredible diversity of receptors that the rearrangement process can generate, it is important that those lymphocytes that mature are likely to be useful in recognizing and responding to foreign antigens, especially as an individual can express only a small fraction of the total possible receptor repertoire in his or her lifetime. We describe how the specificity and affinity of the receptor for self ligands are tested to determine whether the immature lymphocyte will either survive and join the mature repertoire, or die. In general, it seems that developing lymphocytes whose receptors interact weakly with self antigens, or that bind self antigens in a particular way, receive a signal that enables them to survive. This process, known as positive selection, is particularly critical in the development of α:β T cells, which recognize composite antigens consisting of peptides bound to MHC molecules, because it ensures that an individual’s T cells will be able to respond to peptides bound to one’s own MHC molecules. In contrast, lymphocytes with strongly self-reactive receptors must be eliminated to prevent autoimmune reactions; this process of negative selection is one of the ways in which the immune system is made self-tolerant. The default fate of developing lymphocytes, in the absence of any signal being received from the receptor, is death by apoptosis, and as we will see, the vast Development of B lymphocytes. Development of T lymphocytes. Positive and negative selection of T cells. Fig. 8.1 B cells develop in the bone marrow and migrate to peripheral lymphoid organs, where they can be activated by antigens. In the first phase of development, progenitor B cells in the bone marrow rearrange their immunoglobulin genes.It ends in an immature B cell that carries an antigen receptor in the form of cell-surface IgM (second panels), and in the second phase it can now interact with antigens in its environment.Immature B cells that are strongly stimulated by antigen at this stage either die or are inactivated in a process of negative selection, thus removing many self-reactive B cells from the repertoire.

Independent of homocysteine, low levels of circulating vitamin B6 have been associated with inflammation and elevated levels of C-reactive protein.291e and 434e).Since vitamin B6 is necessary for the conversion of homocysteine to cystathionine, it is possible that chronic low-grade vitamin B6 deficiency may result in hyperhomocysteinemia and increased risk of cardiovascular disease (Chaps.Vitamin B6 refers to a family of compounds that includes pyridoxine, pyridoxal, pyridoxamine, and their 5′-phosphate derivatives. 5′-Pyridoxal phosphate (PLP) is a cofactor for more than 100 enzymes involved in amino acid metabolism. Vitamin B6 also is involved in heme and neurotransmitter synthesis and in the metabolism of glycogen, lipids, steroids, sphingoid bases, and several vitamins, including the conversion of tryptophan to niacin. Dietary Sources Plants contain vitamin B6 in the form of pyridoxine, whereas animal tissues contain PLP and pyridoxamine phosphate. The vitamin B6 contained in plants is less bioavailable than that in animal tissues. Rich food sources of vitamin B6 include legumes, nuts, wheat bran, and meat, although it is present in all food groups. Deficiency Symptoms of vitamin B6 deficiency include epithelial changes, as seen frequently with other B vitamin deficiencies. In addition, severe vitamin B6 deficiency can lead to peripheral neuropathy, abnormal electroencephalograms, and personality changes that include depression and confusion. In infants, diarrhea, seizures, and anemia have been reported. Microcytic hypochromic anemia is due to diminished hemoglobin synthesis, since the first enzyme involved in heme biosynthesis (aminolevulinate synthase) requires PLP as a cofactor (Chap. 126). In some case reports, platelet dysfunction has been reported. Since vitamin B6 is necessary for the conversion of homocysteine to cystathionine, it is possible that chronic low-grade vitamin B6 deficiency may result in hyperhomocysteinemia and increased risk of cardiovascular disease (Chaps. 291e and 434e). Independent of homocysteine, low levels of circulating vitamin B6 have been associated with inflammation and elevated levels of C-reactive protein.Pyridoxine should be given concurrently with isoniazid to avoid neuropathy.The increased ratio of AST to ALT seen in alcoholic liver disease reflects the relative vitamin B6 dependence of ALT.

Liver-spleen scans, bone scans, and brain scans are unnecessary unless symptoms or signs suggest metastases to these sites.If the hepatic enzyme values are normal, the likelihood of liver disease is low.The value of PET scanning is still being evaluated (105–107).The findings only rarely preclude laparotomy (103).Ultrasonographic signs of malignancy include an adnexal pelvic mass with areas of complexity, such as irregular borders, multiple echogenic patterns within the mass, and dense multiple irregular septae. Bilateral tumors are more likely to be malignant, although the individual characteristics of the lesions are of greater significance. Transvaginal ultrasonography may have a somewhat better resolution than transabdominal ultrasonography for adnexal neoplasms (93–96). Doppler color flow imaging may enhance the specificity of ultrasonography for demonstrating findings consistent with malignancy (97–99). In postmenopausal women with unilocular cysts measuring 8 to 10 cm or less and normal serial CA125 levels, expectant management is acceptable, and this approach may decrease the number of surgical interventions (100–102). The diagnosis of an ovarian cancer requires an exploratory laparotomy. The preoperative evaluation of the patient with an adnexal mass is outlined in Figure 14.19 (see Chapter 14). Before the planned exploration, the patient should undergo routine hematologic and biochemical assessments. A preoperative evaluation in a patient undergoing laparotomy should include a radiograph of the chest. Abdominal and pelvic computed tomography (CT) or MRI are of limited value for a patient with a definite pelvic mass (103–105). A CT or MRI should be performed for patients with ascites and no pelvic mass to look for liver or pancreatic tumors. The findings only rarely preclude laparotomy (103). The value of PET scanning is still being evaluated (105–107). If the hepatic enzyme values are normal, the likelihood of liver disease is low. Liver-spleen scans, bone scans, and brain scans are unnecessary unless symptoms or signs suggest metastases to these sites.A barium enema or colonoscopy is indicated in selected patients with symptoms and signs suspicious for colon cancer.This study should be performed for any patient who has evidence of occult blood in the stool or of intestinal obstruction.

H1R binding mediates vasodilation, bronchocon-striction, intestinal motility, and myocardial contractility.There are four histamine receptor (HR) subtypes with varying physiologic roles, but they are all members of the rhodopsin family of G-protein coupled receptors.It is interesting that the surface expression of SERT on platelets is sensitive to plasma 5-HT levels, which in turn modulates platelet 5-HT content. Receptors for serotonin are widely distributed in the periphery and are found in the GI tract, cardiovascular system, and some immune cells.172 Serotonin is a potent vasoconstrictor and also modulates cardiac inotropy and chronotropy through nonadrenergic cyclic adenosine mono-phosphate (cAMP) pathways. Serotonin is released at sites of injury, primarily by platelets. Recent work has demonstrated an important role for platelet 5-HT in the local inflammatory response to injury. Using mice that lack the nonneuronal iso-form of tryptophan hydroxylase (Tph1), the rate-limiting step for 5-HT synthesis in the periphery, investigators demonstrated fewer neutrophils rolling on mesenteric venules.173 Tph1-/mice, in response to an inflammatory stimulus, also showed decreased neutrophil extravasation. Together, these data indicate an impor-tant role for nonneuronal 5-HT in neutrophil recruitment to sites of inflammation and injury.HistamineHistamine is a short-acting endogenous amine that is widely distributed throughout the body. It is synthesized by histidine decarboxylase (HDC), which decarboxylates the amino acid his-tidine. Histamine is either rapidly released or stored in neurons, skin, gastric mucosa, mast cells, basophils, and platelets and plasma levels are increased with hemorrhagic shock, trauma, thermal injury, and sepsis.174 Not surprisingly, circulating cyto-kines can increase immune cell expression of HDC to further contribute to histamine synthesis. There are four histamine receptor (HR) subtypes with varying physiologic roles, but they are all members of the rhodopsin family of G-protein coupled receptors. H1R binding mediates vasodilation, bronchocon-striction, intestinal motility, and myocardial contractility.However, H2R can also modulate a range of immune system activities, such as mast cell degranula-tion, antibody synthesis, Th1 cytokine production, and T-cell proliferation.H3R was initially classified as a presynaptic auto-receptor in the peripheral and central nervous system (CNS).However, data using H3R knockout mice demonstrates that it also participates in inflammation in the CNS.

