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A distended or obstructed bladder, suprapubic palpation, catheter insertion, and urinary infection are common triggers.Autonomic dysreflexia describes a dramatic increase in BP in patients with traumatic spinal cord lesions above the T6 level, often in response to stimulation of the bladder, skin, or muscles.Quadriparetic patients exhibit both supine hypertension and OH after upward tilting.Factors that predict a worse prognosis include rapid progression of disability, bladder dysfunction, female gender, the MSA-p subtype, and an older age at onset. Attempts to slow the progression of MSA have thus far been unsuccessful, including trials of lithium, growth hormone, riluzole, rasagiline, minocycline, and a recent trail of rifampicin. Management is symptomatic for neurogenic OH (see below), sleep disorders including laryngeal stridor, and gastrointestinal (GI) and urinary dysfunction. GI management includes frequent small meals, soft diet, stool softeners, and bulk agents. Gastroparesis is difficult to treat; metoclopramide stimulates gastric emptying but worsens parkinsonism by blocking central dopamine receptors. The peripheral dopamine (D2 and D3) receptor antagonist domperidone has been used patients with various GI conditions in many countries and is now available in the United States through the U.S. Food and Drug Administration’s (FDA) Expanded Access to Investigational Drugs program. Autonomic dysfunction is also a common feature in dementia with Lewy bodies (Chap. 448); the severity is usually less than that found in MSA or PD. In multiple sclerosis (MS; Chap. 458), autonomic complications reflect the CNS location of MS involvement and generally worsen with disease duration and disability. Spinal cord lesions from any cause may result in focal autonomic deficits or autonomic hyperreflexia (e.g., spinal cord transection or hemisection) affecting bowel, bladder, sexual, temperature-regulation, or cardiovascular functions. Quadriparetic patients exhibit both supine hypertension and OH after upward tilting. Autonomic dysreflexia describes a dramatic increase in BP in patients with traumatic spinal cord lesions above the T6 level, often in response to stimulation of the bladder, skin, or muscles. A distended or obstructed bladder, suprapubic palpation, catheter insertion, and urinary infection are common triggers.Potential complications Disorders of the Autonomic Nervous System 2642 include intracranial vasospasm or hemorrhage, cardiac arrhythmia, and death.Awareness of the syndrome, identifying the trigger, and careful monitoring of BP during procedures in patients with acute or chronic spinal cord injury are essential.
Emetic type causes nausea and vomiting within 1–5 hours.Keeping rice warm results in germination of spores and enterotoxin formation.Spores survive cooking rice (reheated rice syndrome).Causes food poisoning.Bacillus cereus Gram ⊕ rod.Patients with ⊕ culture receive intrapartum penicillin/ampicillin prophylaxis.Screen pregnant women at 35–37 weeks of gestation with rectal and vaginal swabs.PYR ⊝.Hyaluronic acid capsule and M protein inhibit phagocytosis. Antibodies to M protein enhance host defenses against S pyogenes but can give rise to rheumatic fever. ASO titer or anti-DNase B antibodies indicate recent S pyogenes infection. “Ph”yogenes pharyngitis can result in rheumatic “phever” and glomerulonephritis. Strains causing impetigo can induce glomerulonephritis. Scarlet fever—blanching, sandpaper-like body rash, strawberry tongue, and circumoral pallor in the setting of group A streptococcal pharyngitis (erythrogenic toxin ⊕). Bacillus anthracis Gram ⊕, spore-forming rod that produces anthrax toxin (an exotoxin consisting of protective antigen, lethal factor, and edema factor). Has a polypeptide capsule (poly d-glutamate). Colonies show a halo of projections, sometimes referred to as “medusa head” appearance. Cutaneous anthrax Painless papule surrounded by vesicles ulcer with black eschar A (painless, necrotic) uncommonly progresses to bacteremia and death. Pulmonary anthrax Inhalation of spores, most commonly from contaminated animals or animal products, although also a potential bioweapon flu-like symptoms that rapidly progress to fever, pulmonary hemorrhage, mediastinitis (CXR may show widened mediastinum), and shock. Also called woolsorter’s disease. Gram ⊕ cocci, bacitracin resistant, β-hemolytic, colonizes vagina; causes pneumonia, meningitis, and sepsis, mainly in babies. Produces CAMP factor, which enlarges the area of hemolysis formed by S aureus. (Note: CAMP stands for the authors of the test, not cyclic AMP.) Hippurate test ⊕. PYR ⊝. Screen pregnant women at 35–37 weeks of gestation with rectal and vaginal swabs. Patients with ⊕ culture receive intrapartum penicillin/ampicillin prophylaxis. Bacillus cereus Gram ⊕ rod. Causes food poisoning. Spores survive cooking rice (reheated rice syndrome). Keeping rice warm results in germination of spores and enterotoxin formation. Emetic type causes nausea and vomiting within 1–5 hours.Diarrheal type causes watery, nonbloody diarrhea and GI pain within 8–18 hours.Management: supportive care (antibiotics are ineffective against toxins).Clostridia Gram ⊕, spore-forming, obligate anaerobic rods.Tetanus toxin and botulinum toxin are proteases that cleave SNARE proteins involved in neurotransmission.
The total iron content of normal adult women ranges from 2.0 to 2.5 g, or approximately half that found normally in men.Thus, a hemoglobin concentration below 11.0 g/dL, especially late in pregnancy, is considered abnormal and usually due to irondeficiency anemia rather than pregnancy hypervolemia.Last, it safeguards the mother against the adverse efects of parturition-associated blood loss. Maternal blood volume begins to accrue during the irst trimester. By 12 menstrual weeks, plasma volume expands by approximately 15 percent compared with that prior to pregnancy (Bernstein, 2001). Maternal blood volume grows most rapidly during the midtrimester, rises at a much slower rate during the third trimester, and reaches a plateau during the last 6.5 � 6.0 ! 5.5 5.0 4.0 3.5 • Twin pregnancy• Singleton pregnancy 3.0 7 -6 -ls 5E 4)E) 3�'5r� 2:� Menses First Second Third Postpartum FIGURE 4-6 Estimated daily iron requirements during pregnancy in a 55-kg woman. (Modified from Koenig, 2014.) (n 10) and singletons (n 40). Data shown as medians. (Data from Thomsen, 1994.) several weeks of pregnancy (Fig. 4-5). Blood volume accrues even more dramatically in twin gestations. During blood volume expansion, plasma volume and erythrocyte number rise. Although more plasma than erythrocytes is usually added to the maternal circulation, the increase in erythrocyte volume is considerable and averages 450 mL (Pritchard, 1960). Moderate erythroid hyperplasia develops in the bone marrow, and the reticulocyte count is elevated slightly during normal pregnancy. These changes are almost certainly related to an elevated maternal plasma erythropoietin level. Because ofgreat plasma augmentation, both hemoglobin concentration and hematocrit decline slightly during pregnancy (Appendix, p. 1255).s aresult, whole bloodviscositydecreases (Huisman, 1987). Hemoglobin concentration at term averages 12.5 g/dL, and in approximately 5 percent ofwomen it is below 11.0 g/dL. Thus, a hemoglobin concentration below 11.0 g/dL, especially late in pregnancy, is considered abnormal and usually due to irondeficiency anemia rather than pregnancy hypervolemia. The total iron content of normal adult women ranges from 2.0 to 2.5 g, or approximately half that found normally in men.Although the lower iron levels in women may be partly due to menstrual blood loss, other factors have a role, particularly hepcidin-a peptide hormone that functions as a homeostatic regulator of systemic iron metabolism.
Endocarditis occurs in ~1% of cases, most often affecting the aortic valve (natural or prosthetic).A small proportion of patients develop lymphocytic meningoencephalitis that mimics neurotuberculosis, atypical leptospirosis, or noninfectious conditions and that may be complicated by intracerebral abscess, a variety of cranial nerve deficits, or ruptured mycotic aneurysms.Anterior osteophytes eventually develop, but vertebral destruction or impingement on the spinal cord is rare and usually suggests tuberculosis (Table 194e-1). Other systems may be involved in a manner that resembles typhoid. About one-quarter of patients have a dry cough, usually with few changes visible on the chest x-ray, although pneumonia, empyema, intrathoracic adenopathy, or lung abscess can occur. Sputum or pleural effusion cultures are rarely positive in such cases, which respond well to standard brucellosis treatment. One-quarter of patients have hepatosplenomegaly, and 10–20% have significant lymphadenopathy; the differential diagnosis includes glandular fever–like illness such as that caused by Epstein-Barr virus, Toxoplasma, cytomegalovirus, HIV, or Mycobacterium tuberculosis. Up to 10% of men have acute epididymoorchitis, which must be distinguished from mumps and from surgical problems such as torsion. Prostatitis, inflammation of the seminal vesicles, salpingitis, and pyelonephritis all occur. There is an increased incidence of fetal loss among infected pregnant women, although teratogenicity has not been described and the tendency toward abortions is much less pronounced in humans than in farm animals. Neurologic involvement is common, with depression and lethargy whose severity may not be fully appreciated by either the patient or the physician until after treatment. A small proportion of patients develop lymphocytic meningoencephalitis that mimics neurotuberculosis, atypical leptospirosis, or noninfectious conditions and that may be complicated by intracerebral abscess, a variety of cranial nerve deficits, or ruptured mycotic aneurysms. Endocarditis occurs in ~1% of cases, most often affecting the aortic valve (natural or prosthetic).Nonspecific maculopapular rashes and other skin manifestations are uncommon and are rarely noticed by the patient even if they develop.Because the clinical picture of brucellosis is not distinctive, the diagnosis must be based on a history of potential exposure, a presentation consistent with the disease, and supporting laboratory findings.
Poliovirus protease 2A, for example, cleaves a cellular component of the complex that ordinarily facilitates translation of cellular mRNAs by interacting with their cap structure.Viruses can specifically inhibit host protein synthesis by attacking a component of the translational initiation complex— frequently, a component that is not required for efficient translation of viral RNAs.The concept of host range was originally based on the cell types in which a virus replicates in tissue culture. For the most part, the host range is limited by specific cell-surface proteins required for viral adsorption or penetration—i.e., to the cell types that express receptors or co-receptors for a specific virus. Another common basis for host-range limitation is the degree of transcriptional activity from viral promoters in different cell types. Most DNA viruses depend not only on cellular RNA polymerase II and the basal components of the cellular transcription complex but also on activated components and transcriptional accessory factors, both of which differ among differentiated tissues, among cells at various phases of the cell cycle, and between resting and cycling cells. The importance of host range factors is illustrated by the effects of specific host determinants that limit the replication of influenza virus with avian or porcine hemagglutinins in humans. These viral proteins have adapted to bind avian or porcine sialic acids, and spread of avian or porcine influenza viruses in human populations is limited by their ability to infect human cells. The replication of almost all viruses has adverse effects on the infected cell, inhibiting cellular synthesis of DNA, RNA, or proteins through efficient competition for key substrates and enzymatic processes. These general inhibitory effects enable viruses to nonspecifically limit components of innate host resistance, such as interferon (IFN) production. Viruses can specifically inhibit host protein synthesis by attacking a component of the translational initiation complex— frequently, a component that is not required for efficient translation of viral RNAs. Poliovirus protease 2A, for example, cleaves a cellular component of the complex that ordinarily facilitates translation of cellular mRNAs by interacting with their cap structure.Influenza virus inhibits the processing of mRNA by snatching cap structures from nascent cellular RNAs and using them as primers in the synthesis of viral mRNA.HSV has a virion tegument protein that inhibits cellular mRNA translation.Apoptosis is the expected consequence of virus-induced inhibition of cellular macromolecular synthesis and viral nucleic acid replication.
Theoretical advantages of this approach include more consistent completion of multimodality therapy, downstaging, earlier treatment of micrometastatic disease, and the ability to gauge response at the in situ tumor.)Brunicardi_Ch26_p1099-p1166.indd 114701/03/19 7:13 PM 1148SPECIFIC CONSIDERATIONS PART IIJapan and Korea have indicated a survival advantage with adju-vant chemotherapy after D2 gastrectomy.172-174 The discordance between outcomes in Asia and those from the United States and Europe have been attributed to differences in disease biology or treatment approaches. Proponents of the latter suggest that D2 lymphadenectomy provides sufficient locoregional control and that chemotherapy alone has efficacy after optimal surgery. A preferred adjuvant approach in the United States incorpo-rates chemotherapy and radiation based on the results of the Intergroup trial. This prospective randomized study of adju-vant treatment with chemotherapy (5-fluorouracil and leucovo-rin) and radiation (4500 cGy) demonstrated a survival benefit in resected patients with stage II and III adenocarcinoma of the stomach.175 Only 10% of patients entered in the study actually had D2 gastrectomy, and most (54%) had less than an adequate D1 gastrectomy. Because adequacy of lymphadenectomy has been correlated with survival, particularly in patients with stage III gastric cancer, it has been suggested that the benefits of adjuvant chemoradiation shown in this study would be vitiated by a more extensive operation.Neoadjuvant chemotherapy has emerged as a viable alter-native to adjuvant chemoradiotherapy in Europe and the United States. Theoretical advantages of this approach include more consistent completion of multimodality therapy, downstaging, earlier treatment of micrometastatic disease, and the ability to gauge response at the in situ tumor.Regardless, neoadjuvant approaches are increasingly utilized, and even more rigorous regimens incorporating radio-therapy or targeted agents have been explored, sometimes with promising outcomes.177Recent clinical trials from Asia suggest the potential ben-efit of adjuvant chemotherapy after D2 lymphadenectomy in patients with advanced gastric cancer.
Like genes that exist in different allelic forms, haplotype blocks also come in a limited number of variants that are common in the human population, each representing a combination of DNA polymorphisms passed down from a particular ancestor long ago.These are the haplotype blocks.The majority of polymorphisms are due to the substitution of a single nucleotide, called single-nucleotide polymorphisms or SNPs (Figure 8–50). The rest are due largely to insertions or deletions—called indels when the change is small, or copy number variations (CNVs) when it is large. Although these common variants can be found throughout the genome, they are not scattered randomly—or even independently. Instead, they tend to travel in groups called haplotype blocks—combinations of polymorphisms that are inherited as a unit. To understand why such haplotype blocks exist, we need to consider our evolutionary history. It is thought that modern humans expanded from a relatively small population—perhaps around 10,000 individuals—that existed in Africa about 60,000 years ago. Among that small group of our ancestors, some individuals will have carried one set of genetic variants, others a different set. The chromosomes of a present-day human represent a shuffled combination of chromosome segments from different members of this small ancestral group of people. Because only about two thousand generations separate us from them, large segments of these ancestral chromosomes have passed from parent to child, unbroken by the crossover events that occur during meiosis. As described in Chapter 5, only a few crossovers occur between each set of homologous chromosomes during each meiosis (see Figure 5–53). As a result, certain sets of DNA sequences—and their associated polymorphisms—have been inherited in linked groups, with little genetic rearrangement across the generations. These are the haplotype blocks. Like genes that exist in different allelic forms, haplotype blocks also come in a limited number of variants that are common in the human population, each representing a combination of DNA polymorphisms passed down from a particular ancestor long ago.Most such variations in the human genome occur at locations where they do not significantly affect a gene’s function.Polymorphisms Can Aid the Search for Mutations Associated with Disease Mutations that give rise, in a reproducible way, to rare but clearly defined abnormalities, such as albinism, hemophilia, or congenital deafness, can often be identified by studies of affected families.
Preventing pressure ulcers requires recognition of susceptible and utilizing appropriate measures to reduce pres-sure on areas of the body at risk.Most can be prevented by diligent nursing care in an attentive, cooperative patient.The reconstruction must achieve wound healing and restore support to the pelvic con-tents, accommodate urinary and bowel function, and finally restore the penis in men and the vagina and vulva in women. Local flaps, regional flaps, or free tissue transfer all have pos-sible application depending on the extent of the resection and local tissue compromise.Other Clinical CircumstancesBesides trauma and cancer, other etiologies can cause functional and cosmetic deformities due to tissue impairment for which reconstructive surgery has value. These include pressure sores, diabetic foot ulcers, and lymphedema.Pressure Sores. A pressure ulcer is defined as tissue injury caused by physical pressure applied to the tissues from an exter-nal source at a magnitude that exceeds capillary perfusion pres-sure. Prolonged tissue ischemia leads to local tissue necrosis. Pressure ulcers tend to occur in people debilitated by advanced age, chronic illness, poor nutrition, prolonged immobilization, motor paralysis, or inadequate sensation. Spinal cord injury patients are especially prone to developing pressure sores. Pres-sure sores can also occur in healthy individuals who undergo prolonged surgical operations and parts of the body support-ing the weight of the patient on the operating table (e.g., the occiput, the sacral prominence, the heels of the feet) are improp-erly padded.57Brunicardi_Ch45_p1967-p2026.indd 201201/03/19 6:31 PM 2013PLASTIC AND RECONSTRUCTIVE SURGERYCHAPTER 45Pressure sores are an important contributor to morbidity in patients suffering from limited mobility. Most can be prevented by diligent nursing care in an attentive, cooperative patient. Preventing pressure ulcers requires recognition of susceptible and utilizing appropriate measures to reduce pres-sure on areas of the body at risk.Malnourishment, poor glucose control in diabetics, poor skin hygiene, urinary or bowel incon-tinence, muscle spasms, and joint contractures all increase the risk of pressure sore formation.Mitigating these factors is essential before embarking on a complex reconstructive treat-ment plan.