Kollman et al., Nature 466:879–883, 2010.(A and B, from J.M.Microtubules often have one such “seam” breaking the otherwise uniform helical packing of the protofilaments.Note the longitudinal discontinuity between two protofilaments, which results from the spiral orientation of the γ-tubulin subunits.Within this complex, two accessory proteins bind directly to the γ-tubulin, along with several other proteins that help create a spiral ring of γ-tubulin molecules, which serves as a template that creates a microtubule with 13 protofilaments (Figure 16–46). Figure 16–45 Direct observation of the dynamic instability of microtubules in a living cell. Microtubules in a newt lung epithelial cell were observed after the cell was injected with a small amount of rhodamine-labeled tubulin. Notice the dynamic instability of microtubules at the edge of the cell. Four individual microtubules are highlighted for clarity; each of these shows alternating shrinkage and growth (Movie 16.7). (Courtesy of Wendy C. Salmon and Clare Waterman-Storer.) schematic of ˛-tubulin seven copies of Figure 16–46 Microtubule nucleation by the γ-tubulin ring complex. (A) Two copies of γ-tubulin associate with a pair of accessory proteins to form the γ-tubulin small complex (γ-TuSC). This image was generated by high-resolution electron microscopy of individual purified complexes. (B) Seven copies of the γ-TuSC associate to form a spiral structure in which the last γ-tubulin lies beneath the first, resulting in 13 exposed γ-tubulin subunits in a circular orientation that matches the orientation of the 13 protofilaments in a microtubule. (C) In many cell types, the γ-TuSC spiral associates with additional accessory proteins to form the γ-tubulin ring complex (γ-TuRC), which is likely to nucleate the minus end of a microtubule as shown here. Note the longitudinal discontinuity between two protofilaments, which results from the spiral orientation of the γ-tubulin subunits. Microtubules often have one such “seam” breaking the otherwise uniform helical packing of the protofilaments. (A and B, from J.M. Kollman et al., Nature 466:879–883, 2010.A centrosome typically recruits more than fifty copies of γ-TuRC.In addition, γ-TuRC molecules are found in the cytoplasm, and centrosomes are not absolutely required for microtubule nucleation, since destroying them with a laser pulse does not prevent microtubule nucleation elsewhere in the cell.

It is a solitary, enlarging, ring-like erythematous lesion that may be surrounded by annular satellite lesions.In 60 to 80 percent of cases, a skin lesion (erythema chronicum migrans, or erythema migrans) at the site of a tick bite is the initial manifestation, occurring within 30 days of exposure.Most infections are acquired from May to July.Later, neurologic abnormalities appear, but only in small a proportion of such cases. The early neurologic complications are mainly derivations of meningitis. Unlike syphilis, peripheral and cranial nerves are often damaged (see further on and Chap. 43). Immune factors may be important in the later phases of the disease and in the development of the neurologic syndromes. Lyme disease is less acute than leptospirosis (Weil disease) and less chronic than syphilis. It successively involves the skin, nervous system, heart, and articular structures over a period of a year or longer although one aspect or another may predominate. The responsible organism, as stated earlier, is the spirochete B. burgdorferi and the vector in the United States is the common deer tick (Ixodes dammini). The precise roles of the infecting spirochete, the antibodies it induces, and other features of the human host response in the production of clinical symptoms and signs are not fully understood, but the development of an animal model by Pachner and colleagues suggests that there may be a chronic form of Borrelia infection. Lyme borreliosis has a worldwide distribution but the typical neurologic manifestations differ slightly in Europe and America, as emphasized in the review by Garcia-Monico and Benach (as does the serologic testing). In the United States, where approximately 15,000 cases are reported annually, the disease is found mainly in the Northeast and the North Central states. Most infections are acquired from May to July. In 60 to 80 percent of cases, a skin lesion (erythema chronicum migrans, or erythema migrans) at the site of a tick bite is the initial manifestation, occurring within 30 days of exposure. It is a solitary, enlarging, ring-like erythematous lesion that may be surrounded by annular satellite lesions.This assumes importance in patients who may have acquired the illness in another part of the world in whom the correct diagnosis may be missed if the specific antibody for the regional organism is not sought.The European variant has a propensity to cause the painful lymphocytic meningoradiculitis, Bannwarth syndrome, as summarized in the review by Pachner and Steiner.

23.6 Cerebralinfarction.(A)Infiltrationofacerebralinfarctionbyneutrophilsbeginsattheedgesofthelesion,wherethevascularsupplyisintact.(B)Byday10,anareaofinfarctionshowsthepresenceofmacrophagesandsurroundingreactivegliosis.(C)Oldintracorticalinfarctsareseenasareasoftissuelossandresidualgliosis. http://ebooksmedicine.net MORPHOLOGYHemorrhagic infarcts usuallymanifestasmultiple,sometimesconfluent,petechialhemorrhages( Fig.23.7AandB ).Themicroscopicpictureandevolutionofhemorrhagicinfarctionparallelthoseofischemicinfarction,withtheadditionofbloodextravasationandresorption.Inindividualswithcoagulopathies,hemorrhagicinfarctsmaybeassociatedwithextensiveintracerebralhematomas. Themacroscopicappearanceofanonhemorrhagic infarct evolvesovertime.Duringthefirst6hours,thetissueisunchangedinappearance,butby48hours,thetissuebecomespale,soft,andswollen.Fromdays2to10,theinjuredbrainturnsgelatinousandfriable,andtheboundarybetweennormalandabnormaltissuebecomesmoredistinctasedemaresolvesintheadjacentviabletissue.Fromday10toweek3,thetissueliquefies,eventuallyleavingafluid-filledcavity,whichgraduallyexpandsasdeadtissueisresorbed(see Fig.23.7C Microscopically,thetissuereactionfollowsacharacteristicsequence.Afterthefirst12hours,ischemicneuronalchange(redneurons)(see Fig.23.1A )andcytotoxicandvasogenicedemaappear.Endothelialandglialcells,mainlyastrocytes,swell,andmyelinatedfibersbegintodisintegrate.Duringthefirstseveraldaysneutrophilsinfiltratetheareaofinjury,butthesearereplacedoverthenext2–3weeksbymacrophages.Macrophagescontainingmyelinorredbloodcellbreakdownproductsmaypersistinthelesionformonthstoyears.Astheprocessofphagocytosisandliquefactionproceeds,astrocytesattheedgesofthelesionprogressivelyenlarge,divide,anddevelopaprominentnetworkofcytoplasmicextensions.Afterseveralmonths,thestrikingastrocyticnuclearandcytoplasmicenlargementregresses.Inthewallofthecavity,astrocyteprocessesformadensefeltworkofglialfibersadmixedwithnewcapillariesandafewperivascularconnectivetissuefibers.Subarachnoid hemorrhages most commonly are the result of ruptured aneurysms but also occur with other vascular malformations.Subdural or epidural hemorrhages usually are associated with trauma.Spontaneous (nontraumatic) intraparenchymal hemorrhages are most common in mid to late adult life, with a peak incidence at about 60 years of age.

The analysis of pathobiology from a systems-based perspective is likely to help define specific subsets of patients more likely to respond to particular interventions based on shared disease mechanisms.This will be a lengthy and complicated process but ultimately will lead to better disease prevention and therapy and probably do so from an increasingly personalized perspective.For example, from this perspective, acute myocardial infarction (AMI) and its consequences are a reflection of thrombosis (in the coronary artery), inflammation (in the acutely injured myocardium), and fibrosis (at the site or sites of cardiomyocyte death). In effect, the major therapies for AMI address these intermediate pathophenotypes (e.g., antithrombotics, statins) rather than any organ-specific disease-determining process. This paradigm would argue for a systems-based analysis that would first identify the intermediate pathophenotypes to which a person is predisposed, then determine how and when to intervene to attenuate that adverse predisposition, and finally limit the likelihood that a major organ-specific event will occur. Evidence for the validity of this approach is found in the work of Rzhetsky and colleagues, who reviewed 1.5 million patient records and 161 diseases and found that these disease phenotypes form a network of strong pairwise correlations. This result is consistent with the notion that underlying genetic predispositions to intermediate pathophenotypes form the predicate basis for conventionally defined end organ diseases. Regardless of the specific nature of the systems pathobiologic approach used, these analyses will lead to a drastic revision of the way human disease is defined and treated, establishing the discipline of network medicine. This will be a lengthy and complicated process but ultimately will lead to better disease prevention and therapy and probably do so from an increasingly personalized perspective. The analysis of pathobiology from a systems-based perspective is likely to help define specific subsets of patients more likely to respond to particular interventions based on shared disease mechanisms.

Then an alarming regression occurs, sometimes fairly abruptly.The autistic child is ostensibly normal at birth and may continue to be normal in achieving early behavioral sequences until 18 to 24 months of age.This gene has variants that appear disproportionately often in schizophrenia as well, leading to speculation on common biologic processes.DeMyer found that 4 of 11 monozygotic twins were concordant for autism and that siblings have a 50 times greater risk of developing the disorder than normal children. Bailey and associates and also LeCouteur and associates have reported a concordance rate in monozygotic twins of 71 percent for the autistic spectrum disorder (as defined below) and 92 percent for an even broader phenotype of disordered social communication and stereotypic or obsessive behaviors. DeLong has found an increased incidence of bipolar disease in the families of one group of autistic children and superior mathematical aptitudes in other family members. The elucidation of microdeletions and microduplications within chromosome 16p by Weiss and colleagues, working with the Autism Consortium was the first hint of a genetic locus for susceptibility to autism. Despite a high degree of penetrance in individuals with these changes, the importance of these findings is as a biologic direction for research as it explains no more than 1 percent of cases. Furthermore, certain polymorphisms, particularly in the SHANK3 gene may explain a small number of cases. Shank proteins serve as scaffolds on the post-synaptic membranes of glutamatergic synapses, and are highly expressed in the striatum. This gene has variants that appear disproportionately often in schizophrenia as well, leading to speculation on common biologic processes. The autistic child is ostensibly normal at birth and may continue to be normal in achieving early behavioral sequences until 18 to 24 months of age. Then an alarming regression occurs, sometimes fairly abruptly.The level of activity is reduced or increased.There may be less crying and an apparent indifference to surroundings.Toys are ignored or held tenaciously.Spinning toys or running water may hold a strange fascination for the child.Cuddling may be resisted.Motor developments, on the other hand, proceed normally and may even be precocious.

Alemtuzumab appears to deplete leukemic (and normal) cells by direct antibody-dependent lysis.Alemtuzumab was previously approved for the treatment of B-cell chronic lymphocytic leukemia (CLL) in patients who have been treated with alkylating agents and have failed fludarabine therapy.Rattlesnake and coral snake hyperimmune globulins (antivenoms) are of equine or ovine origin and are effective for North and South American rattlesnakes and some coral snakes (but not Arizona coral snake). Equine and ovine antivenoms are available for rattlesnake envenomations, but only equine antivenom is available for coral snake bite. An Arizona bark scorpion antivenom is also available as equine (Fab)′2. This preparation prevents neurologic manifestations of scorpion envenomation and is generally used in young children and infants. Advances in the ability to manipulate the genes for immunoglobulins have resulted in development of a wide array of humanized and chimeric monoclonal antibodies directed against therapeutic targets. As described above, the only murine elements of humanized monoclonal antibodies are the complementarity-determining regions in the variable domains of immunoglobulin heavy and light chains. Complementarity-determining regions are primarily responsible for the antigen-binding capacity of antibodies. Chimeric antibodies typically contain antigen-binding murine variable regions and human constant regions. The following are brief descriptions of the engineered antibodies that have been approved for clinical use; they are presented alphabetically by indication. Alemtuzumab is a humanized IgG1 with a kappa chain that binds to CD52 found on normal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and a small population of granulocytes. Alemtuzumab was previously approved for the treatment of B-cell chronic lymphocytic leukemia (CLL) in patients who have been treated with alkylating agents and have failed fludarabine therapy. Alemtuzumab appears to deplete leukemic (and normal) cells by direct antibody-dependent lysis.In the latter, alemtuzumab depletes autoimmune inflammatory T and B cells while the drug is in the circulation.Repopulating lymphocytes appear to temporarily rebalance the immune system.Patients receiving this antibody become lymphopenic and may also become neutropenic, anemic, and thrombocytopenic.

Two seemingly unrelated forms of CIN, Chinese herbal nephropathy and Balkan endemic nephropathy, have recently been linked by the underlying etiologic agent aristolochic acid and are now collectively termed aristolochic acid nephropathy (AAN).Nonetheless, it is recommended that heavy users of acetaminophen and NSAIDs be screened for evidence of renal disease.Analgesic nephropathy results from the long-term use of compound analgesic preparations containing phenacetin (banned in the United States since 1983), aspirin, and caffeine. In its classic form, analgesic nephropathy is characterized by renal insufficiency, papillary necrosis (Table 340-3) attributable to the presumed concentration of the drug to toxic levels in the inner medulla, and a radiographic constellation of small, scarred kidneys with papillary calcifications best appreciated by computed tomography (Fig. 340-5). Patients may also have polyuria due to impaired concentrating ability and non-anion-gap metabolic acidosis from tubular damage. Shedding of a sloughed necrotic papilla can cause gross hematuria and ureteric colic due to ureteral obstruction. Individuals with ESRD as a result of analgesic nephropathy are at increased risk of a urothelial malignancy compared to patients with other causes of renal failure. Recent cohort studies in individuals with normal baseline renal function suggest that the moderate chronic use of current analgesic preparations available in the United States, including acetaminophen and NSAIDs, does not seem to cause the constellation of findings known as analgesic nephropathy, although volume-depleted individuals and those with chronic kidney disease are at higher risk of NSAID-related renal toxicity. Nonetheless, it is recommended that heavy users of acetaminophen and NSAIDs be screened for evidence of renal disease. Two seemingly unrelated forms of CIN, Chinese herbal nephropathy and Balkan endemic nephropathy, have recently been linked by the underlying etiologic agent aristolochic acid and are now collectively termed aristolochic acid nephropathy (AAN).Multiple Aristolochia species have been used in traditional herbal remedies for centuries and continue to be available despite official bans on their use in many countries.Molecular evidence has also implicated aristolochic acid in Balkan endemic nephropathy, a chronic tubulointerstitial nephritis found primarily in towns along the tributaries of the Danube River and first described in the 1950s.

Reach for the fetal arm.Enter the vagina and attempt rotation (Wood’s screw).Pressure (suprapubic).Leg elevated (McRoberts’ maneuver).Episiotomy.In the event of dystocia, be the mother’s HELPER: Help reposition.Diagnosed by a prolonged second stage of labor, recoil of the perineum (“turtle sign”), and lack of spontaneous restitution.Williams Obstetrics, 22nd ed. New York: McGraw-Hill, 2005: Fig.11-1.) Molar pregnancy may progress to malignant GTD, including invasive moles (10–15%) and choriocarcinoma (2–5%) with pulmonary or CNS metastases. Trophoblastic pulmonary emboli may also be seen. Affect 3% of all live births. Since 1980, there has been a 65% ↑ in the frequency of dizygotic (fraternal) twins and a 500% ↑ in triplet and high-order births (most due to the advent of assisted reproductive technology). The incidence of monozygotic (identical) twins has remained steady. Hx/PE: Characterized by rapid uterine growth, excessive maternal weight gain, and palpation of three or more large fetal parts on Leopold’s maneuvers. Dx: Ultrasound; hCG, HPL, and MSAFP are elevated for GA. Tx: Multifetal reduction and selective fetal termination is an option for higher-order multiple pregnancies; antepartum fetal surveillance for IUGR. Management by a high-risk specialist is recommended. Cx: Maternal: Patients are six times more likely to be hospitalized with complications—e.g., preeclampsia, preterm labor, preterm PROM (PPROM), placental abruption, pyelonephritis, and postpartum hemorrhage. Fetal: Complications include twin-to-twin transfusion syndrome, IUGR, and preterm labor. Affects 0.6–1.4% of all deliveries in the United States. Risk factors include obesity, diabetes, a history of a macrosomic infant, and a history of prior shoulder dystocia. Diagnosed by a prolonged second stage of labor, recoil of the perineum (“turtle sign”), and lack of spontaneous restitution. In the event of dystocia, be the mother’s HELPER: Help reposition. Episiotomy. Leg elevated (McRoberts’ maneuver). Pressure (suprapubic). Enter the vagina and attempt rotation (Wood’s screw). Reach for the fetal arm.First-stage protraction or arrest: Labor that fails to produce adequate rates of progressive cervical change.Prolonged second-stage arrest: Nulliparous: Inadequate cervical dilation after > 3 hours with regional anesthesia; > 2 hours without.Multiparous: Inadequate cervical dilation after > 2 hours with regional anesthesia; > 1 hour without.See Table 2.11-16.

Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized.Since phenoxybenzamine enters the CNS, it may cause less specific effects including fatigue, sedation, and nausea.Nasal stuffiness and inhibition of ejaculation also occur.The drug also inhibits reuptake of released nor-epinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H1), acetylcholine, and serotonin receptors as well as α receptors (see Chapter 16). The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of α-receptor–mediated events. The most significant effect is attenuation of catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic α2 receptors in cardiac sympathetic nerves. Phenoxybenzamine is absorbed after oral administration, although bioavailability is low; its other pharmacokinetic properties are not well known. The drug is usually given orally, starting with dosages of 10 mg/d and progressively increasing the dose until the desired effect is achieved. A dosage of less than 100 mg/d is usually sufficient to achieve adequate α-receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below). Most adverse effects of phenoxybenzamine derive from its α-receptor–blocking action; the most important are orthostatic hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the CNS, it may cause less specific effects including fatigue, sedation, and nausea. Because phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized.Phentolamine reduces peripheral resistance through blockade of α1 receptors and possibly α2 receptors on vascular smooth muscle.Its cardiac stimulation is due to antagonism of presynaptic α2 receptors (leading to enhanced release of norepinephrine from sympathetic nerves) and sympathetic activation from baroreflex mechanisms.

9.28A ).The horizontal gaze center consists of neurons in the paramedian pontine reticular formation, in the vicinity of the abducens nucleus ( Fig.From the superior colliculus, information is forwarded to distinct sites for control of horizontal and vertical saccades, referred to as the horizontal and vertical gaze centers, respectively.Thecalorictestismoreusefulbecauseitcandistinguishbetweenmalfunctionofthelabyrinthsonthetwosides.Theneckisbentbackwardabout60degreessothatthetwohorizontalcanalsareessentiallyvertical.Ifwarmwaterisintroducedintotheleftear,theendolymphintheouterportionoftheloopoftheleftsemicircularcanaltendstoriseasthespecificgravityoftheendolymphdecreasesbecauseofheating.Thissetsupaconvectionflowofendolymph,andasaresult,thekinociliaoftheleftampullarycresthaircellsaredeflectedtowardtheutricle,asiftheheadhadrotatedtotheleft;thedischargeoftheafferentfibersthatsupplythiscanalincreases;andnystagmusoccurswiththefastphasetowardtheleft.Thenystagmusproducesasensationthattheenvironmentisspinningtotheright,andthepersontendstofalltotheright.Theoppositeeffectsareproducedifcoldwaterisplacedintheear.AmnemonicexpressionthatcanhelpinrememberingthedirectionofthenystagmusinthecalorictestisCOWS (“coldopposite,warmsame”).Inotherwords,coldwaterinoneearresultsinafastphaseofnystagmustowardtheoppositeside,andwarmwatercausesafastphasetowardthesameside. posterior parietal areas). Activity in the superior colliculus is related to computation of the direction and amplitude of the saccade. Indeed, the deep layers of the superior colliculus contain a topographic motor map of saccade locations. From the superior colliculus, information is forwarded to distinct sites for control of horizontal and vertical saccades, referred to as the horizontal and vertical gaze centers, respectively. The horizontal gaze center consists of neurons in the paramedian pontine reticular formation, in the vicinity of the abducens nucleus ( Fig. 9.28A ).Because the circuitry and operation of the horizontal gaze center are better understood than those of the vertical gaze center, it is discussed here in detail.However, cells showing analogous activity patterns have been described in the vertical gaze center.Fig.9.28A is an overview of the neural circuitry by which saccades are generated, and Fig.

In the United States, most cancers in women more than 50 years of age are now detected by mammography ( Fig.Mammography has met this promise, as the average size of invasive carcinomas detected by mammography is about 1 cm (significantly smaller than cancers identified by palpation), and only 15% will have metastasized to regional lymph nodes at the time of diagnosis.Lumpiness, or a diffuse nodularity throughout the breast, is usually a result of normal glandular tissue. When pronounced, imaging studies may help to determine whether a discrete mass is present. Palpable masses can arise from proliferations of stromal cells or epithelial cells and are generally detected when they are 2 to 3 cm in size ( Fig. 19.22 ). Most (~95%) are benign; these tend to be round to oval and to have circumscribed borders. In contrast, malignant tumors usually invade across tissue planes and have irregular borders. However, because some cancers grow deceptively as circumscribed masses, all palpable masses require evaluation. Gynecomastia is the only common breast symptom in males. There is an increase in both stroma and epithelial cells resulting from an imbalance between estrogens, which stimulate breast tissue, and androgens, which counteract these effects. Regardless of presenting symptom, the likelihood of malignancy increases with age. For example, the risk of nipple discharge being due to cancer increases from 7% in women younger than 60 years of age to 30% in women older than 60. Similarly, only 10% of palpable masses in women younger than 40 years of age are carcinomas, as compared to 60% in women older than 50. Mammographic screening was introduced in the 1980s as a means to detect early, nonpalpable asymptomatic breast carcinomas before metastatic spread has occurred. Mammography has met this promise, as the average size of invasive carcinomas detected by mammography is about 1 cm (significantly smaller than cancers identified by palpation), and only 15% will have metastasized to regional lymph nodes at the time of diagnosis. In the United States, most cancers in women more than 50 years of age are now detected by mammography ( Fig.As with symptomatic breast lesions, the likelihood that an abnormal mammographic finding is caused by malignancy increases with age, from 10% at age 40 to more than 25% in women older than age 50.Symptomsaffectingthebreastsareevaluatedprimarilytodetermineifmalignancyispresent.Regardlessofthesymptom,theunderlyingcauseisbenigninthemajorityofcases.

Rarely, suture ligation may be necessary if massive bleed-ing persists.In general, rectal varices are best treated by lowering portal venous pres-sure.Rectal varices, however, may occur and may cause hemorrhage in these patients.It is now understood that hemorrhoidal disease is no more common in patients with portal hypertension than in the normal population.Treatment of exter-nal hemorrhoids and skin tags is only indicated for symptomatic relief.Internal hemorrhoids are located proximal to the dentate line and covered by insensate anorectal mucosa. Internal hem-orrhoids may prolapse or bleed, but they rarely become painful unless they develop thrombosis and necrosis (usually related to severe prolapse, incarceration, and/or strangulation). Inter-nal hemorrhoids are graded according to the extent of prolapse. First-degree hemorrhoids bulge into the anal canal and may prolapse beyond the dentate line on straining. Second-degree hemorrhoids prolapse through the anus but reduce spontane-ously. Third-degree hemorrhoids prolapse through the anal canal and require manual reduction. Fourth-degree hemorrhoids prolapse but cannot be reduced and are at risk for strangulation.Combined internal and external hemorrhoids straddle the dentate line and have characteristics of both internal and external hemorrhoids. Hemorrhoidectomy is often required for large, symptomatic, combined hemorrhoids. Postpartum hemorrhoids result from straining during labor, which results in edema, thrombosis, and/or strangulation. Hemorrhoidectomy is often the treatment of choice, especially if the patient has had chronic hemorrhoidal symptoms. Portal hypertension was long thought to increase the risk of hemorrhoidal bleeding because of the anastomoses between the portal venous system (middle and upper hemorrhoidal plexuses) and the systemic venous system (inferior rectal plexuses). It is now understood that hemorrhoidal disease is no more common in patients with portal hypertension than in the normal population. Rectal varices, however, may occur and may cause hemorrhage in these patients. In general, rectal varices are best treated by lowering portal venous pres-sure. Rarely, suture ligation may be necessary if massive bleed-ing persists.Associated pruritus often may improve with improved hygiene.