Acting primarily through angiotensin II type 1 (AT1) receptors on cell membranes, angiotensin II is a potent pressor substance, the primary tropic factor for the secretion of aldosterone by the adrenal zona glomerulosa, and a potent mitogen that stimulates vascular smooth muscle cell and myocyte growth.of other peptides, including and thereby inactivating the vasodilator bradykinin.Although human plasma contains two to five times more prorenin than renin, there is no evidence that prorenin contributes to the physiologic activity of this system. There are three primary stimuli for renin secretion: (1) decreased NaCl transport in the distal portion of the thick ascending limb of the loop of Henle that abuts the corresponding afferent arteriole (macula densa), (2) decreased pressure or stretch within the renal afferent arteriole (baroreceptor mechanism), and (3) sympathetic nervous system stimulation of renin-secreting cells via β1 adrenoreceptors. Conversely, renin secretion is inhibited by increased NaCl transport in the thick ascending limb of the loop of Henle, by increased stretch within the renal afferent arteriole, and by β1 receptor blockade. In addition, angiotensin II directly inhibits renin secretion due to angiotensin II type 1 receptors on juxtaglomerular cells, and renin secretion increases in response to pharmacologic blockade of either ACE or angiotensin II receptors. Once released into the circulation, active renin cleaves a substrate, angiotensinogen, to form an inactive decapeptide, angiotensin I (Fig. 298-2). A converting enzyme, located primarily but not exclusively in the pulmonary circulation, converts angiotensin I to the active octapeptide, angiotensin II, by releasing the C-terminal histidylleucine dipeptide. The same converting enzyme cleaves a number FIGURE 298-2 Renin-angiotensin-aldosterone axis. ACE, angiotensinconverting enzyme. of other peptides, including and thereby inactivating the vasodilator bradykinin. Acting primarily through angiotensin II type 1 (AT1) receptors on cell membranes, angiotensin II is a potent pressor substance, the primary tropic factor for the secretion of aldosterone by the adrenal zona glomerulosa, and a potent mitogen that stimulates vascular smooth muscle cell and myocyte growth.The angiotensin II type 2 (AT2) receptor has the opposite functional effects of the AT1 receptor.The AT2 receptor induces vasodilation, sodium excretion, and inhibition of cell growth and matrix formation.Experimental evidence suggests that the AT2 receptor improves vascular remodeling by stimulating smooth muscle cell apoptosis and contributes to the regulation of glomerular filtration rate.
Gluten peptides activate mucosal epithelial cells to express MIC molecules MIC IL1R IL1 NKG2D CD8 T cell (IEL) Intraepithelial lymphocytes (IELs) express NKG2D, which binds to MIC molecules and activates the IELs to kill the epithelial cell Fig.The stimulated T cells can now provide help to these B cells, which produce autoantibodies against tTG.Activated gliadin-specific CD4 T cells accumulate in the lamina propria, producing IFN-γ, a cytokine that when present in this location leads to intestinal inflammation. Celiac disease is entirely dependent on the presence of the foreign antigen, gluten. It is not associated with a specific immune response against self antigens in the tissue—the intestinal epithelium—that is damaged during the immune response. Thus, celiac disease is not a classical autoimmune disease. But it does have some features of autoimmunity. Autoantibodies against tissue transglutaminase are found in all patients with celiac disease; indeed, the presence of serum IgA antibodies against this enzyme is used as a sensitive and specific test for the disease. Interestingly, no tTG-specific T cells have been found, and it has been proposed that gluten-reactive T cells provide help to B cells that are reactive to tissue transglutaminase. In support of this hypothesis, gluten can complex with the enzyme and therefore could be taken up and presented by tTG-reactive B cells (Fig. 14.26). There is no evidence, however, that these autoantibodies contribute directly to tissue damage. Fig. 14.26 A hypothesis to explain antibody production against tissue transglutaminase (tTG) in the absence of T cells specific for tTG in celiac patients. tTG-reactive B cells endocytose gluten–tTG complexes and present gluten peptides to the gluten-specific T cells. The stimulated T cells can now provide help to these B cells, which produce autoantibodies against tTG. Gluten peptides activate mucosal epithelial cells to express MIC molecules MIC IL1R IL1 NKG2D CD8 T cell (IEL) Intraepithelial lymphocytes (IELs) express NKG2D, which binds to MIC molecules and activates the IELs to kill the epithelial cell Fig.Gluten peptides can induce the expression of the MHC class Ib molecules MIC-A and MIC-B on gut epithelial cells and the synthesis and release of IL-1 from these cells.
In SLE, biopsies of affected skin show deposition of Ig at the dermalepidermaljunction(DEJ),injurytobasalkeratinocytes,andinflammation dominated by T lymphocytes in the DEJ and around blood vessels and dermal appendages.377e).Thus, interplay between genetic susceptibility, environment, gender, and abnormal immune responses results in autoimmunity (Chap.Genes on theXchromosomethatinfluenceSLE,suchas TREX-1,mayplayarole in gender predisposition, possibly because some genes on the second X in females are not silent. People with XXY karyotype (Klinefelter’s syndrome) have a significantly increased risk for SLE. Several environmental stimuli may influence SLE (Fig. 378-1). Exposure to ultraviolet light causes flares of SLE in approximately 70% of patients, possibly by increasing apoptosis in skin cells or by altering DNA and intracellular proteins to make them antigenic. Some infections induce normal immune responses that involve certain T and B cells that recognize self-antigens; such cells are not appropriately regulated, and autoantibody production occurs. Most SLE patients have autoantibodies for 3 years or more before the first symptoms of disease, suggesting that regulation controls the degree of autoimmunity for years before quantities and qualities of autoantibodies and pathogenic B and T cells cause clinical disease. Epstein-Barr virus (EBV) may be one infectious agent that can trigger SLE in susceptible individuals. Children and adults with SLE are more likely to be infected by EBV than age-, sex-, and ethnicity-matched controls. EBV contains amino acid sequences that mimic sequences on human spliceosomes (RNA/protein antigens) often recognized by autoantibodies in people with SLE. Current tobacco smoking increases risk for SLE (odds ratio [OR] 1.5). Prolonged occupational exposure to silica (e.g., inhalation of soap powder dust or soil in farming activities) increases risk (OR 4.3) in African-American women. Thus, interplay between genetic susceptibility, environment, gender, and abnormal immune responses results in autoimmunity (Chap. 377e). In SLE, biopsies of affected skin show deposition of Ig at the dermalepidermaljunction(DEJ),injurytobasalkeratinocytes,andinflammation dominated by T lymphocytes in the DEJ and around blood vessels and dermal appendages.In renal biopsies, the pattern and severity of injury are important in diagnosisandinselectingthebesttherapy.Mostrecentclinicalstudiesof lupusnephritishaveusedtheInternationalSocietyofNephrology(ISN) and the Renal Pathology Society (RPS) classification (Table 378-2).
Diagnosis can also be made on the basis of a nonfasting (random) blood glucose level >200 mg/dl or a glycated hemoglobin (see p. 340) concentration ≥6.5 mg/dl (normal is <5.7) in an individual with symptoms of hyperglycemia.Individuals with impaired FBG are considered prediabetic and are at increased risk for developing T2D.A FBG of 100–125 mg/dl is categorized as an impaired FBG.Over a period of years, this autoimmune attack on the β cells leads to gradual depletion of the β-cell population (Fig. 25.2). However, symptoms appear abruptly when 80%–90% of the β cells have been destroyed. At this point, the pancreas fails to respond adequately to ingestion of glucose, and insulin therapy is required to restore metabolic control and prevent life-threatening ketoacidosis. β-Cell destruction requires both a stimulus from the environment (such as a viral infection) and a genetic determinant that causes the β cells to be mistakenly identified as “nonself.” [Note: Among monozygotic (identical) twins, if one sibling develops T1D, the other twin has only a 30%– 50% chance of developing the disease. This contrasts with T2D (see p. 341), in which the genetic influence is stronger and, in virtually all monozygotic twinships, the disease eventually develops in both individuals.] A. Diagnosis The onset of T1D is typically during childhood or puberty, and symptoms develop suddenly. Individuals with T1D can usually be recognized by the abrupt appearance of polyuria (frequent urination), polydipsia (excessive thirst), and polyphagia (excessive hunger), often triggered by physiologic stress such as an infection. These symptoms are usually accompanied by fatigue and weight loss. The diagnosis is confirmed by a FBG ≥126 mg/dl (normal is 70–99). [Note: Fasting is defined as no caloric intake for at least 8 hours.] A FBG of 100–125 mg/dl is categorized as an impaired FBG. Individuals with impaired FBG are considered prediabetic and are at increased risk for developing T2D. Diagnosis can also be made on the basis of a nonfasting (random) blood glucose level >200 mg/dl or a glycated hemoglobin (see p. 340) concentration ≥6.5 mg/dl (normal is <5.7) in an individual with symptoms of hyperglycemia.It is most typically used to screen pregnant women for gestational diabetes (see p.342).]When blood glucose is >180 mg/dl, the ability of renal sodium-dependent glucose transporters (SGLT) to reclaim glucose is impaired, and glucose “spills” into urine.The loss of glucose is accompanied by the loss of water, resulting in the characteristic polyuria (with dehydration) and polydipsia of diabetes.
Adenoid regrowth and bleeding rates are both low, and no study has been able to demonstrate the superiority of one technique over the other for either outcome.27,28 Adenoidectomy is not without complications though, beyond VPI and bleeding, halitosis and adenoid bed regrowth (∼1%) are common complications.If the adenoid bed appears hyperplastic on lateral X-ray imaging or endoscopy, a 2-month trial of nasal steroids may be helpful. Adenoidectomy is indicated for recur-rent and chronic infections that have failed conservative man-agement. These infections are not limited to the adenoid bed but also involve the sinuses and the middle year. Adenoidectomy with a myringotomy and ventilation tube placement is benefi-cial for recurrent or chronic otitis media in children because the Brunicardi_Ch18_p0613-p0660.indd 62201/03/19 5:23 PM 623DISORDERS OF THE HEAD AND NECKCHAPTER 18adenoid functions as a reservoir for bacteria that can enter the middle ear through the Eustachian tube.25Adenoidectomy is also the first line of surgical manage-ment for children with chronic sinusitis because the adenoid can obstruct mucociliary clearance from the sinonasal tract into the choana and ultimately into the pharynx. Patients with obstruc-tive systems attributable to the adenoids and suspected benign or malignant neoplasms of the adenoid bed are also candidates. However, the procedure is contraindicated in patients with vel-opalatine insufficiency (VPI) and in patients with a cleft pal-ate. Prior to adenoidectomy, patients should be examined for a submucous cleft, a lack of midline muscular tissue of the soft palate. Clinical signs of this include a bifid uvula, a translucent portion of the muscular diastasis of the soft palate (zona pel-lucida), and a palpable notched hard palate.26 A number of dif-ferent methods can be used to perform an adenoidectomy: cold steel, suction coagulator, microdebrider, and coblation. Adenoid regrowth and bleeding rates are both low, and no study has been able to demonstrate the superiority of one technique over the other for either outcome.27,28 Adenoidectomy is not without complications though, beyond VPI and bleeding, halitosis and adenoid bed regrowth (∼1%) are common complications.
Etiology The ostial obstruction in rhinosinusitis can arise from both infectious and noninfectious causes.Therefore, it is perhaps not surprising that antibiotics are prescribed frequently (in 85–98% of all cases) for this condition.Differentiating acute bacterial from viral sinusitis on clinical grounds is difficult.Although most cases of sinusitis involve more than one sinus, the maxillary sinus is most commonly involved; next, in order of frequency, are the ethmoid, frontal, and sphenoid sinuses. Each sinus is lined with a respiratory epithelium that produces mucus, which is transported out by ciliary action through the sinus ostium and into the nasal cavity. Normally, mucus does not accumulate in the sinuses, which remain mostly sterile despite their adjacency to the bacterium-filled nasal passages. When the sinus ostia are obstructed or when ciliary clearance is impaired or absent, the secretions can be retained, producing the typical signs and symptoms of sinusitis. As these secretions accumulate with obstruction, they become more susceptible to infection with a variety of pathogens, including viruses, bacteria, and fungi. Sinusitis affects a tremendous proportion of the population, accounts for millions of visits to primary care physicians each year, and is the fifth leading diagnosis for which antibiotics are prescribed. It typically is classified by duration of illness (acute vs. chronic); by etiology (infectious vs. noninfectious); and, when infectious, by the offending pathogen type (viral, bacterial, or fungal). Acute rhinosinusitis—defined as sinusitis of <4 weeks’ duration—constitutes the vast majority of sinusitis cases. Most cases are diagnosed in the ambulatory care setting and occur primarily as a consequence of a preceding viral URI. Differentiating acute bacterial from viral sinusitis on clinical grounds is difficult. Therefore, it is perhaps not surprising that antibiotics are prescribed frequently (in 85–98% of all cases) for this condition. Etiology The ostial obstruction in rhinosinusitis can arise from both infectious and noninfectious causes.Obstruction can also occur with nasal and sinus tumors (e.g., squamous cell carcinoma) or granulomatous diseases (e.g., granulomatosis with polyangiitis, rhinoscleroma), and conditions leading to altered mucus content (e.g., cystic fibrosis) can cause sinusitis through impaired mucus clearance.In ICUs, nasotracheal intubation and nasogastric tubes are major risk factors for nosocomial sinusitis.
Currently, three dose ranges are recommended for sugammadex: 2 mg/kg to reverse shallow neuromuscular blockade (spontaneous recovery has reached the second twitch in TOF stimulation), 4 mg/kg to reverse deeper blockade (1–2 posttetanic count and no response to TOF stimulation), and 16 mg/kg for immediate reversal following administration of a single dose of 1.2 mg/kg of rocuronium.Edrophonium has a more rapid onset of action but may be less effective than neostigmine in reversing the effects of nondepolarizing blockers in the presence of profound neuromuscular blockade. These differences are important in determining recovery from residual block, the neuromuscular blockade remaining after completion of surgery and movement of the patient to the recovery room. Unsuspected residual block may result in hypoventilation, leading to hypoxia and even apnea, especially if patients have received central depressant medications in the early recovery period. Sugammadex is a novel reversal agent recently approved for rapid reversal of the steroid neuromuscular blocking agents rocuronium and vecuronium. Although it has been in clinical use in Europe since 2008, its approval in the USA was delayed over concerns that it may cause anaphylaxis and hypersensitivity reactions. Sugammadex is a modified γ-cyclodextrin (a large ring structure with 16 polar hydroxyl groups facing inward and 8 polar carboxyl groups facing outward) that binds tightly to rocuronium in a 1:1 ratio. By binding to plasma rocuronium, sugammadex decreases the free plasma concentration and establishes a concentration gradient for rocuronium to diffuse away from the neuromuscular junction back into the circulation, where it is quickly bound by free sugammadex. Currently, three dose ranges are recommended for sugammadex: 2 mg/kg to reverse shallow neuromuscular blockade (spontaneous recovery has reached the second twitch in TOF stimulation), 4 mg/kg to reverse deeper blockade (1–2 posttetanic count and no response to TOF stimulation), and 16 mg/kg for immediate reversal following administration of a single dose of 1.2 mg/kg of rocuronium.In patients with renal insufficiency, complete urinary elimination may take much longer.The plasma half-life of sugammadex in patients with renal impairment increases significantly as CrCl is reduced.In mild to moderate renal insufficiency (CrCl between 30 and 80 mL/min), the half-life varies between 4 and 6 hours.
Specify if: Performance only: If the fear is restricted to speaking or performing in public.If another medical condition (e.g., Parkinson’s disease, obesity, disfigurement from bums or injury) is present, the fear, anxiety, or avoidance is clearly unrelated or is excessive.J.Marked tear or anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others. Examples include social interactions (e.g., hav- ing a conversation, meeting unfamiliar people), being observed (e.g., eating or drink- ing), and performing in front of others (e.g., giving a speech). Note: In children, the anxiety must occur in peer settings and not just during interac- tions with adults. B. The individual fears that he or she will act in a way or show anxiety symptoms that will be negatively evaluated (i.e., will be humiliating or embarrassing; will lead to rejection or offend others). C. The social situations almost always provoke tear or anxiety. Note: In children, the fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking, or failing to speak in social situations. D. The social situations are avoided or endured with intense fear or anxiety. E. The fear or anxiety is out of proportion to the actual threat posed by the social situation and to the sociocultural context. F. The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more. G. The fear, anxiety, or avoidance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. H. The fear, anxiety, or avoidance is not attributable to the physiological effects of a sub- stance (e.g., a drug of abuse, a medication) or another medical condition. I. The fear. anxiety, or avoidance is not better explained by the symptoms of another mental disorder, such as panic disorder, body dysmorphic disorder, or autism spectrum disorder. J. If another medical condition (e.g., Parkinson’s disease, obesity, disfigurement from bums or injury) is present, the fear, anxiety, or avoidance is clearly unrelated or is excessive. Specify if: Performance only: If the fear is restricted to speaking or performing in public.Performance fears may also manifest in work, school, or academic settings in which regular public presenta- tions are required.Individuals with performance only social anxiety disorder do not fear or avoid nonperformance social situations.
There is marked right ventricular hypertrophy, since that chamber functions as the systemic ventricle; the left ventricle is hypoplastic, since it pumps only to the low-resistance pulmonary circulation.11.4, B ).Indeed, VSDs occur in one third of cases (see Fig.Moreover, as the child grows and the heart increases in size, the pulmonic orifice does not expand proportionately, leading to progressive worsening of the stenosis. Fortuitously, the pulmonic outflow stenosis protects the pulmonary vasculature from pressure and volume overloads, so that pulmonary hypertension does not develop, and right ventricular failure is rare. Nevertheless, patients develop the typical sequelae of cyanotic heart disease, such as hypertrophic osteoarthropathy and polycythemia (due to hypoxia) with attendant hyperviscosity; right-to-left shunting also increases the risk for infective endocarditis and systemic embolization. Complete surgical repair is possible with classic tetralogy of Fallot but is more complicated in the setting of pulmonary atresia. Transposition of the Great Arteries Transposition of the great arteries is a discordant connection of the ventricles to their vascular outflow. The embryologic defect is an abnormal formation of the truncal and aortopulmonary septa so that the aorta arises from the right ventricle and the pulmonary artery emanates from the left ventricle ( Fig. 11.4B ). The atrium-to-ventricle connections, however, are normal (concordant), with the right atrium joining the right ventricle and the left atrium emptying into the left ventricle. The functional outcome is separation of the systemic and pulmonary circulations, a condition incompatible with postnatal life unless a shunt (such as a VSD) allows delivery of oxygenated blood to the aorta. Indeed, VSDs occur in one third of cases (see Fig. 11.4, B ). There is marked right ventricular hypertrophy, since that chamber functions as the systemic ventricle; the left ventricle is hypoplastic, since it pumps only to the low-resistance pulmonary circulation.The dominant manifestation is cyanosis, with the prognosis depending on the magnitude of shunting, the degree of tissue hypoxia, and the ability of the right ventricle to maintain systemic pressures.Without surgery (even with stable shunting), most patients with uncorrected transposition of the great arteries die within the first months of life.
The sudden appearance of lumbar pain in a patient receiving anticoagulants suggests retroperitoneal hemorrhage.A mass in the iliopsoas region can produce unilateral lumbar pain with radiation toward the groin, labia, or testicle.Pathology in retroperitoneal structures (hemorrhage, tumors, pyelonephritis) can produce paraspinal pain that radiates to the lower abdomen, groin, or anterior thighs.A dimple or small lipoma may overlie the defect. Most cases are asymptomatic and discovered incidentally during an evaluation for back pain. Tethered cord syndrome usually presents as a progressive cauda equina disorder (see below), although myelopathy may also be the initial manifestation. The patient is often a young adult who complains of perineal or perianal pain, sometimes following minor trauma. MRI studies reveal a low-lying conus (below L1 and L2) and a short and thickened filum terminale. Diseases of the thorax, abdomen, or pelvis may refer pain to the posterior portion of the spinal segment that innervates the diseased organ. Occasionally, back pain may be the first and only manifestation. Upper abdominal diseases generally refer pain to the lower thoracic or upper lumbar region (eighth thoracic to the first and second lumbar vertebrae), lower abdominal diseases to the midlumbar region (second to fourth lumbar vertebrae), and pelvic diseases to the sacral region. Local signs (pain with spine palpation, paraspinal muscle spasm) are absent, and little or no pain accompanies routine movements of the spine. Low Thoracic or Lumbar Pain with Abdominal Disease Tumors of the posterior wall of the stomach or duodenum typically produce epigastric pain (Chaps. 109 and 348), but midline back or paraspinal pain may occur if retroperitoneal extension is present. Fatty foods occasionally induce back pain associated with biliary disease. Diseases of the pancreas can produce right or left paraspinal back pain. Pathology in retroperitoneal structures (hemorrhage, tumors, pyelonephritis) can produce paraspinal pain that radiates to the lower abdomen, groin, or anterior thighs. A mass in the iliopsoas region can produce unilateral lumbar pain with radiation toward the groin, labia, or testicle. The sudden appearance of lumbar pain in a patient receiving anticoagulants suggests retroperitoneal hemorrhage.The classic clinical triad of abdominal pain, shock, and back pain occurs in <20% of patients.The typical patient at risk is an elderly male smoker with back pain.The diagnosis may be missed because the symptoms and signs can be nonspecific.Misdiagnoses include nonspecific back pain, diverticulitis, renal colic, sepsis, and myocardial infarction.
Attention has also been drawn to the regional alterations of cerebral blood flow in chronic stable schizophrenic patients, as revealed by positron emission tomography (PET) and functional MRI.It is unclear, however, if these changes represent primary defects or are secondary to an inherent lack of motivation.These deficits correlate with reduced cognitive activation activity in functional MRI.Equally compelling is the finding that young individuals having 2 or more relatives with the disease, and therefore being at risk for developing schizophrenia, have certain volumetric brain changes detected by imaging studies (Lawrie et al). In unaffected relatives, the left hippocampal–amygdaloid region was smaller than in healthy people, but slightly larger than in affected relatives. In an attempt to organize the imaging findings, Murray and coworkers raised the possibility that there are 2 types of this disease: one with ventricular enlargement and a negative family history and the other with normal ventricles and a positive family history. In the first group of sporadic, “acquired” schizophrenia, environmental factors, such as birth injury, and EEG abnormalities (see in the following text) were considered to be more frequent. In summarizing the many cerebral changes observed in schizophrenic patients, Harrison concluded that several are quite consistent. These include mild enlargement of the lateral and third ventricles; decreased cortical volume, perhaps disproportionate in the temporal lobe; microscopically, diminution in size of cortical and hippocampal neurons; a diminished number of neurons in the dorsal thalamus; and a notable absence of gliosis. EEG data, for the most part not useful, were alluded to earlier. Detailed neuropsychologic testing has disclosed deficits in attention and abnormalities of the P300 waves (cortical “event-related” potentials). These deficits correlate with reduced cognitive activation activity in functional MRI. It is unclear, however, if these changes represent primary defects or are secondary to an inherent lack of motivation. Attention has also been drawn to the regional alterations of cerebral blood flow in chronic stable schizophrenic patients, as revealed by positron emission tomography (PET) and functional MRI.Friston and associates found consistent abnormalities in the left parahippocampal region in all forms of chronic schizophrenia.Studies of regional glucose metabolism and postmortem norepinephrine measurements have yielded equivocal data, although most patients show a reduction in glucose metabolism in the thalamus and frontal cortex.
Some rapidly develop an obstructive hydrocephalus and require a ventricular shunt.37-14) and CT, and it is apparent that many infants with smaller hemorrhages survive.Lesser degrees of this cerebral hemorrhage are now being identified by ultrasonography (Fig.Many but not all have epilepsy in addition to the motor abnormalities and there is an unavoidable overlap in considering the causes and mechanisms of these three clinical states. The following discussion is given from the perspective of the three major etiologic syndromes: matrix hemorrhages in the immature infant, hypoxic-ischemic encephalopathy, and certain other developmental motor abnormalities including those due to intrauterine stroke. In low-weight and premature immature infants (20 to 35 weeks’ gestational age), there sometimes occurs, within a few days after birth, a catastrophic decline in cerebral function, usually preceded by respiratory distress (hyaline membrane disease) with spells of cyanosis and apnea. Also evident are deficiencies of brainstem automatisms (sucking and swallowing), bulging of the fontanels, and sanguineous CSF. If the infant becomes completely unresponsive, death usually ensues within a few days. Autopsy discloses a small lake of blood in each cerebral hemisphere (often asymmetrically distributed), occupying the highly cellular (subependymal) germinal matrix zone, near the caudate nucleus at the level of the foramen of Monro. This region is supplied by the lenticulostriate, choroidal, and Heubner recurrent arteries and is drained by deep veins, which enter the vein of Galen. In approximately 25 percent of cases, the blood remains loculated in the matrix zone, while in the majority it ruptures into the lateral ventricle or adjacent brain tissue. In a series of 914 consecutive autopsies in newborns, subependymal hemorrhage was found in 284 (31 percent); practically all of these neonates were of low birth weight, according to Banker and Bruce-Gregorios. Lesser degrees of this cerebral hemorrhage are now being identified by ultrasonography (Fig. 37-14) and CT, and it is apparent that many infants with smaller hemorrhages survive. Some rapidly develop an obstructive hydrocephalus and require a ventricular shunt.Several series of surviving cases have now been followed for many years.Those in whom the hemorrhage was more extensive are often left with motor and intellectual handicaps.Viewed from the perspective of cerebral palsy, just over half of the patients in the Swedish series of Hagberg and Hagberg with spastic diplegia had matrix hemorrhages, leukomalacia (see further on), or both.
The pathogenesis of viral myocarditis has been extensively studied in murine models.Infectious myocarditis has been reported with almost all types of infective agents but is most commonly associated with viruses and the protozoan Trypanosoma cruzi.Interest in the potential for recovery of cardiomyopathy has been FIGURE 287-2 Dilated cardiomyopathy. This gross specimen of a heart removed at the time of transplantation shows massive left ventricular dilation and moderate right ventricular dilation. Although the left ventricular wall in particular appears thinned, there is significant hypertrophy of this heart, which weighs more than 800 g (upper limit of normal = 360 g). A defibrillator lead is seen traversing the tricuspid valve into the right ventricular apex. (Image courtesy of Robert Padera, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, Boston.) further stimulated by occasional “recovery” of left ventricular function after prolonged mechanical circulatory support. The diagnosis and therapy for dilated cardiomyopathy are generally dictated by the stage of heart failure (Chap. 279), with specific aspects discussed for relevant etiologies below. Myocarditis (inflammation of the heart) can result from multiple causes but is most commonly attributed to infective agents that can injure the myocardium through direct invasion, production of cardiotoxic substances, or chronic inflammation with or without persistent infection. Myocarditis cannot be assumed from a presentation of decreased systolic function in the setting of an acute infection, as any severe infection causing systemic cytokine release can depress cardiac function transiently. Infectious myocarditis has been reported with almost all types of infective agents but is most commonly associated with viruses and the protozoan Trypanosoma cruzi. The pathogenesis of viral myocarditis has been extensively studied in murine models.Viral infection and replication can cause myocardial injury and lysis.For example, the enteroviral protease 2A facilitates viral replication and infection through degradation of the myocyte protein dystrophin, which is crucial for myocyte stability.Activation of viral receptor proteins can also activate host tyrosine kinases, which modify the cytoskeleton to facilitate further viral entry.
The family and even the primary physician often identify the problem as abrupt in onset and having no precedent as the patient seemingly functioned well previously.Authoritative writers have suggested that confusion is causal to subsequent dementia but evidence for this is so far lacking.However, the characteristic features in neuroleptic malignant syndrome (NMS) are progressive muscle rigidity and evidence of myonecrosis as indicated by elevations of the serum creatine kinase; usually there is in addition some elevation of body temperature. The clinical examination and a thorough history aid greatly in determining which category of drug is implicated. Dementing Disease Complicated by Confusional States and Delirium in the Elderly Physicians are all too familiar with the situation of an elderly patient who enters the hospital with a medical or surgical illness or begins a prescribed course of medication and displays a newly acquired mental confusion. Presumably, the liability to this state is determined by preexisting brain disease, most often Alzheimer disease but sometimes Parkinson disease, multiple small deep cerebral infarctions, or another dementing process, which may or may not have been obvious to the family before. All the clinical features that one observes in the acute confusional states may be present, but their severity varies greatly. Confusion may be reflected only in the patient’s inability to relate the history of the illness sequentially, or it may be so severe that the patient is virtually non compos mentis. An analysis of other studies by Witlox and colleagues has estimated that the risk of dementia in persons over 85 years if an episode of global confusion has occurred is almost 9 times the rate in others of the same age. Authoritative writers have suggested that confusion is causal to subsequent dementia but evidence for this is so far lacking. The family and even the primary physician often identify the problem as abrupt in onset and having no precedent as the patient seemingly functioned well previously.
The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes.Mechanisms of Action & Resistance The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes (Figure 48–1).Table 48–2 summarizes the differences among six of the azoles.The adverse effects of flucytosine result from metabolism (possibly by intestinal flora) to the toxic antineoplastic compound fluorouracil. Bone marrow toxicity with anemia, leukopenia, and thrombocytopenia are the most common adverse effects, with derangement of liver enzymes occurring less frequently. A form of toxic enterocolitis can occur. There seems to be a narrow therapeutic window, with an increased risk of toxicity at higher drug levels and resistance developing rapidly at subtherapeutic concentrations. The use of drug concentration measurements may be helpful in reducing the incidence of toxic reactions, especially when flucytosine is combined with nephrotoxic agents such as amphotericin B. Azoles are synthetic compounds that can be classified as either imidazoles or triazoles according to the number of nitrogen atoms in the five-membered azole ring, as indicated below. The imidazoles consist of ketoconazole, miconazole, and clotrimazole FIGURE 48–2 Structural formulas of some antifungal azoles. (Figure 48–2). The latter two drugs are now used only in topical therapy. The triazoles include itraconazole, fluconazole, voriconazole, isavuconazole, and posaconazole. Other triazoles are currently under investigation. N X X = C, imidazole X = N, triazole N The pharmacology of each of the azoles is unique and accounts for some of the variations in clinical use. Table 48–2 summarizes the differences among six of the azoles. Mechanisms of Action & Resistance The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes (Figure 48–1). The selective toxicity of azole drugs results from their greater affinity for fungal than for human cytochrome P450 enzymes.Resistance to azoles occurs via multiple mechanisms.Once rare, increasing numbers of resistant strains are being reported, suggesting that increasing use of these agents for prophylaxis and therapy may be selecting for clinical drug resistance in certain settings.
55-1).Carnitine is a crucial cofactor in the transport of long-chain fatty acids across the mitochondrial inner membrane (see Fig.Confirmatory testing is similar to that for the other fatty acid oxidation disorders.Glutaric aciduria type II exhibits autosomal recessive inheritance.Some patients respond to administration of riboflavin.Glutaric aciduria type II (multiple acyl-CoA dehydrogenase deficiency) is a clinical disease produced by a defect in the transfer of electrons from flavine adenine nucleotides to the electron transport chain (electron transfer flavoprotein [ETF], or ETF dehydrogenase); this defect results in a deficiency of multiple fatty acyl CoA dehydrogenases (see Fig. 55-1). medium-chain fatty acyl-CoA dehydrogenase, short-chain fatty acyl-CoA dehydrogenase, β-ketothiolase, (6) β-hydroxy-β-methylglutaryl-CoA synthase, (7) β-hydroxy-β-methylglutaryl-CoA lyase, (8) β-hydroxybutyrate dehydrogenase. CoA, Coenzyme A. It should not be confused with glutaric acidemia type I (see Chapter 54). When the enzyme essentially is nonfunctional, congenital anomalies are common, including renal cysts, facial abnormalities, rocker-bottom feet, and hypospadias. Severely affected infants have nonketotic hypoglycemia, metabolic acidosis, and the odor of sweaty feet soon after birth; these infants may die within the neonatal period. Less severely affected infants may have a more episodic, Reye syndrome–like illness. Skeletal and cardiac myopathy can be prominent in this complex, multisystemic disease. Onset in later childhood may be marked by recurrent hypoglycemia and myopathy. Treatment has not been effective in infants with complete deficiency. Milder forms respond to avoidance of fasting and caloric support during metabolic stress. Some patients respond to administration of riboflavin. Glutaric aciduria type II exhibits autosomal recessive inheritance. Confirmatory testing is similar to that for the other fatty acid oxidation disorders. Carnitine is a crucial cofactor in the transport of long-chain fatty acids across the mitochondrial inner membrane (see Fig. 55-1).Carnitine deficiency is either primary (caused by failure of intake, synthesis, or transport of carnitine) or secondary (caused by the excretion of excessive amounts of carnitine as carnityl esters in patients with other inborn errors of metabolism; treatment with drugs that complex carnitine, such as valproic acid; or as a result of renal replacement therapy).
An alternative cause in these neuropathies that are characterized mainly by painful burning is that there is an abnormality of the sodium channel that renders the sensory neurons or fibers hyperexcitable.Presumably, in the idiopathic cases, there is a similar small-fiber neuropathy, but the common clinical situation is that an etiology cannot be found.Most of these cases are idiopathic, but there is a broad differential diagnosis, including the diseases mentioned earlier, as outlined by Mendell and Sahenk (Table 43-5 is adapted from their discussion). Electrophysiologic tests are likewise normal or virtually so; a few show diminished sural nerve potentials and minor changes of motor amplitudes. When the causes listed in the table have been excluded, a substantial group of patients is left and are in need of symptomatic relief. Some have been helped by gabapentin or by antidepressants and analgesic cream applied nightly to the soles and toes. A few of the more severe cases have apparently responded to gamma globulin infusions, but these observations require corroboration (Gorson and Ropper, 1995). In a number of cases of burning feet, the intradermal sensory nerves in skin biopsy specimens are depleted, but the meaning of this finding is not certain (Periquet et al) and the clinical diagnosis of a small-fiber neuropathy in affected older patients can be inferred without this procedure. Identifiable causes for painful sensory neuropathy in the elderly include mainly diabetes, alcoholic–nutritional deficiency states, connective tissue disease, amyloidosis, and vasculitis. Presumably, in the idiopathic cases, there is a similar small-fiber neuropathy, but the common clinical situation is that an etiology cannot be found. An alternative cause in these neuropathies that are characterized mainly by painful burning is that there is an abnormality of the sodium channel that renders the sensory neurons or fibers hyperexcitable.The mutation caused a gain of function in this gene and allowed dorsal root ganglion neurons to become hyperexcitable (Faber at al).Yet another rare cause of this syndrome has been the finding of antibodies to peripherin, which is a dominantly inherited trait (Stogbauer et al).A polyneuropathy that advances slowly over 10 years or more is almost invariably genetic in origin.