Cholelithiasis and nephrolithiasis occur with increased frequency.Other Manifestations Some female patients have repeated spontaneous abortions, and most become amenorrheic prior to diagnosis.The features are diverse and may include loss of emotional control (temper tantrums, crying bouts), depression, hyperactivity, or loss of sexual inhibition.In severe hepatic failure, hemolytic anemia may develop because large amounts of copper derived from hepatocellular necrosis are released into the bloodstream. The association of hemolysis and liver disease makes Wilson’s disease a likely diagnosis. Neurologic Features The neurologic manifestations of Wilson’s dis-2519 ease typically occur in patients in their early twenties, although the age of onset extends into the sixth decade of life. MRI and CT scans reveal damage in the basal ganglia and occasionally in the pons, medulla, thalamus, cerebellum, and subcortical areas. The three main movement disorders include dystonia, incoordination, and tremor. Dysarthria and dysphagia are common. In some patients, the clinical picture closely resembles that of Parkinson’s disease. Dystonia can involve any part of the body and eventually leads to grotesque positions of the limbs, neck, and trunk. Autonomic disturbances may include orthostatic hypotension and sweating abnormalities as well as bowel, bladder, and sexual dysfunction. Memory loss, migraine-type headaches, and seizures may occur. Patients have difficulty focusing on tasks, but cognition usually is not grossly impaired. Sensory abnormalities and muscular weakness are not features of the disease. Psychiatric Features Half of patients with neurologic disease have a history of behavioral disturbances with onset in the 5 years before diagnosis. The features are diverse and may include loss of emotional control (temper tantrums, crying bouts), depression, hyperactivity, or loss of sexual inhibition. Other Manifestations Some female patients have repeated spontaneous abortions, and most become amenorrheic prior to diagnosis. Cholelithiasis and nephrolithiasis occur with increased frequency.Microscopic hematuria is common, and levels of urinary excretion of phosphates, amino acids, glucose, or urates may increase; however, a full-blown Fanconi syndrome is rare.Sunflower cataracts and Kayser-Fleischer rings (copper deposits in the outer rim of the cornea) may be seen.Electrocardiographic and other cardiac abnormalities have been reported but are not common.

The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma.55553 5555 5.55 m BE 95555 $55me £0.65 555255 53559:.“ 5553 50558.5»...— wczfiwot: HBBEAuEABEK .5555me 5555 55m @5538 $5385 mm 55m 855 .5558 93.555 chsz $55: 5 555894. 5a§5§t§8§m§ 559535555 :0 5355 5: .5 :55: B 58 muzwc a 55553 50 505585 2.: 55:55.5 555m 558.550 5: ohm 35w: $3 533505 5555533 55 50:55 95mg 5553 5mm5|m2=mc 50 9555ng 535:5 5058555555 555 0.5sz 5555582 5563 @55325 .932 55558?” 35.55: 555—mm: 55:55:85 5 5535 525? 3mg 6.355 2 5mm: 55 :8 @593 :25me 2.5..— ..555855 5:53 @5555— 5 @5533 $350me $555.58 mm 553 @593 555 .mmm 58 5555 55me 55“...on 9 5me .wfixumn E 35qu m5. m5 .555 _.5 wacmbumufib 5: 553 555.3 555.55 5 555 5% 5:5 >32 .8395 355 m 2 5w 9 @555 m305£ 555 35: mme £55855 .55 9555 .5 59: .5 5.55 55.. 2 5mm: 52 55.5% .5258me ww5m5u 5m: 50 .5535 9.5.532 55m m3o5m5m 553 5555 E 505555 5.55 5550 m5 $Em~5505>5w 55555 55 wczmwgmc 52559, .555 @5355 £502 mini 95: $525 55553 595555 553 9555555 5:555an mam “8.55% 5329:953an .355 £33855 5.5.5 BEE 555 .5553 555555 85.5“ $355 55:55 025500 «55:55:08 wEmEou 035589.52 w ”45:. A. B. A disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift atten- tion) and awareness (reduced orientation to the environment). The disturbance develops over a short period of time (usually hours to a few days), rep- resents a change from baseline attention and awareness, and tends to fluctuate in se- verity during the course of a day. . An additional disturbance in cognition (e.g., memory deficit, disorientation, language, visuospatial ability, or perception). . The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma.Specify whether: Substance intoxication delirium: This diagnosis should be made instead of sub- stance intoxication when the symptoms in Criteria A and C predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention.Coding note: The |CD-9-CM and ICD-10-CM codes for the [specific substance] in- toxication delirium are indicated in the table below.

Figure 366e-12 Chronic hepatitis C with bridging fibrosis (arrow) (Masson trichrome, 10×).Figure 366e-15 Liver allograft with cytomegalovirus infection showing hepatocytes with nuclear inclusions (arrows) surrounded by a neutrophilic and lymphoid infiltrate (H&E, 10×).Figure 366e-5 Chronic hepatitis C with portal inflammation and interface hepatitis (erosion of the limiting plate of periportal hepato-cytes by infiltrating mononuclear cells) (H&E, 20×). Figure 366e-8 Chronic hepatitis B with hepatocellular nuclear stain-ing for hepatitis B core antigen (immunoperoxidase, 20×). Figure 366e-6 Lobular inflammation with acidophilic body (apop-totic body) surrounded by lymphoid cells (H&E, 40×). Figure 366e-9 Autoimmune hepatitis with portal and lobular inflammation, interface hepatitis, and cholestasis (H&E, 10×). Figure 366e-10 Autoimmune hepatitis, higher magnification, showing dense plasma cell infiltrate in the portal and periportal regions (H&E, 40×). Figure 366e-13 Cirrhosis with architectural alteration resulting from fibrosis and nodular hepatocellular regeneration (Masson trichrome, 2×). Figure 366e-11 Primary biliary cirrhosis with degenerating bile duct epithelium (“florid ductular lesion”) (arrow) surrounded by epi-thelioid granulomatous reaction and lymphoplasmacytic infiltrate (H&E, 40×). Figure 366e-14 Acute cellular rejection of orthotopic liver allograft demonstrating a mixed inflammatory cell infiltrate (lymphoid cells, eosinophils, neutrophils) of the portal tract as well as endothelialitis of the portal vein (arrow) and bile duct injury (H&E, 10×). Figure 366e-15 Liver allograft with cytomegalovirus infection showing hepatocytes with nuclear inclusions (arrows) surrounded by a neutrophilic and lymphoid infiltrate (H&E, 10×). Figure 366e-12 Chronic hepatitis C with bridging fibrosis (arrow) (Masson trichrome, 10×).Figure 366e-19 α1 Antitrypsin deficiency with higher magnification of PAS-positive, diastase-resistant globules (PAS, 40×).Figure 366e-17 Combined acetaminophen hepatotoxicity and alcoholic liver injury at higher magnification showing necrotic cen-trilobular area with Mallory bodies (H&E 20×).