The pancreatic duct (of Wirsung) extends through the length of the gland and empties into the duodenum at the hepatopan creatic ampulla (of Vater), through which the common bile duct from the liver and gallbladder also enters the duodenum.The centrally located body of the pancreas crosses the midline of the human body, and the tail extends toward the hilum of the spleen.Therefore, the final modification of bile is mainly the result of the active transport of Na , Cl, and HCO3 , and the passive, aquaporin-mediated transport of water across the plasma membrane of epithelial cells of the gallbladder. FIGURE 18.18 • Photomicrograph of the Rokitansky-Aschoff sinuses in the wall of the gallbladder. This photomicrograph shows deep invaginations of the mucosa extending into the muscularis externa. These invaginations are referred to as Rokitansky-Aschoff sinuses. 120. FIGURE 18.19 • Diagram of pancreas, duodenum, and associated excretory ducts. The main pancreatic duct (of Wirsung) traverses the length of the pancreas and enters the duodenum after joining with the common bile duct. An accessory pancreatic duct (of Santorini) is commonly present, as shown, and empties into the duodenum at a separate minor duodenal papilla. The site of entry of the common bile duct and main pancreatic duct into the duodenum is typically marked by a major duodenal papilla visible on the inner surface of the duodenum. The pancreas is an elongate gland described as having a head, body, and tail. The head is an expanded portion that lies in the C-shaped curve of the duodenum (Fig. 18.19). It is joined to the duodenum by connective tissue. The centrally located body of the pancreas crosses the midline of the human body, and the tail extends toward the hilum of the spleen. The pancreatic duct (of Wirsung) extends through the length of the gland and empties into the duodenum at the hepatopan creatic ampulla (of Vater), through which the common bile duct from the liver and gallbladder also enters the duodenum.In some individuals, an ac cessory pancreatic duct (of Santorini) is present, a vestige of the pancreas’s origin from two embryonic endodermal pri mordia that evaginate from the foregut.A thin layer of loose connective tissue forms a capsule around the gland.From this capsule, septa extend into the gland, dividing it into ill-defined lobules.
Many individuals have some underlying concerns that diagnostic testing needs to be performed or that something is being missed.Often, the first step is to reassure the patient that this is a functional disease and is not related to cancer or malignancy, assuming those were eliminated by history and examination.Management General management of IBS can be extremely difficult.This spectrum of symptoms renders diagnosis difficult and led to a consensus group that created the Rome criteria in 1992, revised in 2005 (57). The resulting Rome III criteria are: recurrent abdominal pain or discomfort for at least 3 days per month for 3 months associated with two or more of the following: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in the appearance of the stool IBS should be a diagnosis of exclusion with consideration initially given to other causes for the dominant symptom. If that is diarrhea, considerations of lactose intolerance, infectious etiology, malabsorption, or celiac disease should be entertained. Symptoms that result in weight loss, rectal bleeding, anemia, or that are noctural or progressive could indicate something other than IBS unless proven otherwise. A basic workup might include complete blood count and chemistries. Evaluation of diarrhea, if that is the dominant symptom, should potentially include stool cultures if infectious etiology is suspected or 24-hour stool collection (if osmotic) of secretory diarrhea is suspected. Flexible sigmoidoscopy is not done routinely unless needed to rule out inﬂammatory conditions or malignancy in families with Lynch syndrome. Initiate dietary reviews for lactose intolerance or gluten sensitivity. Management General management of IBS can be extremely difficult. Often, the first step is to reassure the patient that this is a functional disease and is not related to cancer or malignancy, assuming those were eliminated by history and examination. Many individuals have some underlying concerns that diagnostic testing needs to be performed or that something is being missed.The patient needs to be an active participant in her care and understand the chronic nature of the disease.A symptom diary for several weeks may show a link between various foods and stressors that may be modifiable.Some individuals are able to link various stressors in their lives to symptoms while others will not have identifiable causes.
where molecules at 37°C can exert an osmotic pressure of 2.54 n = number of dissociable particles per molecule × 10−2 atm, as calculated with eq.Glucoseistransportedbytheepithelialcellsthatlinethegastrointestinaltract(smallintestine),andbycellsthatformtheproximaltubulesofthekidneys.Inthegastrointestinaltract,theglucoseisabsorbedfromingestedfood.Inthekidney,theproximaltubulereabsorbstheglucosethatwasfilteredacrosstheglomerularcapillariesandtherebypreventsitfrombeinglostintheurine.Theuptakeofglucoseintotheepithelialcellfromthelumenofthesmallintestineandfromthelumenoftheproximaltubuleisasecondaryactiveprocessinvolvingthesodium-glucose–linkedtransportersSGLT-1andSGLT-2.SGLT-2transportsoneglucosemoleculewithoneNa+ ion,andtheenergyintheelectrochemicalgradientforNa+ (intothecell)drivesthesecondaryactiveuptakeofglucose.Accordingtothefollowingequation,forcalculatingtheelectrochemicalgradient,andifthemembranepotential(Vm)is−60mVandthereisa10-fold[Na+]gradientacrossthemembrane,anapproximate100-foldglucosegradientcouldbegeneratedbySGLT-2:[Glucose]i [Na+ ]o V 615. mV Thus,iftheintracellularglucoseconcentrationwas2mmol/L,thecellcouldlowertheextracellularglucoseconcentrationtoapproximately0.02mmol/L.However,byincreasingthenumberofNa+ ionstransportedwithglucosefromonetotwo,SGLT-1cangenerateanearly10,000-foldglucosegradient: 615. mV Again,iftheintracellularglucoseconcentrationis2mmol/L,SGLT-1couldremovevirtuallyallglucosefromeitherthelumenofthesmallintestineorthelumenoftheproximaltubule(i.e.,theluminalglucoseconcentration≅ 0.0002mmol/L). where molecules at 37°C can exert an osmotic pressure of 2.54 n = number of dissociable particles per molecule × 10−2 atm, as calculated with eq.
Listed next are a few important tenets and caveats when considering mendelian disorders: Mutations involving single genes follow one of three patterns of inheritance: autosomal dominant, autosomal recessive, or X-linked. A single-gene mutation may have many phenotypic effects (pleiotropy) and, conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity). For example, Marfan syndrome, which results from a basic defect in connective tissue, is associated with widespread effects involving the skeleton, eyes, and cardiovascular system, all of which stem from a mutation in the gene encoding fibrillin, a component of connective tissues. On the other hand, several different types of mutations can cause retinitis pigmentosa, an inherited disorder associated with abnormal retinal pigmentation and consequent visual impairment. Recognition of genetic heterogeneity not only is important in genetic counseling but also facilitates understanding of the pathogenesis of common disorders such as diabetes mellitus (Chapter 20). • It is now increasingly recognized that the phenotypic manifestations of mutations affecting a known single Table 7.1 Estimated Prevalence of Selected Mendelian Disorders Among Live-Born Infants Huntingtondisease1in10,000 Sicklecellanemia1in500(U.S.AfricanAmericans) Cysticfibrosis1in3200(U.S.Caucasians) Tay-Sachsdisease1in3500(U.S.AshkenaziJewish;FrenchCanadians) Phenylketonuria1in10,000 MPSs—alltypes1in25,000 Glycogenstoragediseases—all1in50,000types Galactosemia1in60,000 Duchennemusculardystrophy1in3500(U.S.males) Hemophilia1in5000(U.S.males) *Theprevalenceofheterozygoussicklecelltraitis1in12forU.S.AfricanAmericans.MPS, Mucopolysaccharidosis.†Althoughfull-blownsymptomsrequirebiallelicmutations,heterozygotesforthalassemiaandsicklecellanemiamaypresentwithmildclinicaldisease.Thus,thesedisorderssometimesarecategorizedas“autosomalcodominant”entities.http://ebooksmedicine.net gene are influenced by other genetic loci, which are called modifier genes.
Cardiorespiratory monitoring for 12 to 24 hours in the hospital can provide information on respiratory and cardiac patterns and feeding difficulties (choking, gagging, emesis); provide time to get more history and assess the home situation; and alleviate parental anxiety.If gastroesophageal reflux is suspected, a barium swallow or pH probe study may be useful.Central nervous system (CNS) causes (e.g., seizures, breath-holding spells, intracranial bleeding from accidental or nonaccidental trauma) account for approximately 15% of cases, and cardiovascular events and metabolic derangements account for smaller percentages. Acute infection with respiratory viruses (respiratory syncytial virus [RSV] and others), pertussis, and serious bacterial infections (sepsis, meningitis) can also cause apnea in infants. In most cases, a careful history can lead to a correct diagnosis. Questions should include history of premature birth, prior apnea, level of consciousness at the time of the event, presence or absence of respiratory effort, limpness or stiffness, jerking movements (seizure), feeding history, intercurrent illnesses, any trauma, and the social situation of the family. The physical examination should focus on bruising and injury, the general and neurologic condition of the infant, nutritional status, respiratory pattern, and cardiac status. The laboratory evaluation may include serum electrolytes, serum glucose, blood urea nitrogen, creatinine, hemoglobin, hematocrit, white blood cell count, a chest radiograph, and blood gas analysis. Testing for respiratory viruses and pertussis in patients with evidence of respiratory infection should occur. If gastroesophageal reflux is suspected, a barium swallow or pH probe study may be useful. Cardiorespiratory monitoring for 12 to 24 hours in the hospital can provide information on respiratory and cardiac patterns and feeding difficulties (choking, gagging, emesis); provide time to get more history and assess the home situation; and alleviate parental anxiety.There are no standard recommendations for when home monitoring should be prescribed.Polysomnography is not useful in predicting which children with ALTEs are likely to progress to sudden infant death syndrome (SIDS).The key to prevention of future events is to identify the underlying cause and treat it.
The earliest abnormality of hyaline and elastic cartilage noted histologically is a focal or diffuse loss of basophilic staining indicating depletion of proteoglycan from the cartilage matrix.Most patients will require the use of an assistive device such as a cane, walker, or wheelchair within 5–10 years of onset. In general, the oldertheageofonsetinIBM,themorerapidlyprogressiveisthecourse. abnormalities, skin lesions, and glomerulonephritis. Relapsing polychondritis has been estimated to have an incidence of 3.5 per million population per year. The peak age of onset is between the ages of 40 and 50 years, but relapsing polychondritis may affect children and the elderly. It is found in all races, and both sexes are equally affected. No familial tendency is apparent. A significantly higher frequency of HLA-DR4 has been found in patients with relapsing polychondritis than in healthy individuals. A predominant subtype allele(s) of HLA-DR4 was not found. Approximately 30% of patients with relapsing polychondritis will have another rheumatologic disorder, the most frequent being systemic vasculitis, followed by rheumatoid arthritis, and systemic lupus erythematosus (SLE). Nonrheumatic aSystemic vasculitis is the most common association, followed by rheumatoid arthritis and systemic lupus erythematosus. Source: Modified from CJ Michet et al: Ann Intern Med 104:74, 1986. disorders associated with relapsing polychondritis include Hashimoto’s thyroiditis, primary biliary cirrhosis, and myelodysplastic syndrome (Table 389-1). In most cases, these disorders antedate the appearance of relapsing polychondritis, usually by months or years; however, in other instances, the onset of relapsing polychondritis can accompany disease presentation. The earliest abnormality of hyaline and elastic cartilage noted histologically is a focal or diffuse loss of basophilic staining indicating depletion of proteoglycan from the cartilage matrix.In acute disease, polymorphonuclear white cells may also be present.Destruction of cartilage begins at the outer edges and advances centrally.There is lacunar breakdown and loss of chondrocytes.Degenerating cartilage is replaced by granulationtissueandlaterbyfibrosis andfocal areasofcalcification.Smallloci of cartilage regeneration may be present.
This situation usually results in considerable mortality among all age groups.In holoand hyperendemic areas (e.g., certain regions of tropical Africa or coastal New Guinea) where there is intense P. falciparum transmission, people may sustain more than one infectious mosquito bite per day and are infected repeatedly throughout their lives. In such settings, rates of morbidity and mortality due to malaria are considerable during early childhood. Immunity against disease is hard won in these areas, and the burden of disease in young children is high; by adulthood, however, most malarial infections are asymptomatic. As control measures progress and urbanization expands, environmental conditions become less conducive to transmission, and all age groups may lose protective immunity and become susceptible to illness. Constant, frequent, year-round infection is termed stable transmission. In areas where transmission is low, erratic, or focal, full protective immunity is not acquired, and symptomatic disease may occur at all ages. This situation usually exists in hypoendemic areas and is termed unstable transmission. Even in stable-transmission areas, there is often an increased incidence of symptomatic malaria coinciding with increased mosquito breeding and transmission during the rainy season. Malaria can behave like an epidemic disease in some areas, particularly those with unstable malaria, such as northern India (the Punjab region), the horn of Africa, Rwanda, Burundi, southern Africa, and Madagascar. An epidemic can develop when there are changes in environmental, economic, or social conditions, such as heavy rains following drought or migrations (usually of refugees or workers) from a nonmalarious region to an area of high transmission, along with failure to invest in national programs; a breakdown in malaria control and prevention services caused by war or civil disorder can intensify epidemic conditions. This situation usually results in considerable mortality among all age groups.More than 100 of the >400 anopheline species can transmit malaria, but the ~40 species that do so commonly vary considerably in their efficiency as malaria vectors.
Advantages of cMRI over CT scans include better soft-tissue evaluation without the need for iodinated contrast and no expo-sure to ionizing radiation.It is important in the initial workup to distinguish a cardiac tumor from an intracardiac thrombus, which may be common in the atria of patients with AF and can mimic echocardiographic features of atrial myxomas.While rare, myxomatous tumor emboli have also been identified in the coronary arteries, common iliac and femoral arteries, kidney, spleen, pancreas, and liver.294Certain clinical features may be helpful in distinguishing benign from malignant primary cardiac tumors.292 Malignant tumors, primarily sarcomas, do not demonstrate a gender pref-erence and tend to present after the fourth decade of life. They are often multifocal within the right atrium, and intramyocardial invasion can lead to refractory congestive heart failure, arrhyth-mias, hemopericardium, and ischemia. Conversely, benign tumors, primarily myxomas, are typically unifocal in the left atrium, have a 3:1 female preference, and occur in younger patients. Arrhythmias and pericardial effusions are very rare in this population.Diagnosis and Characterization of Cardiac Masses. Trans-thoracic echocardiography is the mainstay imaging technique for the detection of cardiac tumors.292 However, echocardiogra-phy is limited by dependence on an acoustic window, subopti-mal visualization of extracardiac extension, and poor soft-tissue visualization. TEE is generally only beneficial for small local-ized tumors due to its limited field of view. cMRI is therefore the current standard for delineating the anatomical extent of the tumor and assessing the paracardiac space and great vessels. Advantages of cMRI over CT scans include better soft-tissue evaluation without the need for iodinated contrast and no expo-sure to ionizing radiation.It is important in the initial workup to distinguish a cardiac tumor from an intracardiac thrombus, which may be common in the atria of patients with AF and can mimic echocardiographic features of atrial myxomas.Moreover, anticoagulation can potentially increase the risk of peripheral embolization in patients with cardiac tumors.Delayed enhance-ment cMRI is the best modality to separate these two entities.cMRI may show vascularization, areas of necrosis, hemorrhage, or calcification in cardiac tumors that are not present in thrombi.MyxomaPathology and Genetics.
The tumor originates most frequently in the adrenal glands, posterior mediastinum, neck, or pelvis but can arise in any sympathetic ganglion.Neuro-blastomas arise from the neural crest cells and show different levels of differentiation.Over 80% of cases present before the age of 4 years, and the peak incidence is two years of age.If bilateral disease is encountered, both lesions are biopsied, and chemotherapy is administered followed by a nephron-sparing procedure.Chemotherapy. Following nephroureterectomy for Wilms’ tumor, the need for chemotherapy and/or radiation therapy are determined by the histology of the tumor and the clinical stage of the patient (Table 39-3). Essentially, patients who have dis-ease confined to one kidney completely excised surgically receive a short course of chemotherapy and can expect a 97% 4-year survival, with tumor relapse rare after that time. Patients with more advanced disease or with unfavorable histol-ogy receive more intensive chemotherapy and radiation. Even in stage IV, high cure rates may be achieved. The survival rates are worse in the small percentage of patients considered to have unfavorable histology.NeuroblastomaClinical Presentation. Neuroblastoma is the third most com-mon pediatric malignancy and accounts for approximately 10% of all childhood cancers. The vast majority of patients have advanced disease at the time of presentation, and unlike Wilms’ tumor, in which cure is expected in the vast majority of patients, the overall survival of patients with neuroblastoma is significantly lower. Over 80% of cases present before the age of 4 years, and the peak incidence is two years of age. Neuro-blastomas arise from the neural crest cells and show different levels of differentiation. The tumor originates most frequently in the adrenal glands, posterior mediastinum, neck, or pelvis but can arise in any sympathetic ganglion.The tumor may cross the midline, and a majority of patients will already show signs of metastatic disease.Occasionally, children may experience pain from the tumor mass or from bony metastases.Proptosis and perior-bital ecchymosis may occur due to the presence of retrobulbar metastasis.