Parents often try to impose behavioral change in an emotionally charged atmosphere, most often at the time of a behavioral violation.It is easiest to learn when the lesson is simple, clear, and consistent and presented in an atmosphere free of fear or intimidation.For the child, behavioral change must be learned, not simply imposed.By assuming the role of a nonjudgmental, supportive listener, the clinician creates a climate of trust, allowing the family to express difficult or painful thoughts and feelings. Expressing emotions may allow the parent or caregiver to move on to the work of understanding and resolving the problem. Interview techniques may facilitate clarification of the problem for the family and for the clinician. The family’sideas about the causes of the problem and attempts at coping can provide a basis for developing strategies for problemmanagement that are much more likely to be implementedsuccessfully because they emanate, in part, from the family.The clinician shows respect by endorsing the parent’s ideaswhen appropriate; this can increase self-esteem and sense of competency. Educating parents about normal and aberrant development and behavior may prevent problems through early detection and anticipatory guidance and communicates the physician’s interest in hearing parental concerns. Early detection allows intervention before the problem becomes entrenched and associated problems develop. The severity of developmental and behavioral problems ranges from variations of normal to problematic responses to stressful situations to frank disorders. The clinician must try to establish the severity and scope of the patient’s symptoms so that appropriate intervention can be planned. For the child, behavioral change must be learned, not simply imposed. It is easiest to learn when the lesson is simple, clear, and consistent and presented in an atmosphere free of fear or intimidation. Parents often try to impose behavioral change in an emotionally charged atmosphere, most often at the time of a behavioral violation.Apart from management strategies directed specifically at the problem behavior, regular times for positive parent-child interaction should be instituted.Frequent, brief, affectionate physical contact over the day provides opportunities for positive reinforcement of desirable child behaviors and for building a sense of competence in the child and the parent.

Attempts to move an affected part passively yield an almost rock-like immobility, perceptibly different from spasticity, paratonia, or extrapyramidal rigidity.The spasms impart a robotic appearance to walking and an exaggerated lumbar lordosis.In addition to the association with polyneuropathy, a state of continuous muscular activity has also been described in association with lung cancer and thymoma in which cases an immune mechanism has been inferred as noted above in Morvan syndrome (see reviews by Thompson and by Newsom-Davis and Mills and the discussion of paraneoplastic syndromes in Chap. 30). Treatment Phenytoin or carbamazepine often abolish the continuous muscular activity and cause a return of reflexes. Acetazolamide has been helpful in other cases (Celebisoy et al). Many of the idiopathic cases will improve spontaneously after several years, however, plasma exchange may be tried if the symptoms are intractable. This is a condition of persistent and intense spasms, particularly of the proximal lower limbs and lumbar paraspinal muscles. It was originally described by Moersch and Woltman in 1956 as stiff man syndrome. Since then, many examples have been reported all over the world and the term stiff person syndrome has been used to indicate its occurrence in both women and men. For lack of a better place in the book to discuss it, it is included here with other processes that cause muscular spasms and cramps. The onset is insidious, usually in middle life. No genetic predisposition is known. At first the stiffness and spasms are intermittent, then gradually they become more or less continuously active in the proximal leg and axial trunk muscles and increasingly painful. The spasms impart a robotic appearance to walking and an exaggerated lumbar lordosis. Attempts to move an affected part passively yield an almost rock-like immobility, perceptibly different from spasticity, paratonia, or extrapyramidal rigidity.We have observed brief periods of cyanosis and respiratory arrest during episodes of intense spasm, and one of our patients died during such an episode.The eye muscles are rarely affected.As the illness progresses, any noise or other sensory stimulus or attempted passive or voluntary movement may precipitate painful spasms of all the involved musculature.

With a progressive reduction in intravascular pressure, vessel diameter decreases (as does vessel wall tension, according to the law of Laplace) and blood flow eventually ceases, although pressure within the arteriole is still greater than tissue pressure.Occlusion is caused by infolding of the endothelium and by trapping of blood cells in the vessel.To calculate wall tension, pressure in mm Hg is converted to dynes per square centimeter according to the equation P = hρg, where h is the height of an Hg column in centimeters, ρ is the density of Hg in g/cm3, and g is gravitational acceleration in cm/s2. For a capillary with a pressure of 25mmHg and a radius of 5 × 10−4 cm, the pressure (2.5 cm Hg × 13.6 g/cm3 × 980 cm/sec2) is 3.33 × 104 •Fig. 17.23 Diagram of a Small Blood Vessel to Illustrate the Law of Laplace. T=Pr,whereP=intraluminalpressure,r=radiusofthevessel,andT=walltensionastheforceperunitlengthtangentialtothevesselwall.Walltensionpreventsrupturealongatheoreticallongitudinalslitinthevessel. dyne/cm2. Wall tension is then 16.7 dyne/cm. For an aorta with a pressure of 100 mm Hg and a radius of 1.5 cm, wall tension is 2 × 105 dyne/cm. Thus at the pressures normally found in the aorta and capillaries, the wall tension of the aorta is approximately 12,000 times greater than that of the capillaries. In a person standing quietly, capillary pressure in the feet may reach 100 mm Hg. Even under such conditions, capillary wall tension increases to a value that is still only one three-thousandth of the wall tension in the aorta at the same internal pressure. The diameter of the resistance vessels (arterioles) is determined from the balance between the contractile force of the vascular smooth muscle and the distending force produced by intraluminal pressure. The greater the contractile activity of the vascular smooth muscle of an arteriole, the smaller its diameter. In small arterioles, contraction can continue to the point at which the vessel is completely occluded. Occlusion is caused by infolding of the endothelium and by trapping of blood cells in the vessel. With a progressive reduction in intravascular pressure, vessel diameter decreases (as does vessel wall tension, according to the law of Laplace) and blood flow eventually ceases, although pressure within the arteriole is still greater than tissue pressure.The critical closing pressure is low when vasomotor activity is reduced by inhibition of sympathetic nerve activity in the vessel and is increased when vasomotor tone is enhanced by activation of the vascular sympathetic nerve fibers.

Note, again, that the epithelial cells even at the surface still retain their nuclei and there is no evidence of keratinization.epithelium are more clearly seen here (arrows), in some instances outlined by the surrounding closely packed cells of the basal epithelial cell layer.Many blood vessels (BV) are seen in the connective tissue.This is a higher-magnification micrograph of the basal portion of the epithelium (Ep) between connective tissue papillae. Note the regularity and dense packing of the basal epithelial cells. They are the stem cells for the stratified squamous epithelium. Daughter cells of these cells migrate toward the surface Muscularis, vagina, human, H&E ×125. This higher-magnification micrograph of the smooth muscle of the vaginal wall emphasizes the irregularity of the arrangement of the muscle bundles. At the right edge of the figure is a bundle of smooth muscle cut in a longitudinal section (SML). superficial cells, keratinization does not occur in human vaginal epithelium. Thus, nuclei can be observed throughout the entire thickness of the epithelium despite the fact that the cytoplasm of most of the cells above the basal layers appears empty. These cells are normally filled with large deposits of glycogen that is lost in the processes of fixation and embedding of the tissue. The rectangle outlines a portion of the epithelium and connective tissue papillae that is examined at higher magnification below. The muscular layer of the vaginal wall consists of smooth muscle arranged in two ill-defined layers. The outer layer is generally said to be longitudinally arranged (SML), and the inner layer is generally said to be circularly arranged (SMC), but the fibers are more usually organized as interlacing bundles surrounded by connective tissue. Many blood vessels (BV) are seen in the connective tissue. epithelium are more clearly seen here (arrows), in some instances outlined by the surrounding closely packed cells of the basal epithelial cell layer. Note, again, that the epithelial cells even at the surface still retain their nuclei and there is no evidence of keratinization.The highly cellular connective (CT) tissue immediately beneath the basal layer (B) of the epithelium typically contains many lymphocytes (L).The number of lymphocytes varies with the stage of the ovarian cycle.Lymphocytes invade the epithelium around the time of menstruation and appear along with the epithelial cells in vaginal smears.

The T-cell receptor (TCR) on a helper CD4 T lymphocyte (TH2 cell) recognizes both the antigen and the MHC II molecule, activating the helper CD4 T lymphocyte.As an antigen-presenting cell, a B cell internalizes the BCR–antigen complex, partially digests the antigen, and then displays parts of it on the surface of its own MHC II molecules.The binding usually involves a reaction between CD40 molecules on a B-cell surface with their ligands (CD40L or CD154) residing at the surface of a helper T cell. These interactions complete the activation process of a B lymphocyte and induce an involved T cell to secrete specific cytokines that stimulate divisions and differentiation of B cells. Details of B-cell activation are illustrated in Figure 14.6. FIGURE 14.5 • Schematic diagram of the molecular interactions that occur during antigen presentation. To become activated, both cytotoxic and helper T lymphocytes need to identify presented antigens as “nonself” as well as recognize the appropriate class of MHC molecules. Note that each interaction between an antigen–MHC complex with its specific T-cell receptor (TCR) requires a costimulatory signal from the interaction of CD28 with B7 molecules. Without a costimulatory signal, the T cell cannot be fully activated. a. In all nucleated cells of the body, viral antigen or cancer (tumor-specific) proteins are displayed in the context of MHC I molecules to interact with cytotoxic CD8 T lymphocytes. b. On antigen-presenting cells (e.g., macrophages), the foreign antigen is displayed in the context of MHC II molecules to interact with a helper CD4 T lymphocyte. FIGURE 14.6 • Schematic diagram of B lymphocyte activation leading to plasma cell and B memory cell formation. B cells are activated by the binding of antigen (Ag) to B-cell receptors (BCRs; membrane-bound antibodies) expressed on their surface. As an antigen-presenting cell, a B cell internalizes the BCR–antigen complex, partially digests the antigen, and then displays parts of it on the surface of its own MHC II molecules. The T-cell receptor (TCR) on a helper CD4 T lymphocyte (TH2 cell) recognizes both the antigen and the MHC II molecule, activating the helper CD4 T lymphocyte.Note the presence of a costimulatory molecule complex between the B and T cells.Ab, antibody.FIGURE 14.7 • Schematic diagram of activation of natural killer cells leading to destruction of a transformed tumor cell by antibody-dependent, cell-mediated cytotoxicity (ADCC).

Mucous neck cells are located in the narrow neck of the gland.The opening of the gland is called the isthmus and is lined with surface mucous cells and a few parietal cells.Surface epithelial cells extend slightly into the duct opening.29.2 .The structure of a gastric gland from the oxyntic glandular region is illustrated in Fig.Functional Anatomy of the Stomach The stomach is divided into three regions: the cardia, the corpus (also referred to as the fundus or body), and the antrum ( Fig. 29.1 ). However, when discussing the physiology of the stomach, it is helpful to think of it as subdivided into two functional regions: the proximal and distal parts of the stomach. The proximal portion of the stomach (called proximal because it is the most cranial) and the distal portion of the stomach (furthest away from the mouth) have quite different functions in the postprandial response to a meal, which will be discussed later. The lining of the stomach is covered with a columnar epithelium folded into gastric pits; each pit is the opening of a duct into which one or more gastric glands empty (Fig. 29.2 ). The gastric pits account for a significant fraction of the total surface area of the gastric mucosa. The gastric mucosa is divided into three distinct regions based on the structure of the glands. The small cardiac glandular region, located just below the lower esophageal sphincter (LES), primarily contains mucus-secreting gland cells. The remainder of the gastric mucosa is divided into the oxyntic or parietal (acid-secreting) gland region, located above the gastric notch (equivalent to the proximal part of the stomach), and the pyloric gland region, located below the notch (equivalent to the distal part of the stomach). The structure of a gastric gland from the oxyntic glandular region is illustrated in Fig. 29.2 . Surface epithelial cells extend slightly into the duct opening. The opening of the gland is called the isthmus and is lined with surface mucous cells and a few parietal cells. Mucous neck cells are located in the narrow neck of the gland.Oxyntic glands also contain enterochromaffin-like (ECL) cells that secrete histamine, and D cells that secrete somatostatin.

It can be performed easily, with no morbidity, and is much less expensive than excisional or open biopsy.Precise guidelines for this technique are available (72).Fine-Needle Aspiration With FNAC, cells from a breast tumor are aspirated with a small (usually 22-gauge) needle and examined by a pathologist.Figures 21.4 and 21.5 present algorithms for management of breast masses in premenopausal and postmenopausal patients. Simultaneous evaluation of a breast mass using clinical breast examination, radiography, and needle biopsy can lower the risk of missing cancer to only 1%, effectively reducing the rate of diagnostic failure and increasing the quality of patient care (70). If the presence of breast cancer is strongly suggested by physical examination, the diagnosis can be confirmed by FNAC or CNB, and the patient may be counseled regarding treatment. Treatment should not be determined based on results of physical examination and mammography alone, in the absence of biopsy results. The most reasonable approach to the diagnosis and treatment of breast cancer is outpatient biopsy (either FNAC, CNB, or EB), followed by definitive surgery at a later date if needed. This two-step approach allows patients to adjust to the diagnosis of cancer, carefully consider alternative forms of therapy, and seek a second opinion. Studies show no adverse effect from the 1to 2-week delay associated with the two-step procedure (71). Because cancer is found in the minority of patients who require biopsy for diagnosis of a breast mass, definitive treatment should not be undertaken without an unequivocal histologic diagnosis of cancer. Fine-Needle Aspiration With FNAC, cells from a breast tumor are aspirated with a small (usually 22-gauge) needle and examined by a pathologist. Precise guidelines for this technique are available (72). It can be performed easily, with no morbidity, and is much less expensive than excisional or open biopsy.Cytologic diagnoses must be correlated with clinical and imaging findings to achieve triple-test concordance and to decrease the false-negative rate (73).The triple-test concordance (i.e., concordance between fine-needle aspiration, physical examination, and mammography) is the foundation of breast evaluation.The triple-test results are more powerful than each modality alone (74).

Muscles in the anterior compartment (quadriceps femoris) predominantly extend the knee.The large muscles (hamstrings) in the posterior compartment act on the hip (extension) and knee (flexion) because they attach to both the pelvis and bones of the leg.There is a metatarsal for each of the five digits, and each digit has three phalanges except for the great toe (digit I), which has only two. The metatarsophalangeal joints allow flexion, extension, abduction, and adduction of the digits, but the range of movement is more restricted than in the hand. The interphalangeal joints are hinge joints and allow flexion and extension. The bones of the foot are not organized in a single plane so that they lie flat on the ground. Rather, the metatarsals and tarsals form longitudinal and transverse arches (Fig. 6.10). The longitudinal arch is highest on the medial side of the foot. The arches are flexible in nature and are supported by muscles and ligaments. They absorb and transmit forces during walking and standing. Muscles of the gluteal region consist predominantly of extensors, rotators, and abductors of the hip joint (Fig. 6.11). In addition to moving the thigh on a fixed pelvis, these muscles also control the movement of the pelvis relative to the limb bearing the body’s weight (weight-bearing or stance limb) while the other limb swings forward (swing limb) during walking. Major flexor muscles of the hip (iliopsoas—psoas major and iliacus) do not originate in the gluteal region or the thigh. Instead, they are attached to the posterior abdominal wall and descend through the gap between the inguinal ligament and pelvic bone to attach to the proximal end of the femur (Fig. 6.12). Muscles in the thigh and leg are separated into three compartments by layers of fascia, bones, and ligaments (Fig. 6.13). In the thigh, there are medial (adductor), anterior (extensor), and posterior (flexor) compartments: Most muscles in the medial compartment act mainly on the hip joint. The large muscles (hamstrings) in the posterior compartment act on the hip (extension) and knee (flexion) because they attach to both the pelvis and bones of the leg. Muscles in the anterior compartment (quadriceps femoris) predominantly extend the knee.Muscles in the anterior compartment dorsiflex the foot and extend the digits.Muscles in the posterior compartment plantarflex the foot and flex the digits; one of the muscles can also flex the knee because it attaches superiorly to the femur.Specific muscles in each of the three compartments in the leg also provide dynamic support for the arches of the foot.