468e); cinchonism (hearing loss, tinnitus, nausea, vomiting, vertigo, ataxia, headache, flushing, diaphoresis) and blindness with quinoline antimalarials Discontinue the offending agent(s); the serotonin receptor antagonist cyproheptadine may be helpful in severe cases.469e. bSee above and Chap. 468e. Promotion of serotonin release, inhibition of serotonin reuptake, or direct stimulation of CNS and peripheral serotonin receptors (primarily 5-HT-1a and 5-HT-2), alone or in combination Blockade of fast sodium membrane channels prolongs phase 0 (depolarization) of the cardiac action potential, which prolongs QRS duration and promotes reentrant (monomorphic) ventricular tachycardia. Class Ia, Ic, and III antiarrhythmics also block potassium channels during phases 2 and 3 (repolarization) of the action potential, prolonging the JT interval and promoting early after-depolarizations and polymorphic (tor-sades des pointes) ventricular tachycardia. Similar effects on neuronal membrane channels cause CNS dysfunction. Some agents also block α-adrenergic and cholinergic receptors or have opioid effects (see above and Chap. 468e). Altered mental status (agitation, confusion, mutism, coma, seizures), neuromuscular hyperactivity (hyperreflexia, myoclonus, rigidity, tremors), and autonomic dysfunction (abdominal pain, diarrhea, diaphoresis, fever, flushing, labile hypertension, mydriasis, tearing, salivation, tachycardia). Complications include hyperthermia, lactic acidosis, rhabdomyolysis, and multisystem organ failure. QRS and JT prolongation (or both) with hypotension, ventricular tachyarrhythmias, CNS depression, seizures; anticholinergic effects with amantadine, antihistamines, carbamazepine, disopyramide, antipsychotics, and cyclic antidepressants (see above); opioid effects with meperidine and propoxyphene (see Chap. 468e); cinchonism (hearing loss, tinnitus, nausea, vomiting, vertigo, ataxia, headache, flushing, diaphoresis) and blindness with quinoline antimalarials Discontinue the offending agent(s); the serotonin receptor antagonist cyproheptadine may be helpful in severe cases.468e); extra-corporeal removal for some agents (see text).
Intramuscular injections of vitamin D would be an alternative form of therapy, but there are currently no FDA-approved intramuscular preparations available in the United States.Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease.However, calcifediol is only approved in the United States for use in chronic kidney disease and secondary hyperparathyroidism.The important common feature in this group of diseases appears to be malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, although its importance in patients other than those with terminal liver failure remains in dispute. The major explanation for the low 25(OH)D levels in patients with liver disease is the reduction in D-binding protein production, the major carrier of vitamin D metabolites in the blood. Free 25(OH)D is generally normal in patients with liver disease. The malabsorption of vitamin D is probably not limited to exogenous vitamin D as the liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are normally reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites in addition to limiting absorption of dietary vitamin D. In mild forms of malabsorption, high doses of vitamin D (25,000–50,000 IU one to three times per week) should suffice to raise serum levels of 25(OH)D into the normal range. Many patients with severe disease do not respond to vitamin D. Clinical experience with the other metabolites is limited, but both calcitriol and calcifediol have been used successfully in doses similar to those recommended for treatment of renal osteodystrophy. Theoretically, calcifediol should be the drug of choice under these conditions, because no impairment of the renal metabolism of 25(OH)D to 1,25(OH)2D and 24,25(OH)2D exists in these patients. However, calcifediol is only approved in the United States for use in chronic kidney disease and secondary hyperparathyroidism. Both calcitriol and 24,25(OH)2D may be of importance in reversing the bone disease. Intramuscular injections of vitamin D would be an alternative form of therapy, but there are currently no FDA-approved intramuscular preparations available in the United States.As in the other diseases discussed, treatment of intestinal osteodystrophy with vitamin D and its metabolites should be accompanied by appropriate dietary calcium supplementation and monitoring of serum calcium and phosphate levels.Osteoporosis is defined as abnormal loss of bone predisposing to fractures.It is most common in postmenopausal women but also occurs in men.
When this regulator binds to this sequence, it blocks access of RNA polymerase to the promoter, thereby preventing transcription of the operon (and thus production of the tryptophan-producing enzymes).Within the operon’s promoter is a cis-regulatory sequence that is recognized by a transcription regulator.When tryptophan concentrations are low, the operon is transcribed; the resulting mRNA is translated to produce a full set of biosynthetic enzymes, which work in tandem to synthesize tryptophan from much simpler molecules. When tryptophan is abundant, however—for example, when the bacterium is in the gut of a mammal that has just eaten a protein-rich meal—the amino acid is imported into the cell and shuts down production of the enzymes, which are no longer needed. E. coli chromosome series of enzymes required for tryptophan biosynthesis Figure 7–12 A cluster of bacterial genes can be transcribed from a single promoter. each of these five genes encodes a different enzyme, and all of these enzymes are needed to synthesize the amino acid tryptophan from simpler molecules. the genes are transcribed as a single mrnA molecule, a feature that allows their expression to be coordinated. Clusters of genes transcribed as a single mrnA molecule are common in bacteria. each of these clusters is called an operon because its expression is controlled by a cis-regulatory sequence called the operator (green), situated within the promoter. (in this and subsequent figures, the yellow blocks in the promoter represent DnA sequences that bind rnA polymerase; see figure 6–12). start of transcription We now understand exactly how this repression of the tryptophan operon comes about. Within the operon’s promoter is a cis-regulatory sequence that is recognized by a transcription regulator. When this regulator binds to this sequence, it blocks access of RNA polymerase to the promoter, thereby preventing transcription of the operon (and thus production of the tryptophan-producing enzymes).These components are controlled in a simple way: the repressor can bind to DNA only if it has also bound several molecules of tryptophan (Figure 7–13).The tryptophan repressor is an allosteric protein, and the binding of tryptophan causes a subtle change in its three-dimensional structure so that the protein can bind to the operator sequence.
lincosamides Clindamycin is the only lincosamide in clinical use.These agents block translocation of the growing peptide chain by binding to the tunnel from which the chain exits the ribosome.tetracyclines and glycylcyclines Tetracyclines (doxycycline, minocycline, tetracycline) bind reversibly to the 16S rRNA of the 30S ribosomal subunit and block the binding of aminoacyl tRNA to the ribosomal A site, thereby inhibiting peptide elongation. Active transport of tetracyclines into bacterial but not mammalian cells contributes to the selectivity of these agents. Tigecycline, a derivative of minocycline and Antibacterial Agent(s) Major Target Mechanism(s) of Action Mechanism(s) of Resistance cytoplasmic membranes Daptomycin Cell membrane Produces membrane channel and membrane leakage Abbreviations: LPS, lipopolysaccharide; NAG, N-acetylglucosamine; PBP, penicillin-binding protein. 1. 2. 3. 1. 2. 1. 2. 1. 2. 3. Decreased permeation to target due to active efflux 1. 2. 1. 2. 1. Same as macrolides 2. 1. 2. Methylation of ribosome binding site 1. 2. 1. 2. 3. Protection of target from drug 4. 1. 2. 3. Altered cell membrane charge with reduced drug binding Altered cell membrane with reduced drug binding Treatment and Prophylaxis of Bacterial Infections the only available glycylcycline, acts similarly to the tetracyclines but is distinctive for its ability to circumvent the most common mechanisms of resistance to the tetracyclines. macrolides and Ketolides In contrast to the aminoglycosides and tetracyclines, the macrolides (azithromycin, clarithromycin, erythromycin) and ketolides (telithromycin) bind to the 23S rRNA of the 50S ribosomal subunit. These agents block translocation of the growing peptide chain by binding to the tunnel from which the chain exits the ribosome. lincosamides Clindamycin is the only lincosamide in clinical use.streptogramins The only streptogramin in clinical use is a combination of quinupristin, a group B streptogramin, and dalfopristin, a group A streptogramin.
The long C-terminal tail domain of talin, for example, includes a large number of binding sites for the actin-regulatory protein vinculin.The same is true for cell– matrix junctions.We saw earlier that mechanotransduction at cadherin-based cell–cell junctions likely depends on junctional proteins that change their structure when the junction is stretched by tension (see Figure 19–12).In addition to phosphorylating other proteins at the adhesion sites, these kinases then phosphorylate FAK on additional tyrosines, creating docking sites for a variety of additional intracellular signaling proteins. In this way, outside-in signaling from integrins, via FAK and Src family kinases, is relayed into the cell in much the same way as receptor tyrosine kinases generate signals (as discussed in Chapter 15). Cell–Matrix adhesions respond to Mechanical Forces Like the cell–cell junctions we described earlier, cell–matrix junctions can sense and respond to the mechanical forces that act on them. Most cell–matrix junctions, for example, are connected to a contractile actin network that tends to pull the junctions inward, away from the matrix. When cells are attached to a rigid matrix that strongly resists such pulling forces, the cell–matrix junction is able to sense the resulting high tension and trigger a response in which it recruits additional integrins and other proteins to increase the junction’s ability to withstand that tension. Cell attachment to a relatively soft matrix generates less tension and therefore a less robust response. These mechanisms allow cells to sense and respond to differences in the rigidity of extracellular matrices in different tissues. We saw earlier that mechanotransduction at cadherin-based cell–cell junctions likely depends on junctional proteins that change their structure when the junction is stretched by tension (see Figure 19–12). The same is true for cell– matrix junctions. The long C-terminal tail domain of talin, for example, includes a large number of binding sites for the actin-regulatory protein vinculin.The N-terminal end of talin binds integrin and the C-terminal end binds actin (see Figure 19–55); thus, when actin filaments are pulled by myosin motors inside the cell, the resulting tension stretches the talin rod, thereby exposing vinculin-binding sites.The vinculin molecules then recruit and organize additional actin filaments.Tension thereby increases the strength of the junction.
Budesonide is available as an oral preparation.Agents such as budesonide, beclomethasone dipropionate, and tixocortol pivalate undergo rapid hepatic degradation that significantly decreases systemic toxicity.These compounds decrease inflammation by inhibition of cyclooxygenase and 5-lipoxygenase in the gut mucosa. They require direct contact with affected mucosa for efficacy. Mul-tiple preparations are available for administration to different sites in the small intestine and colon (sulfasalazine, mesalamine [Pentasa, Asacol, Rowasa]).Antibiotics Antibiotics are often used to decrease the intra-luminal bacterial load in Crohn’s disease. Metronidazole has been reported to improve Crohn’s colitis and perianal disease, but the evidence is weak. Fluoroquinolones may also be effec-tive in some cases. In the absence of fulminant colitis or toxic megacolon, antibiotics are not used to treat ulcerative colitis.Corticosteroids Corticosteroids (either oral or parenteral) are a key component of treatment for an acute exacerbation of either ulcerative colitis or Crohn’s disease. Corticosteroids are nonspecific inhibitors of the immune system, and 75% to 90% of patients will improve with the administration of these drugs. However, corticosteroids have a number of serious side effects, and use of these agents should be limited to the short-est course possible. In addition, corticosteroids should be used judiciously in children because of the potential adverse effect on growth. Failure to wean corticosteroids is a relative indication for surgery.Because of the systemic effects of corticosteroids, an effort has been made to develop drugs that act locally and have limited systemic absorption. Agents such as budesonide, beclomethasone dipropionate, and tixocortol pivalate undergo rapid hepatic degradation that significantly decreases systemic toxicity. Budesonide is available as an oral preparation.These agents are useful for treating ulcerative colitis and Crohn’s disease in patients who have failed salicylate therapy or who are dependent on, or refractory to, corticosteroids.
Graphical representation of the relationship between oxygen utilization (VO2) and oxygen delivery (DO2).For example, cardiac output, hemoglobin concentration of blood, or the oxygen content of arterial blood each can be inadequate 1Introduction 433Arterial Blood Pressure 434Noninvasive Measurement of Arterial Blood Pressure / 434Invasive Monitoring of Arterial Blood Pressure / 435Electrocardiographic Monitoring 435Algorithmic Integrative Monitoring 436Cardiac Output and Related Parameters 436Determinants of Cardiac Performance / 436Placement of the Pulmonary Artery Catheter 437Hemodynamic Measurements 438Measurement of Cardiac Output by Thermodilution / 439Mixed Venous Oximetry / 439Effect of Pulmonary Artery Catheterization on Outcome 440Minimally Invasive Alternatives to the Pulmonary Artery Catheter 442Transpulmonary Thermodilution / 442Doppler Ultrasonography / 443Impedance Cardiography / 443Pulse Contour Analysis / 443Partial Carbon Dioxide Rebreathing / 444Transesophageal Echocardiography / 444Assessing Preload Responsiveness / 444Near-Infrared Spectroscopic Measurement of Tissue Hemoglobin Oxygen Saturation / 444Respiratory Monitoring 445Arterial Blood Gases / 445Determinants of Oxygen Delivery / 445Peak and Plateau Airway Pressure / 446Pulse Oximetry / 446Pulse CO-Oximetry / 446Capnometry /447Renal Monitoring 447Urine Output / 447Bladder Pressure / 447Neurologic Monitoring 447Intracranial Pressure / 447Electroencephalogram and Evoked Potentials / 448Transcranial Doppler Ultrasonography / 448Jugular Venous Oximetry / 448Transcranial Near-Infrared Spectroscopy / 449Brain Tissue Oxygen Tension / 449Conclusions 449Brunicardi_Ch13_p0433-p0452.indd 43322/02/19 2:20 PM 434Figure 13-1. Graphical representation of the relationship between oxygen utilization (VO2) and oxygen delivery (DO2).Technological advances in monitoring have at least a theoretical risk of exceeding our ability to under-stand the clinical implications of the derived information.This could result in the use of monitoring data to make inap-propriate clinical decisions.
The lamina propria contains many types of immune cells, including IgA-producing plasma cells, conventional CD4 and CD8 T cells with effector and memory phenotypes, innate lymphoid cells, dendritic cells, macrophages, and mast cells.The lymphoid component of the epithelium consists mainly of lymphocytes, which in the small intestine are virtually all CD8 T cells.Together, the dendritic cells and primed T cells then activate B cells and initiate class switching to IgA. All these processes— the uptake of antigen by M cells, the migration of dendritic cells into the epithelial layer, the production of chemokines, and the subsequent migration of dendritic cells into T-cell areas—are markedly increased in the presence of pathogenic organisms and their products due to the ligation of pattern recognition receptors on epithelial cells and immune cells (see Section 3-5). Similar processes also underlie the induction of immune responses in isolated lymphoid follicles of the gut and in the MALT of other mucosal surfaces. 12-4 The mucosal immune system contains large numbers of effector lymphocytes even in the absence of disease. In addition to the organized lymphoid organs, mucosal surfaces such as the gut and lung contain enormous numbers of lymphocytes and other leukocytes scattered throughout the tissue. Most of the scattered lymphocytes have the appearance of cells that have been activated by antigen, and they comprise the effector T cells and plasma cells of the mucosal immune system. In the intestine, effector cells are found in two main compartments: the epithelium and the lamina propria (see Fig. 12.5). These tissues are quite distinct in immunological terms, despite being separated by only a thin layer of basement membrane. The lymphoid component of the epithelium consists mainly of lymphocytes, which in the small intestine are virtually all CD8 T cells. The lamina propria contains many types of immune cells, including IgA-producing plasma cells, conventional CD4 and CD8 T cells with effector and memory phenotypes, innate lymphoid cells, dendritic cells, macrophages, and mast cells.12.8), which attracts them into the tissue from the bloodstream.Intraepithelial lymphocytes (IELs) are mostly CD8 T cells and express either the conventional Fig.12.8 Priming of naive T cells and the redistribution of effector T cells in the intestinal immune system.
In contrast to our understanding of the pathogenesis of HF with a depressed EF, our understanding of the mechanisms that contribute to the development of HF with a preserved EF is still evolving.However, with time, the sustained activation of these systems can lead to secondary end-organ damage within the ventricle, with worsening left ventricular remodeling and subsequent cardiac decompensation. (From D Mann: Circulation 100:999, 1999.) to sustain and modulate LV function for a period of months to years. The compensatory mechanisms that have been described thus far include (1) activation of the renin-angiotensin-aldosterone (RAA) and adrenergic nervous systems, which are responsible, respectively, for maintaining cardiac output through increased retention of salt and water (Fig. 279-2), and (2) increased myocardial contractility. In addition, there is activation of a family of countervailing vasodilatory molecules, including the atrial and brain natriuretic peptides (ANP and BNP), prostaglandins (PGE2 and PGI2), and nitric oxide (NO), that offsets the excessive peripheral vascular vasoconstriction. Genetic background, sex, age, or environment may influence these compensatory mechanisms, which are able to modulate LV function within a physiologic/homeostatic range so that the functional capacity of the patient is preserved or is depressed only minimally. Thus, patients may remain asymptomatic or minimally symptomatic for a period of years; however, at some point patients become overtly symptomatic, with a resultant striking increase in morbidity and mortality rates. Although the exact mechanisms that are responsible for this transition are not known, as will be discussed below, the transition to symptomatic HF is accompanied by increasing activation of neurohormonal, adrenergic, and cytokine systems that lead to a series of adaptive changes within the myocardium collectively referred to as LV remodeling. In contrast to our understanding of the pathogenesis of HF with a depressed EF, our understanding of the mechanisms that contribute to the development of HF with a preserved EF is still evolving.BASIC MECHANISMS OF HEART FAILURE Heart Failure with a Reduced Ejection Fraction LV remodeling develops in response to a series of complex events that occur at the cellular and molecular levels (Table 279-3).
Paired nerves exit the spinal cord at each level.Sensory information (afferent pathways) enters via dorsal nerve roots, travels cranially via the dorsal columns (proprio-ception and fine touch) or spinothalamic tract (pain and tem-perature), and into the brain stem.The corticospinal tract is the major motor tract, while the medial lemniscus and spinothalamic tracts are the major sensory tracts. The nuclei of cranial nerves III through XII are also located within the brain stem. These nerves relay the motor, sensory, and special sense functions of the eye, face, mouth, and throat.The cerebellum arises from the dorsal aspect of the brain stem. It integrates somatosensory, vestibular, and motor infor-mation for coordination and timing of movement. Midline, or vermian, lesions lead to truncal ataxia. Lateral, or hemispheric, lesions lead to tremor and dyscoordination in the extremities.The ventricular system is the cerebrospinal fluid (CSF)–containing contiguous space inside the brain, continuous with the subarachnoid space outside the brain. The paired lateral ventricles consist of temporal, occipital, and frontal horns, as well as the main body. CSF travels from each lateral ventricle through the foramina of Monroe to the third ventricle, located between the left and right thalami. CSF then drains through the cerebral aqueduct to the fourth ventricle within the brain stem. The foramen of Magendie (midline) and paired foram-ina of Luschka (lateral) drain to the subarachnoid space. The approximate CSF volume in an average adult is 150 mL, and the choroid plexus produces approximately 500 mL of CSF per day.The spinal cord starts at the bottom of the medulla and extends caudally through the spinal canal to the first lumbar ver-tebra, approximately. Motor tracts (efferent pathways) continue from the brain stem down via the lateral and anterior corticospi-nal tracts to anterior horn cells, and then exit via ventral nerve roots. Sensory information (afferent pathways) enters via dorsal nerve roots, travels cranially via the dorsal columns (proprio-ception and fine touch) or spinothalamic tract (pain and tem-perature), and into the brain stem. Paired nerves exit the spinal cord at each level.The C5–T1 spinal nerves intersect in the brachial plexus and divide to form the main nerve branches to the arm, including the median, ulnar, and radial nerves.The L2–S4 spinal nerves intersect in the lumbosacral plexus, and divide to form the main nerve branches to the leg, including the femoral and sciatic nerves.The principal motor tract of the spinal cord is the cortico-spinal tract.
inactive, soluble Sar1-GDP (A) amphiphilic helix active, membrane-bound Sar1-GTP donor membrane (ER) Sar1-GEF GTPGTPGDPGDPCYTOSOL ER LUMEN not all Transport vesicles are spherical Although vesicle-budding is similar at various locations in the cell, each cell membrane poses its own special challenges.It then inactivates ARF, causing the coat to disassemble.The hydrolysis of bound GTP to GDP causes the GTPase to change its conformation so that its hydrophobic tail pops out of the membrane, causing the vesicle’s coat to disassemble. Although it is not known what triggers the GTP hydrolysis, it has been proposed that the GTPases work like timers, which hydrolyze GTP at slow but predictable rates, to ensure that vesicle formation is synchronized with the requirements of the moment. COPII coats accelerate GTP hydrolysis by Sar1, and a fully formed vesicle will be produced only when bud formation occurs faster than the timed disassembly process; otherwise, disassembly will be triggered before a vesicle pinches off, and the process will have to start again, perhaps at a more appropriate time and place. Once a vesicle pinches off, GTP hydrolysis releases Sar1, but the sealed coat is sufficiently stabilized through many cooperative interactions, including binding to the cargo receptors in the membrane, that it may stay on the vesicle until the vesicle docks at a target membrane. There, a kinase phosphorylates the coat proteins, which completes coat disassembly and readies the vesicle for fusion. Clathrinand COPI-coated vesicles, by contrast, shed their coat soon after they pinch off. For COPI vesicles, the curvature of the vesicle membrane serves as a trigger to begin uncoating. An ARF-GAP is recruited to the COPI coat as it assembles. It interacts with the membrane, and senses the lipid packing density. It becomes activated when the curvature of the membrane approaches that of a transport vesicle. It then inactivates ARF, causing the coat to disassemble. inactive, soluble Sar1-GDP (A) amphiphilic helix active, membrane-bound Sar1-GTP donor membrane (ER) Sar1-GEF GTPGTPGDPGDPCYTOSOL ER LUMEN not all Transport vesicles are spherical Although vesicle-budding is similar at various locations in the cell, each cell membrane poses its own special challenges.Thus, the coordinated action of clathrin coats and membrane-bending proteins has to produce sufficient force to introduce curvature, especially at the neck of the bud where sharp bends are required for the pinching-off processes.
168).156), particularly those involving surgical wounds (Chap.Enterococci are commonly isolated from soft tissue infections (Chap.Conversely, specific treatment for enterococci in the first episode of intraabdominal infections originating in the community and affecting previously healthy patients with no important cardiac risk factors for endocarditis does not appear to be beneficial.The presence of enterococci in intraabdominal infections is sometimes considered to be of little clinical relevance. Several studies have shown that the role of enterococci in intraabdominal infections originating in the community and involving previously healthy patients is minor, because surgery and broad-spectrum antimicrobial drugs that do not target enterococci are often sufficient to treat these infections successfully. In the last few decades, however, these organisms have become prominent as a cause of intraabdominal infections in hospitalized patients because of the emergence and spread of vancomycin resistance among enterococci and the increase in rates of nosocomial infections due to multidrug-resistant E. faecium isolates. In fact, several studies have now documented treatment failures due to enterococci, with consequently increased rates of postoperative complications and death among patients with intraabdominal infections. Thus, anti-enterococcal therapy is recommended for nosocomial peritonitis in immunocompromised and severely ill patients who have had a prolonged hospital stay, have undergone multiple procedures, have persistent abdominal sepsis and collections, or have risk factors for the development of endocarditis (e.g., prosthetic or damaged heart valves). Conversely, specific treatment for enterococci in the first episode of intraabdominal infections originating in the community and affecting previously healthy patients with no important cardiac risk factors for endocarditis does not appear to be beneficial. Enterococci are commonly isolated from soft tissue infections (Chap. 156), particularly those involving surgical wounds (Chap. 168).The clinical relevance of enterococci in some of these infections—as in intraabdominal infections—is a matter of debate; differentiating between colonization and true infection is sometimes challenging, although in some cases enterococci have been recovered from lung, liver, and skin abscesses.
Patients who do achieve an early virologic response should be retested at week 24, and treatment should be discontinued if HCV RNA remains detectable.rules for futility: HCV RNA ≥100 IU/mL at week 12 or any detectable HCV RNA at week 24 Telaprevir 750 mg three times daily with fatty food started at the beginning of therapy without a PEG IFN–ribavirin lead-in and without a response-guided approach, i.e., all patients receive a full 48-week course, independent of early responsiveness. prior relapsers, follow guidelines for treatment-naïve patients above. partial responders and null responders should receive triple-drug therapy (PEG IFN, ribavirin, telaprevir) for 12 weeks then PEG IFN and ribavirin for another 36 weeks, for a total of 48 weeks. • Stopping rules for futility: HCV RNA >1000 IU/mL at week 4 or 12 or any detectable HCV RNA at week 24 HCV genotype 1 but protease inhibitors unavailable or contraindicated: 48 weeks of therapy PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (<75 kg) to 1200 mg/d (≥75 kg) or PEG IFN-α2b 1.5 μg/kg weekly plus weight-based ribavirin 800 mg/d (≤65 kg), 1000 mg/d (>65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) HCV genotype 4: 48 weeks of PEG IFN–ribavirin therapy PEG IFN-α2a 180 μg weekly plus weight-based ribavirin 1000 mg/d (<75 kg) to 1200 mg/d (≥75 kg) or PEG IFN-α2b 1.5 μg/kg weekly plus weight-based ribavirin 800 mg/d (≤65 kg), 1000 mg/d (>65–85 kg), 1200 mg/d (>85–105 kg), or 1400 mg/d (>105 kg) Treatment should be discontinued in patients who do not achieve an early virologic response at week 12. Patients who do achieve an early virologic response should be retested at week 24, and treatment should be discontinued if HCV RNA remains detectable.Protease inhibitors may be used for genotype 1; however, because of potential drug-drug interactions between HCV protease inhibitors and HIV antiretroviral drugs, HCV protease inhibitors should be used cautiously in HCV/HIV co-infected patients.If protease inhibitors are used, a full 48-week course is recommended without response-guided therapy.
tyrosinase Enzyme in melanin synthesis pathway and frequently a tumor rejection antigen in melanoma.type III secretion system (T3SS) Specialized appendage of Gram-negative bacteria used to aid infection of eukaryotic cells by direct secretion of effector proteins into their cytoplasm.type II interferon The antiviral interferon IFN-γ.type I interferons The antiviral interferons IFN-α and IFN-β.tropism The characteristic of a pathogen that describes the cell types it will infect. TSC Protein complex that acts as a GTPase-activating protein (GAP) for Rheb in its non-phosphorylated state. TSC is inactivated when phosphorylated by Akt. TSLP Thymic stroma-derived lymphopoietin. A cytokine thought to be involved in promoting B-cell development in the embryonic liver. tumor necrosis factor-α See TNF family. tumor rejection antigens Antigens on the surface of tumor cells that can be recognized by T cells, leading to attack on the tumor cells. TRAs are peptides of mutant or overexpressed cellular proteins bound to MHC class I molecules on the tumor-cell surface. type 1 diabetes mellitus Disease in which the β cells of the pancreatic islets of Langerhans are destroyed so that no insulin is produced. The disease is believed to result from an autoimmune attack on the β cells. It is also known as insulin-dependent diabetes mellitus (IDDM), because the symptoms can be ameliorated by injections of insulin. type 1 immunity Class of effector activities aimed at elimination of intracellular pathogens. type 2 immunity Class of effector activities aimed at elimination of parasites and promoting barrier and mucosal immunity. type 3 immunity Class of effector activities aimed at elimination of extracellular pathogens such as bacteria and fungi. type I interferons The antiviral interferons IFN-α and IFN-β. type II interferon The antiviral interferon IFN-γ. type III secretion system (T3SS) Specialized appendage of Gram-negative bacteria used to aid infection of eukaryotic cells by direct secretion of effector proteins into their cytoplasm. tyrosinase Enzyme in melanin synthesis pathway and frequently a tumor rejection antigen in melanoma.See also CD45.tyrosine protein kinases Enzymes that specifically phosphorylate tyrosine residues in proteins.They are critical in the signaling pathways that lead to Tand B-cell activation.UBC13 See TRIKA1.ubiquitin A small protein that can be attached to other proteins and functions as a protein interaction module or to target them for degradation by the proteasome.
167e and 183e).249) and Capnocytophaga canimorsus, a bacterium carried in the mouths of animals (Chaps.The splenectomized patient should be counseled about the risks of infection with certain organisms, such as the protozoan Babesia (Chap.The loss of the spleen through trauma similarly predisposes the normal host to overwhelming infection throughout life.A physical predisposition to infection in patients with cancer (Table 104-1) can be a result of the neoplasm’s production of a break in the skin. For example, a squamous cell carcinoma may cause local invasion infection, and obstruction of the bile duct can cause cholangitis. Part of the host’s normal defense against infection depends on the continuous emptying of a viscus; without emptying, a few bacteria that are present as a result of bacteremia or local transit can multiply and cause disease. A similar problem can affect patients whose lymph node integrity has been disrupted by radical surgery, particularly patients who have had radical node dissections. A common clinical problem following radical mastectomy is the development of cellulitis (usually caused by streptococci or staphylococci) because of lymphedema and/or inadequate lymph drainage. In most cases, this problem can be addressed by local measures designed to prevent fluid accumulation and breaks in the skin, but antibiotic prophylaxis has been necessary in refractory cases. A life-threatening problem common to many cancer patients is the loss of the reticuloendothelial capacity to clear microorganisms after splenectomy, which may be performed as part of the management of hairy cell leukemia, chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML) and in Hodgkin’s disease. Even after curative therapy for the underlying disease, the lack of a spleen predisposes such patients to rapidly fatal infections. The loss of the spleen through trauma similarly predisposes the normal host to overwhelming infection throughout life. The splenectomized patient should be counseled about the risks of infection with certain organisms, such as the protozoan Babesia (Chap. 249) and Capnocytophaga canimorsus, a bacterium carried in the mouths of animals (Chaps. 167e and 183e).148) against the capsular polysaccharides of these organisms.
Once the patient * Names for the adrenal steroid synthetic enzymes include the following: P450c11 (11β-hydroxylase), P450c17 (17α-hydroxylase), P450c21 (21α-hydroxylase).The most common defect is a decrease in or lack of P450c21 (21α-hydroxylase) activity. * As can be seen in Figure 39–1, this would lead to a reduction in cortisol synthesis and thus produce a compensatory increase in ACTH release. The adrenal becomes hyper-plastic and produces abnormally large amounts of precursors such as 17-hydroxyprogesterone that can be diverted to the androgen pathway, which leads to virilization and can result in ambiguous genitalia in the female fetus. Metabolism of this compound in the liver leads to pregnanetriol, which is characteristically excreted into the urine in large amounts in this disorder and can be used to make the diagnosis and to monitor efficacy of glucocorticoid substitution. However, the most reliable method of detecting this disorder is the increased response of plasma 17-hydroxyprogesterone to ACTH stimulation. If the defect is in 11-hydroxylation, large amounts of deoxycorticosterone are produced, and because this steroid has mineralocorticoid activity, hypertension with or without hypokalemic alkalosis ensues. When 17-hydroxylation is defective in the adrenals and gonads, hypogonadism is also present. However, increased amounts of 11-deoxycorticosterone are formed, and the signs and symptoms associated with mineralocorticoid excess—such as hypertension and hypokalemia— also are observed. When first seen, the infant with congenital adrenal hyperplasia may be in acute adrenal crisis and should be treated as described above, using appropriate electrolyte solutions and an intravenous preparation of hydrocortisone in stress doses. Once the patient * Names for the adrenal steroid synthetic enzymes include the following: P450c11 (11β-hydroxylase), P450c17 (17α-hydroxylase), P450c21 (21α-hydroxylase).The dosage is adjusted to allow normal growth and bone maturation and to prevent androgen excess.Alternate-day therapy with prednisone has also been used to achieve greater ACTH suppression without increasing growth inhibition.Fludrocortisone, 0.05–0.2 mg/d, should also be administered by mouth, with added salt to maintain normal blood pressure, plasma renin activity, and electrolytes.
ANF activity causes natriuresis.One leading hypothesis concerning the mechanism of hyponatremia in these cases is secretion of another oligopeptide, atrial natriuretic factor (ANF) that is found mainly in the walls of the cardiac atria but also in neurons surrounding the third ventricle in the anteroventral hypothalamic region.Our usual procedure in patients with serum sodium concentrations of 117 to 125 mEq/L is to slowly correct the sodium concentration by restricting water to 400 to 800 mL/d and to verify the desired urinary loss of water by checking the patient’s weight and serum sodium until it reaches approximately 130 mEq/L. If there is drowsiness, confusion, or seizures that cannot be confidently attributed to the underlying neurologic illness, or if the serum sodium is in the range of 100 to 115 mEq/L, isotonic or 3 percent NaCl should be infused over 3 to 4 h and furosemide 20 to 40 mg administered to prevent fluid overload. In order to avoid osmotic demyelination, a safe clinical rule is to raise the serum sodium by no more than 12 mEq/L in the first 24 h and by no more than 20 mEq/L in 48 h. A moderate reduction in the serum sodium concentration is a common finding in patients with acute intracranial diseases and postoperatively in neurosurgical patients. Originally it was described as a “cerebral salt-wasting” syndrome by Peters and colleagues. Later it was erroneously identified as SIADH, until the pathophysiological understanding of this disorder subsequently returned to the concept of natriuresis rather than water retention caused by ADH secretion. As Nelson and colleagues demonstrated many years ago, neurosurgical patients with hyponatremia have a reduction in blood volume, suggesting sodium loss rather than water retention. This distinction has important clinical implications because fluid restriction, which is used to treat SIADH, can have disastrous results when a patient has volume depletion associated with salt wasting. One leading hypothesis concerning the mechanism of hyponatremia in these cases is secretion of another oligopeptide, atrial natriuretic factor (ANF) that is found mainly in the walls of the cardiac atria but also in neurons surrounding the third ventricle in the anteroventral hypothalamic region. ANF activity causes natriuresis.Like some other neural peptides, ANF is secreted in bursts, and the natriuresis it produces may be evident only if total urinary sodium content is measured over many hours or days.
Surgical procedures such as removal of the first rib and resection of the scalenus anticus muscle are necessary occasionally for relief of symptoms or treatment of ischemia.Many patients benefit from shoulder girdle exercises.They should be advised to avoid the positions that cause symptoms.Most patients can be managed conservatively.FIGURE 302-2 Atheroembolism causing cyanotic discoloration and impending necrosis of the toes (“blue toe” syndrome). Examination of a patient with arterial thoracic outlet compression syndrome is often normal unless provocative maneuvers are performed. Occasionally, distal pulses are decreased or absent and digital cyanosis and ischemia may be evident. Several maneuvers that support the diagnosis of arterial thoracic outlet compression syndrome may be used to precipitate symptoms, cause a subclavian artery bruit, and diminish arm pulses. These maneuvers include the abduction and external rotation test, in which the affected arm is abducted by 90° and the shoulder is externally rotated; the scalene maneuver (extension of the neck and rotation of the head to the side of the symptoms); the costoclavicular maneuver (posterior rotation of shoulders); and the hyperabduction maneuver (raising the arm 180°). A chest x-ray will indicate the presence of cervical ribs. Duplex ultrasonography, MRA, and contrast angiography can be performed during provocative maneuvers to demonstrate thoracic outlet compression of the subclavian artery. Neurophysiologic tests such as the electromyogram, nerve conduction studies, and somatosensory evoked potentials may be abnormal if the brachial plexus is involved, but the diagnosis of neurogenic thoracic outlet syndrome is not necessarily excluded if these tests are normal owing to their low sensitivity. Most patients can be managed conservatively. They should be advised to avoid the positions that cause symptoms. Many patients benefit from shoulder girdle exercises. Surgical procedures such as removal of the first rib and resection of the scalenus anticus muscle are necessary occasionally for relief of symptoms or treatment of ischemia.Thrombosis, 1647 embolism, or popliteal artery aneurysm may occur.The pulse examination may be normal unless provocative maneuvers such as ankle dorsiflexion and plantar flexion are performed.The diagnosis is confirmed by duplex ultrasound, CTA, MRA, or conventional angiography.Treatment involves surgical release of the popliteal artery or vascular reconstruction.