While pathogen-based diagnostics continue to be the mainstay for diagnosing infection, serologic testing has long been the basis of a strategy to diagnose infection by measuring host responses.These differences can be measured and, since transcription is one of the most rapid responses to cell stress (minutes to hours), can be used to determine whether cells are resistant or susceptible much more rapidly than is possible if one waits for growth in the presence of antibiotics (days). Like DNA, RNA can be readily detected through predictable rules governing base pairing via either amplification or hybridization-based methods. Changes in a carefully selected set of transcripts form an expression signature that can represent the total cellular response to antibiotic without requiring full characterization of the entire transcriptome. Preliminary proof-of-concept studies suggest that this approach may identify antibiotic susceptibility on the basis of transcriptional phenotype much more quickly than is possible with growth-based assays. Because of its sensitivity in detecting even very rare nucleic acid fragments, sequencing is now permitting studies of unprecedented depth into complex populations of cells and tissues. The strength of this depth and sensitivity applies not only to the detection of rare, novel pathogens in a sea of host signal but also to the identification of heterogeneous pathogen subpopulations in a single host that may differ, for example, in drug resistance profiles or pathogenesis determinants. Future studies will be needed to elucidate the clinical significance of these variable subpopulations, even as deep sequencing is now providing unprecedented levels of detail about majority and minority members of this population. While pathogen-based diagnostics continue to be the mainstay for diagnosing infection, serologic testing has long been the basis of a strategy to diagnose infection by measuring host responses.Rather than using antibody responses as a retrospective biomarker for infection, recent efforts have focused on transcriptomic analysis of the host response as a new direction with diagnostic implications for human disease.

If the estriol level is <0.25 MoM and the fetus appears to be male, chromosomal microarray analysis or fluorescence in situ hybridization to assess the steroid sulfatase locus on the X-chromosome may be considered.In such cases, it may be associated with Kallmann syndrome, chondrodysplasia punctata, and/or mental retardation (Langlois, 2009).13, p. 260).Many of these complications are assumed to result from placental damage or dysfunction. However, the sensitivity and positive-predictive values of these markers are considered too low to be useful for screening or management. No speciic program of maternal or fetal surveillance has been found to favorably afect pregnancy outcomes (Dugof, 2010). At Parkland Hospital, prenatal care for these women is not altered unless a specific complication arises. Despite the extensive list of possible adverse outcomes, it is reassuring that most women with unexplained elevation of these analytes have normal outcomes. Low Maternal Serum Estriol Level. A maternal serum estriol level less than 0.25 MoM has been associated with two uncommon but important conditions. he irst, Smith-Lemli-Opitz syndrome, is an autosomal recessive condition resulting from mutations in the 7 -dehydrocholesterol reductase gene. It is characterized by abnormalities of the central nervous system, heart, idney, and extremities; with ambiguous genitalia; and with fetal-growth restriction. For this reason, the Society for Maternal-Fetal Medicine has recommended that sonographic evaluation be performed if an unconjugated estriol level is <0.25 MoM (Dugof, 2010). If abnormalities are identified, an elevated amnionic luid 7 -dehydrocholesterol level can conirm the diagnosis. he second condition is steroid suatase diciency, also known as X-linked ichthyosis. It is typically an isolated condition, but it may also occur in the setting of a contiguous gene deletion syndrome (Chap. 13, p. 260). In such cases, it may be associated with Kallmann syndrome, chondrodysplasia punctata, and/or mental retardation (Langlois, 2009). If the estriol level is <0.25 MoM and the fetus appears to be male, chromosomal microarray analysis or fluorescence in situ hybridization to assess the steroid sulfatase locus on the X-chromosome may be considered.Combined screening test options require coordination between the provider and laboratory.Specifically, if a second sample is required, it is obtained during the appropriate gestational age window, sent to the same laboratory, and linked to the first-trimester results.

Bipolar II—a hypomanic and a depressive episode (no history of manic episodes).length of time).Lasts ≥ 4 consecutive days.No psychotic features.Abnormally  activity or energy usually present.Delusional disorder ≥ 1 delusion(s) lasting > 1 month, but without a mood disorder or other psychotic symptoms. Daily functioning, including socialization, may be impacted by the pathological, fixed belief but is otherwise unaffected. Can be shared by individuals in close relationships (folie à deux). Schizotypal personality Cluster A personality disorder that also falls on the schizophrenia spectrum. May include brief disorder psychotic episodes (eg, delusions) that are less frequent and severe than in schizophrenia. Mood disorder Characterized by an abnormal range of moods or internal emotional states and loss of control over them. Severity of moods causes distress and impairment in social and occupational functioning. Includes major depressive, bipolar, dysthymic, and cyclothymic disorders. Episodic superimposed psychotic features (delusions, hallucinations, disorganized speech/behavior) may be present. Manic episode Distinct period of abnormally and persistently elevated, expansive, or irritable mood and  activity or energy lasting ≥ 1 week. Diagnosis requires hospitalization or marked functional impairment with ≥ 3 of the following (manics DIG FAST): Distractibility • Flight of ideas—racing thoughts Impulsivity/Indiscretion—seeks pleasure •  goal-directed Activity/psychomotor without regard to consequences (hedonistic) Agitation Hypomanic episode Similar to a manic episode except mood disturbance is not severe enough to cause marked impairment in social and/or occupational functioning or to necessitate hospitalization. Abnormally  activity or energy usually present. No psychotic features. Lasts ≥ 4 consecutive days. length of time). Bipolar II—a hypomanic and a depressive episode (no history of manic episodes).Use of antidepressants can destabilize mood.High suicide risk.Treatment: mood stabilizers (eg, lithium, valproic acid, carbamazepine, lamotrigine), atypical antipsychotics.Cyclothymic disorder—milder form of bipolar disorder fluctuating between mild depressive and hypomanic symptoms.Must last ≥ 2 years with symptoms present at least half of the time, with any remission lasting ≤ 2 months.

All cardiac imaging modalities can provide direct measurements of left ventricular ejection fraction (LVEF).Assessment of ejection fraction, or the percentage of blood ejected with each beat, has been the primary method to assess systolic function and is generally calculated by subtracting end-systolic volume from end-diastolic volume and dividing by end-diastolic volume.The left ventricle will hypertrophy under any condition in which its afterload is increased, including conditions that obstruct outflow, such as aortic stenosis, hypertrophic cardiomyopathy, and subaortic membranes; in postcardiac aortic obstruction seen in coarctation; or in systemic conditions characterized by increased afterload, such as hypertension. The pattern of ventricular hypertrophy can change depending on the etiology. Aortic stenosis and hypertension are typically characterized by concentric hypertrophy, in which the ventricular walls thicken “concentrically” and cavity size is usually small. In volume overload conditions such as mitral or aortic regurgitation, there may be minimal increase in ventricular wall thickness, but substantial ventricular dilatation leads to marked increases in left ventricular mass. Ventricular wall thickness can be measured and ventricular mass can be calculated by either echocardiography or CMR. Although radionuclide imaging and cardiac CT can also provide measures of left ventricular mass, they are not generally used for this purpose. Although measurement of wall thickness with echocardiography is relatively straightforward and accurate, determining left ventricular mass by echocardiography requires using one of several formulas that takes into account both wall thickness and ventricular cavity dimensions. Assessment of left ventricular mass by CMR has the advantage of not requiring geometric assumptions and is thus more accurate than echocardiography. Assessment of ejection fraction, or the percentage of blood ejected with each beat, has been the primary method to assess systolic function and is generally calculated by subtracting end-systolic volume from end-diastolic volume and dividing by end-diastolic volume. All cardiac imaging modalities can provide direct measurements of left ventricular ejection fraction (LVEF).A LVEF of 55% or greater is generally considered normal, and an LVEF of 50–55% is considered in the low-normal range.Newer methods to assess systolic function, such as myocardial strain or deformation imaging using speckle-tracking methods on echocardiography or myocardial tagging on CMR, can provide a more sensitive approach to detection of systolic dysfunction.