Because the hair cells rest on the phalangeal cells, it can be concluded that the upper three nuclei belong to outer hair cells, whereas the lower three nuclei belong to outer phalangeal cells.The hair and outer phalangeal cells can be distinguished in this figure by their location (see inset) and because their nuclei are well aligned.Both the scala vestibuli and the scala tympani are perilymphatic spaces; these communicate at the apex of the cochlea. The cochlear duct, on the other hand, is the space of the membranous labyrinth and is filled with endolymph. It is thought that the endolymph is formed by the portion of the spiral ligament that faces the cochlear duct, the stria vascularis (StV ). This is highly vascularized and contains specialized “secretory” cells. A shelf of bone, the osseous spiral lamina (OSL), extends from the modiolus to the basilar membrane. Branches of the cochlear nerve (CN) travel along the spiral lamina to the modiolus, where the main trunk of the nerve is formed. The components of the cochlear nerve are bipolar neurons whose cell bodies constitute the spiral ganglion (SG). These cell bodies are shown at higher magnification in the inset (upper right). The spiral lamina supports an elevation of cells, the limbus spiralis (LS). The surface of the limbus is composed of columnar cells. Organ of Corti, ear, guinea pig, H&E 180; inset 380. The components of the organ of Corti, beginning at the limbus spiralis (LS), are as follows: inner border cells (IBC ); inner phalangeal and hair cells (IP&HC); inner pillar cells (IPC ); (the sequence continues, repeating itself in reverse) outer pillar cells (OPC ); hair cells (HC ) and outer phalangeal cells (OP); and outer border cells or cells of Hensen (CH ). Hair cells are receptor cells; the other cells are collectively referred to as supporting cells. The hair and outer phalangeal cells can be distinguished in this figure by their location (see inset) and because their nuclei are well aligned. Because the hair cells rest on the phalangeal cells, it can be concluded that the upper three nuclei belong to outer hair cells, whereas the lower three nuclei belong to outer phalangeal cells.The free surface of the receptor cells fits into openings in the reticular membrane, and the “hairs” of these cells project toward, and make contact with, the tectorial membrane (TM ).The latter is a cuticular extension from the columnar cells of the limbus spiralis.In ideal preparations, nerve fibers can be traced from the hair cells to the cochlear nerve (CN).
Presentation and Evaluation Perianal pain and fever are the hallmarks of an abscess.353-7).Anorectal abscesses are perianal in 40–50% of patients, ischiorectal in 20–25%, intersphincteric in 2–5%, and supralevator in 2.5% (Fig.When stool accidentally enters the anal glands, the glands become infected and an abscess develops.Late complications include fecal incontinence as a result of injury to the sphincter during the dissection. Anal stenosis may develop from overzealous excision, with loss of mucosal skin bridges for reepithelialization. Finally, an ectropion (prolapse of rectal mucosa from the anal canal) may develop. Patients with an ectropion complain of a “wet” anus as a result of inability to prevent soiling once the rectal mucosa is exposed below the dentate line. FIGURE 353-7 Common locations of anorectal abscess (left) and fistula in ano (right). ANORECTAL ABSCESS Incidence and Epidemiology The development of a perianal abscess is more common in men than women by a ratio of 3:1. The peak incidence is in the third to fifth decade of life. Perianal pain associated with the presence of an abscess accounts for 15% of office visits to a colorectal surgeon. The disease is more prevalent in immunocompromised patients such as those with diabetes, hematologic disorders, or inflammatory bowel disease and persons who are HIV positive. These disorders should be considered in patients with recurrent perianal infections. Anatomy and Pathophysiology An anorectal abscess is an abnormal fluid-containing cavity in the anorectal region. Anorectal abscess results from an infection involving the glands surrounding the anal canal. Normally, these glands release mucus into the anal canal, which aids in defecation. When stool accidentally enters the anal glands, the glands become infected and an abscess develops. Anorectal abscesses are perianal in 40–50% of patients, ischiorectal in 20–25%, intersphincteric in 2–5%, and supralevator in 2.5% (Fig. 353-7). Presentation and Evaluation Perianal pain and fever are the hallmarks of an abscess.A prostatic abscess may present with similar complaints, including dysuria.Patients with a prostatic abscess will often have a history of recurrent sexually transmitted diseases.On physical examination, a large fluctuant area is usually readily visible.Routine laboratory evaluation shows an elevated white blood cell count.
47e SECTion 5 AlTERATionS in CiRCulAToRy AnD RESPiRAToRy FunCTionS ALGORITHM FOR THE INPUTS IN DYSPNEA PRODUCTION FIGuRE 47e-1 Hypothetical model for integration of sensory inputs in the production of dyspnea.A given disease state may lead to dyspnea by one or more mechanisms, some of which may be operative under some cir-cumstances (e.g., exercise) but not others (e.g., a change in position).CHAPTER 46e Atlas of Oral Manifestations of Disease Figure 46e-26 Fissured tongue. Figure 46e-27 White coated tongue —likely candidiasis. Dr. Jane Atkinson was a co-author of this chapter in the 17th edition. Some of the materials have been carried over into this edition. 47e-1 Dyspnea Richard M. Schwartzstein DYSPNEA The American Thoracic Society defines dyspnea as a “subjective expe-rience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interac-tions among multiple physiological, psychological, social, and environ-mental factors and may induce secondary physiological and behavioral responses.” Dyspnea, a symptom, can be perceived only by the person experiencing it and must be distinguished from the signs of increased work of breathing. MECHANISMS OF DYSPNEA Respiratory sensations are the consequence of interactions between the efferent, or outgoing, motor output from the brain to the ventilatory muscles (feed-forward) and the afferent, or incoming, sensory input from receptors throughout the body (feedback) as well as the integra-tive processing of this information that we infer must be occurring in the brain (Fig. 47e-1). In contrast to painful sensations, which can often be attributed to the stimulation of a single nerve ending, dys-pnea sensations are more commonly viewed as holistic, more akin to hunger or thirst. A given disease state may lead to dyspnea by one or more mechanisms, some of which may be operative under some cir-cumstances (e.g., exercise) but not others (e.g., a change in position). 47e SECTion 5 AlTERATionS in CiRCulAToRy AnD RESPiRAToRy FunCTionS ALGORITHM FOR THE INPUTS IN DYSPNEA PRODUCTION FIGuRE 47e-1 Hypothetical model for integration of sensory inputs in the production of dyspnea.Afferents also project to the areas of the brain responsible for control of ventilation.The motor cortex, responding to input from the control centers, sends neural messages to the ventilatory muscles and a corollary discharge to the sensory cortex (feed-forward with respect to the instructions sent to the muscles).
In these settings, the amyloidogenic proteins seem to be derived either from polypeptide hormones (e.g., medullary carcinoma) or from unique proteins (e.g., islet amyloid polypeptide). Amyloid of Aging. Several well-documented forms of amyloid deposition occur with aging. Senile systemic amyloidosis refers to the systemic deposition of amyloid in elderly patients (usually in their seventies and eighties). Because of the dominant involvement and related dysfunction of the heart, this form was previously called senile cardiac amyloidosis. Those who are symptomatic present with a restrictive cardiomyopathy and arrhythmias (Chapter 11). The amyloid in this form, in contrast to familial forms, is derived from normal TTR. MORPHOLOGYTherearenoconsistentordistinctivepatternsoforganortissuedistributionofamyloiddepositsinanyofthecategoriescited,butafewgeneralizationscanbemade.InAAamyloidosissecondarytochronicinflammatorydisorders,kidneys,liver,spleen,lymphnodes,adrenalglands,thyroidglands,andmanyothertissuesaretypicallyaffected.AlthoughALamyloidosisassociatedwithplasmacellproliferationscannotreliablybedistinguishedfromtheAAformbyitsorgandistribution,itmoreofteninvolvestheheart,gastrointestinaltract,respiratorytract,peripheralnerves,skin,andtongue.Thelocalizationofamyloiddepositsinthehereditarysyndromesisvaried.InfamilialMediterraneanfever,theamyloidosisisoftheAAtypeandaccordinglymaybewidespread,involvingthekidneys,bloodvessels,spleen,respiratorytract,and(rarely)liver. Amyloidmaybeappreciatedmacroscopicallywhenitaccumulatesinlargeamounts.Theorganisfrequentlyenlarged,andthetissueappearsgrayandhasawaxy,firmconsistency.Histologically,theamyloiddepositionisalwaysextracellularandbeginsbetweencells,oftencloselyadjacenttobasementmembranes( Fig.5.43A ).Astheamyloidaccumulates,itencroachesonthecells,intimesurroundinganddestroyingthem.Intheformassociatedwithplasmacellproliferation,perivascularandvasculardepositsarecommon.5.43B ).Thisstainingreactionissharedbyallformsofamyloidandisimpartedbythecrossedβ-pleatedsheetconfigurationofamyloidfibrils.Confirmationcanbeobtainedbyelectronmicroscopy,whichrevealsamorphousnonorientedthinfibrils.Subtypingofamyloidismostreliablydonebymassspectroscopy,asimmunohistochemicalstainsarenotentirelysensitiveorspecific.Thepatternoforganinvolvementindifferentformsofamyloidosisisvariable.
Notable clinical manifestations associated with Hashimoto thyroiditis include fatigue, weight gain, hyperlipidemia, dry hair, dry skin, cold intolerance, depression, menstrual irregularities, bradycardia, and or memory impairment.At later stages of the disease, hypothyroidism can be found without a goiter.Patients often present with a goiter, which can involve the parietal lobe.Three classic types of autoimmune injury are found in Hashimoto thyroiditis: (i) complement-mediated cytotoxicity, (ii) antibody-dependent cell-mediated cytotoxicity, and (iii) stimulation or blockade of hormone receptors, which results in hypo-or hyperfunction or growth (Fig. 31.11). The histologic picture of Hashimoto thyroiditis includes cellular hyperplasia, disruption of follicular cells, and infiltration of the gland by lymphocytes, monocytes, and plasma cells. Occasionally, adjacent lymphadenopathy may be noted. Some epithelial cells are enlarged and demonstrate oxyphilic changes in the cytoplasm (Askanazy cells or H¨urthle cells, which are not specific to this disorder). The interstitial cells show fibrosis and lymphocytic infiltration. Graves disease and Hashimoto thyroiditis may cause very similar histologic findings manifested by a similar mechanism of injury. Clinical Characteristics and Diagnosis of Hashimoto Thyroiditis Patients with Hashimoto thyroiditis may present with typical symptoms of hypothyroidism or may be relatively asymptomatic. Patients often present with a goiter, which can involve the parietal lobe. At later stages of the disease, hypothyroidism can be found without a goiter. Notable clinical manifestations associated with Hashimoto thyroiditis include fatigue, weight gain, hyperlipidemia, dry hair, dry skin, cold intolerance, depression, menstrual irregularities, bradycardia, and or memory impairment.This variant is estimated to occur in 4% to 8% of patients with Hashimoto thyroiditis.In the setting of Hashitoxicosis, the patient requires frequent follow-up and the potential for adjustments in thyroid supplementation.These patients often become hypothyroid during the course of treatment.In many cases, an elevated serum TSH is detected during routine screening.
It is interesting that butorphanol has also been shown to cause significantly greater FIGURE 31–1 Potential receptor mechanisms of analgesic drugs.Butorphanol and nalbuphine have shown some clinical success as analgesics, but they can cause dysphoric reactions and have limited potency.Relation of physiologic effects to receptor type—The majority of currently available opioid analgesics act primarily at the μ-opioid receptor (Table 31–2). Analgesia and the euphoriant, respiratory depressant, and physical dependence properties of morphine result principally from actions at μ receptors. In fact, the μ receptor was originally defined using the relative potencies for clinical analgesia of a series of opioid alkaloids. However, opioid analgesic effects are complex and include interaction with δ and κ receptors. This is supported in part by the study of genetic knockouts of the μ, δ, and κ genes in mice. The development of μ-receptor–selective agonists could be clinically useful if their side-effect profiles (respiratory depression, risk of dependence) were more favorable than those found with current μ-receptor agonists, such as morphine. Although morphine does act at κ and δ receptor sites, it is unclear to what extent this contributes to its analgesic action. The endogenous opioid peptides differ from most of the alkaloids in their affinity for the δ and κ receptors (Table 31–1). In an effort to develop opioid analgesics with a reduced incidence of respiratory depression or propensity for addiction and dependence, compounds that show preference for κ-opioid receptors have been developed. Butorphanol and nalbuphine have shown some clinical success as analgesics, but they can cause dysphoric reactions and have limited potency. It is interesting that butorphanol has also been shown to cause significantly greater FIGURE 31–1 Potential receptor mechanisms of analgesic drugs.Pain stimuli can be attenuated in the periphery (under inflammatory conditions) by opioids acting at μ-opioid receptors (MOR) or blocked in the afferent axon by local anesthetics (not shown).
A patient may be withdrawn from thyroid hormone so that endogenous TSH is secreted and, ideally, the serum TSH level is >25 mIU/L at the time of 131I therapy.To achieve high serum TSH levels, there are two approaches.In addition, well-differentiated thyroid cancer often incorporates radioiodine, although less efficiently than normal thyroid follicular cells. Radioiodine uptake is determined primarily by expression of the NIS and is stimulated by TSH, requiring expression of the TSH R. The retention time for radioactivity is influenced by the extent to which the tumor retains differentiated functions such as iodide trapping and organification. Consequently, for patients at risk of recurrence and for those with known distant metastatic disease, 131I ablation may also potentially treat residual tumor cells. Indications Not all patients benefit from radioiodine therapy. Neither recurrence nor survival rates are improved in stage I patients with T1 tumors (≤2 cm) confined to the thyroid. However, in higher risk patients (larger tumors, more aggressive variants of papillary cancer, tumor vascular invasion, presence of large-volume lymph node metastases), radioiodine reduces recurrence and may increase survival. 131I Thyroid Ablation and Treatment As noted above, the decision to use 131I for thyroid ablation should be coordinated with the surgical approach, because radioablation is much more effective when there is minimal remaining normal thyroid tissue. Radioiodine is administered after iodine depletion (patient follows a low-iodine diet for 1≤2 weeks) and in the presence of elevated serum TSH levels to stimulate uptake of the isotope into both the remnant and potentially any residual tumor. To achieve high serum TSH levels, there are two approaches. A patient may be withdrawn from thyroid hormone so that endogenous TSH is secreted and, ideally, the serum TSH level is >25 mIU/L at the time of 131I therapy.Alternatively, recombinant human TSH (rhTSH) is administered as two daily consecutive injections (0.9 mg) with administration of 131I 24 h after the second injection.The patient can continue to take levothyroxine and remains euthyroid.Both approaches have equal success in achieving remnant ablation.
Successful education involves who are poor perceivers of airway obstruction, have moderate FEV1 or PEF <40% (severe) Oxygen to achieve SaO2 ˜90% High-dose inhaled SABA plus Ipratropium by nebulizer or MDI plus valved holding chamber, every 20 minutes or continuously for 1 hour Oral systemic corticosteroids FEV1 or PEF ˜40% (mild-to-moderate) Oxygen to achieve SaO2 ˜90% Inhaled SABA by nebulizer or MDI with valved holding chamber, up to 3 doses in first hour Oral systemic corticosteroids if no immediate response or if patient recently took oral systemic corticosteroids Initial assessment Brief history, physical examination (auscultation, use of accessory muscles, heart rate, respiratory rate), PEF or FEV1, oxygen saturation, and other tests as indicated Severe exacerbation FEV1 or PEF <40% predicted/personal best Physical exam: severe symptoms at rest, accessory muscle use, chest retraction History: high-risk patient No improvement after initial treatment Oxygen Nebulized SABA plus Ipratropium, hourly or continuous Oral systemic corticosteroids Consider adjunct therapies Moderate exacerbation FEV1 or PEF 40–69% predicted/personal best Physical exam: moderate symptoms Inhaled SABA every 60 minutes Oral systemic corticosteroid Continue treatment 1–3 hours, provided there is improvement; make admit decision in <4 hours Admit to hospital intensive care (see box below) Repeat assessment Symptoms, physical examination, PEF, O2 saturation, other tests as needed Good response FEV1 or PEF ˜70% Response sustained 60 minutes after last treatment No distress Physical exam: normal Incomplete response FEV1 or PEF 40–69% Mild-to-moderate symptoms Poor response FEV1 or PEF <40% PCO2 ˜42 mm Hg Physical exam: symptoms severe, drowsiness, confusion Individualized decision re: hospitalization (see text) Discharge home Continue treatment with inhaled SABA Continue course of oral systemic corticosteroid Consider initiation of an ICS Patient education Review medications, including inhaler technique Review/initiate action plan Recommend close medical follow-up Admit to hospital ward Oxygen Inhaled SABA Systemic (oral or intravenous) corticosteroid Consider adjunct therapies Monitor vital signs, FEV1 or PEF, SaO2 Improve Improve Admit to hospital intensive care Oxygen Inhaled SABA hourly or continuously Intravenous corticosteroid Consider adjunct therapies Possible intubation and mechanical ventilation Discharge home Continue treatment with inhaled SABAs. Continue on ICS.For those not on long-term-control therapy, consider initiation of an ICS. Patient education (e.g., review medications, including inhaler technique: review/initiate action plan and, whenever possible, environmental control measures; and recommend close medical follow-up).
Seizure activity spreading from an electrical focus in a mass or infarct can explain global cognitive dysfunction caused by relatively small lesions. It is very common for patients to experience delirium at the end of life in palliative care settings. This condition, sometimes described as terminal restlessness, must be identified and treated aggressively because it is an important cause of patient and family discomfort at the end of life. It should be remembered that these patients also may be suffering from more common etiologies of delirium such as systemic infection. A cost-effective approach to the diagnostic evaluation of delirium allows the history and physical examination to guide further tests. No established algorithm for workup will fit all delirious patients due to the staggering number of potential etiologies, but one stepwise approach is detailed in Table 34-3. If a clear precipitant is STEPwiSE EvALuATion of A PATiEnT wiTH DELiRiuM History with special attention to medications (including over-the-counter and herbals) General physical examination and neurologic examination Complete blood count Electrolyte panel including calcium, magnesium, phosphorus Liver function tests, including albumin Renal function tests Electrocardiogram Arterial blood gas Serum and/or urine toxicology screen (perform earlier in young persons) Brain imaging with MRI with diffusion and gadolinium (preferred) or CT Suspected CNS infection: lumbar puncture after brain imaging Suspected seizure-related etiology: electroencephalogram (EEG) (if high suspicion, should be performed immediately) Second-tier further evaluation Vitamin levels: B12, folate, thiamine Endocrinologic laboratories: thyroid-stimulating hormone (TSH) and free T4; cortisol Serum ammonia Sedimentation rate Autoimmune serologies: antinuclear antibodies (ANA), complement levels; p-ANCA, c-ANCA.identified, such as an offending medication, further testing may not be required.If, however, no likely etiology is uncovered with initial evaluation, an aggressive search for an underlying cause should be initiated.Basic screening labs, including a complete blood count, electrolyte panel, and tests of liver and renal function, should be obtained in all patients with delirium.
These complexes are eliminated in a variety of ways, including destruction by NK cells and phagocytosis by macrophages and eosinophils.The specific antibody produced by the plasma cell binds to the stimulating antigen, forming an antigen–antibody complex. Memory B cells respond more quickly to the next encounter with the same antigen.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. The activated helper CD4 T lymphocyte releases interleukins IL-2, IL-4, IL-5, IL-10, and IL-13, which promote division and differentiation of the B lymphocyte into plasma cells and memory B cells. 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). The ADCC reaction involves (1) activation of natural killer (NK) cells by the binding of interferon (IFN-), the powerful NK cell activator, to its cell surface receptor (IFNreceptor) and (2) the binding of an antibodyor an antibodyand complement-coated target cell to an NK cell bearing Fc receptors. These reactions induce apoptosis, or lysis, of the target cell, usually through the action of tumor-specific antibodies or the action of perforins and granzymes (fragmentins) secreted by activated NK cells. Activated B lymphocytes differentiate into plasma cells and memory B cells. Plasma cells synthesize and secrete a specific antibody. During this process, activated B cells switch from synthe sizing their BCRs as integral membrane proteins to form ing a soluble version, which are called antibodies. Memory B cells respond more quickly to the next encounter with the same antigen. The specific antibody produced by the plasma cell binds to the stimulating antigen, forming an antigen–antibody complex. These complexes are eliminated in a variety of ways, including destruction by NK cells and phagocytosis by macrophages and eosinophils.The membranes of a number of cells, including NK cells, macrophages, neutrophils, and eosinophils, possess immunoglobulin Fc receptors and can kill certain target cells.NK cells recognize the Fc region of antibodies and preferentially attack and destroy target cells, usually those coated with IgG antibodies (Fig.14.7).
An ADH V2–receptor antagonist (Conivaptan) is now available to improve hy-ponatremia and to increase the free water diuresis without loss of other ions in the urine of patients with SIADH.Treatment of SIADH depends on the underlying etiology and includes fluid restrictions as well as pharmacological treatment.The increase in ADH secretion may be related to CNS disorders (tumors, injuries, infections, or cerebrovascular accidents); pulmonary diseases (pneumo-nia, chronic obstructive pulmonary disease, a lung abscess, or tuberculosis); tumors that secrete ADH (small-cell carci-noma of the lung, tumors of the pancreas, thymoma, or lym-phomas); and certain drugs (anti-inflammatories, nicotine, diuretics, and many others). Treatment of SIADH depends on the underlying etiology and includes fluid restrictions as well as pharmacological treatment. An ADH V2–receptor antagonist (Conivaptan) is now available to improve hy-ponatremia and to increase the free water diuresis without loss of other ions in the urine of patients with SIADH.This H&E–stained section is from a median cut through the pine cone–shaped gland.The conical anterior end of the gland is at the top of the micrograph.The arrows indicate the part of the gland that connects with the posterior commissure.The gland is formed by an evagination of the posterior portion of the roof of the third ventricle (diencephalon).
Differential Diagnosis The causes of postmenopausal bleeding and the percentage of patients who seek treatment for different conditions are presented in Table 14.16.Other genital lesions, such as urethral diverticula or embryonic cysts, may cause similar symptoms.Management of these conditions is discussed in Chapter 27.Malignancy—cervical, vaginal Some vaginal lesions are asymptomatic and are noted incidentally on examination. Fibroepithelial polyps consist of polypoid folds of connective tissue, capillaries, and stroma covered by vaginal epithelium. Although they can be excised easily in the office, their vascularity can be troublesome, and excision is not necessary unless the diagnosis is in question. Cysts of embryonic origin can arise from mesonephric, paramesonephric, and urogenital sinus epithelium. Gartner’s duct cysts are of mesonephric origin and are usually present on the lateral vaginal wall. They rarely cause symptoms and, therefore, do not require treatment. Other embryonic cysts can arise anterior to the vagina and beneath the bladder. Cysts that arise from the urogenital sinus epithelium are located in the area of the vulvar vestibule. Vaginal adenosis, the presence of epithelial-lined glands within the vagina, is associated with in utero exposure to diethylstilbestrol. No therapy is necessary other than close observation and periodic palpation to detect nodules that may need to be evaluated by biopsy to rule out vaginal clear cell adenocarcinoma (see Chapter 36). Women will sometimes describe a bulging lesion of the vagina and vulvar area, variably associated with symptoms of pressure or discomfort. The most common cause of such a lesion is one of the disorders of vaginal support. Management of these conditions is discussed in Chapter 27. Other genital lesions, such as urethral diverticula or embryonic cysts, may cause similar symptoms. Differential Diagnosis The causes of postmenopausal bleeding and the percentage of patients who seek treatment for different conditions are presented in Table 14.16.Women who are taking hormone therapy during menopause may be using a variety of hormonal regimens that can result in bleeding (see Chapter 34).
The typical syndrome includes liver abscess, bacteremia, and metastatic infection.These community-acquired infections have been linked to a virulent hypermucoviscous K. pneumoniae phenotype and to a specific genotype.Klebsiella pneumoniae liver abscess has been well described in Southeast Asia for more than 20 years and has become an emerging syndrome in North America and elsewhere.Other tests of liver function may yield normal results, but 50% of patients have elevated serum levels of bilirubin, and 48% have elevated concentrations of aspartate aminotransferase. Other laboratory findings include leukocytosis in 77% of patients, anemia (usually normochromic, normocytic) in 50%, and hypoalbuminemia in 33%. Concomitant bacteremia is found in one-third to one-half of patients. A liver abscess is sometimes suggested by chest radiography, especially if a new elevation of the right hemidiaphragm is seen; other suggestive findings include a right basilar infiltrate and a right pleural effusion. Imaging studies are the most reliable methods for diagnosing liver abscesses. These studies include ultrasonography, CT (Fig. 159-4), indium-labeled WBC or gallium scan, and MRI. More than one such FIGURE 159-4 Multilocular liver abscess on CT scan. Multiple or multilocular abscesses are more common than solitary abscesses. (Reprinted with permission from B Lorber [ed]: Atlas of Infectious Diseases, vol VII: Intra-abdominal Infections, Hepatitis, and Gastroenteritis. Philadelphia, Current Medicine, 1996, Fig. 1.22.) study may be required. Organisms recovered from liver abscesses vary with the source. In liver infection arising from the biliary tree, enteric gram-negative aerobic bacilli and enterococci are common isolates. Klebsiella pneumoniae liver abscess has been well described in Southeast Asia for more than 20 years and has become an emerging syndrome in North America and elsewhere. These community-acquired infections have been linked to a virulent hypermucoviscous K. pneumoniae phenotype and to a specific genotype. The typical syndrome includes liver abscess, bacteremia, and metastatic infection.Unless previous surgery has been performed, anaerobes are not generally involved in liver abscesses arising from biliary infections.In contrast, in liver abscesses arising from pelvic and other intraperitoneal sources, a mixed flora including both aerobic and anaerobic species is common; B. fragilis is the species most frequently isolated.
One can construct a lipid molecule, for example, with a fluorescent dye or a small gold particle attached to its polar head group and follow the diffusion of even individual molecules in a membrane.Various techniques have been used to measure the motion of individual lipid molecules and their components.3 When amphiphilic molecules are exposed to an aqueous environment, they behave as you would expect from the above discussion. They spontaneously aggregate to bury their hydrophobic tails in the interior, where they are shielded 2 from the water, and they expose their hydrophilic heads to water. Depending Figure 10–5 Cholesterol in a lipid bilayer. Schematic drawing (to scale) of a cholesterol molecule interacting with two phospholipid molecules in one monolayer of a lipid bilayer. behavior, fundamental to the creation of a living cell, follows directly from the shape and amphiphilic nature of the phospholipid molecule. A lipid bilayer also has other characteristics that make it an ideal structure for cell membranes. One of the most important of these is its fluidity, which is crucial to many membrane functions (Movie 10.2). the lipid Bilayer Is a two-dimensional Fluid Around 1970, researchers first recognized that individual lipid molecules are able to diffuse freely within the plane of a lipid bilayer. The initial demonstration came from studies of synthetic (artificial) lipid bilayers, which can be made in the form of spherical vesicles, called liposomes (Figure 10–9); or in the form of planar bilayers formed across a hole in a partition between two aqueous compartments or on a solid support. Various techniques have been used to measure the motion of individual lipid molecules and their components. One can construct a lipid molecule, for example, with a fluorescent dye or a small gold particle attached to its polar head group and follow the diffusion of even individual molecules in a membrane.(A) these molecules spontaneously form micelles or bilayers in water, depending on their shape.cone-shaped amphiphilic molecules (above) form micelles, whereas cylinder-shaped amphiphilic molecules such as phospholipids (below) form bilayers.(B) A micelle and a lipid bilayer seen in cross section.
By binding to the PD-1 marker on T cells, nivolumab and pembrolizumab block the binding of PD ligand-1 (PD-L1) on tumor cells, which suppresses T cell activity.Nivolumab, Pembrolizumab, and Atezolizumab allow potential anti-tumor T cells to remain activated.Binding of daratumumab to CD38 on myeloma cells likely induces cell death by apoptosis, complement-dependent cytotoxicity, or antibody-dependent cytotoxicity. It is approved by the FDA for use in multiple myeloma patients who are refractory to standard treatments, although phase III trials are ongoing regarding its use as a frontline therapy. Elotuzumab is FDA approved for the treatment of relapsed multiple myeloma. This Mab binds signaling lymphocytic activation molecule F7 (SLAMF7) on myeloma cells. It enables killing of multiple myeloma tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Dinutuximab is a ganglioside D2 (GD2)-binding Mab approved for pediatric patients with high-risk neuroblastoma in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA) who achieve at least a partial response to prior first-line multiagent, multimodality therapy. It has a black box warning for serious infusion reactions and neurotoxicity in the majority of patients. Necitumumab is a Mab directed against epidermal growth factor receptor (EGFR) and approved for use in patients with squamous non-small cell lung cancer in combination with gemcitabine and cisplatin. There is a black box warning for cardiopulmonary arrest and hypomagnesemia. Ipilimumab (Yervoy) binds to CTLA-4 on T cells, preventing CD80/86 from delivering a suppressive signal to T cells. This has the effect of maintaining T-cell activation. It is approved for the treatment of unresectable or metastatic melanoma and treatment of cutaneous melanoma with regional nodes in the adjuvant surgical setting. Nivolumab, Pembrolizumab, and Atezolizumab allow potential anti-tumor T cells to remain activated. By binding to the PD-1 marker on T cells, nivolumab and pembrolizumab block the binding of PD ligand-1 (PD-L1) on tumor cells, which suppresses T cell activity.Nivolumab is approved for Hodgkin’s lymphoma, renal cell carcinoma, non-small cell lung cancer, and melanoma.Pembrolizumab is approved for the treatment of head and neck cancer, melanoma (and ipilimumab-resistant melanoma), Merkel cell carcinoma, non-small cell lung cancer, and cancers in HIV-positive patients.
16-18 Enhancing the immune response to tumors by vaccination holds promise for cancer prevention and therapy.Monoclonal antibodies coupled to γ-emitting radioisotopes have also been used successfully to image tumors for the purposes of diagnosis and monitoring tumor spread.None of these immunized women subsequently became infected by HPV-16. An anti-HPV vaccine marketed as Gardasil is now available and recommended for use in girls and young women as a protection from cervical cancer caused by HPV serotypes 6, 11, 16, and 18. mMU, milli-Merck units. The HPV-16 vaccine induces high titers of specifc antibody that persist long after vaccination 1000 uninfected recipients of placebo recipients previously infected with HPV-16 placebo recipients not previously infected with HPV-16 Another drug–antibody conjugate, brentuximab vedotin, links an anti-CD30 antibody with a different microtubule inhibitor and is approved for certain forms of relapsed lymphomas. A variation on this approach is to link an antibody to an enzyme that metabolizes a nontoxic pro-drug to the active cytotoxic drug, a technique known as antibody-directed enzyme/pro-drug therapy (ADEPT). With this technique, a small amount of enzyme localized by the antibody can generate much larger amounts of active cytotoxic drug in the immediate vicinity of tumor cells. Monoclonal antibodies linked to radioisotopes (see Fig. 16.19) have been successfully used to treat refractory B-cell lymphoma, using anti-CD20 antibodies linked to yttrium-90 (ibritumomab tiuxetan). These approaches have the advantage of also killing neighboring tumor cells, because the released drug or radioactive emissions can affect cells adjacent to those that bind the antibody. Monoclonal antibodies coupled to γ-emitting radioisotopes have also been used successfully to image tumors for the purposes of diagnosis and monitoring tumor spread. 16-18 Enhancing the immune response to tumors by vaccination holds promise for cancer prevention and therapy.Cancer vaccines are based on the idea that tumors are intrinsically poorly immunogenic, and the vaccine should act to supply the immunogenicity.A second approach, called checkpoint blockade, which we will discuss in the next section, is based on the idea that the immune system has been primed but is held in check by tolerance mechanisms, which can be blocked by therapeutic interventions.
For example, when given with low-dose ritonavir, saquinavir and indinavir can be given on twice-a-day schedules and taken with food.As mentioned above, the pharmacodynamic boosting property of ritonavir, seen with doses as low as 100–200 mg once or twice a day, is often used in the setting of cART for HIV infection to derive more convenient regimens.A summary of known resistance mutations for protease inhibitors is shown in Fig. 226-46. The protease inhibitors preferred for use according to the DHHS Panel on the use of antiretroviral drugs are ritonavir (only as a pharmacokinetic enhancer), atazanavir, and darunavir. Ritonavir was the first protease inhibitor for which clinical efficacy was demonstrated. In a study of 1090 patients with CD4+ T cell counts <100/μL who were randomized to receive either placebo or ritonavir in addition to any other licensed medications, patients receiving ritonavir had a reduction in the cumulative incidence of clinical progression or death from 34% to 17%. Mortality decreased from 10.1% to 5.8%. At full doses, ritonavir is poorly tolerated. Among the main side effects are nausea, diarrhea, abdominal pain, hyperlipidemia, and circumoral paresthesia. Ritonavir has a high affinity for several isoforms of cytochrome P450 (3A4, 2D6), and its use can result in large increases in the plasma concentrations of drugs metabolized by these pathways. Among the agents affected in this manner are most other protease inhibitors, macrolide antibiotics, R-warfarin, ondansetron, rifabutin, most calcium channel blockers, glucocorticoids, and some of the chemotherapeutic agents used to treat KS and/or lymphomas. In addition, ritonavir may increase the activity of glucuronyltransferases, thus decreasing the levels of drugs metabolized by this pathway. Overall, great care must be taken when prescribing additional drugs to patients taking protease inhibitors in general and ritonavir in particular. As mentioned above, the pharmacodynamic boosting property of ritonavir, seen with doses as low as 100–200 mg once or twice a day, is often used in the setting of cART for HIV infection to derive more convenient regimens. For example, when given with low-dose ritonavir, saquinavir and indinavir can be given on twice-a-day schedules and taken with food.An advantage of atazanavir is that total cholesterol and triglyceride levels do not increase as much with atazanavir as with other protease inhibitors.This coupled with the fact that it can be given on a once-daily schedule made atazanavir a popular component of initial treatment regimens following its licensure.
(b) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring.This allows the chromosome to be stably propagated.In chromosomes that do survive, however, one of the centromeres has somehow become inactivated, even though it contains all the necessary DNA sequences.(A) In the yeast Saccharomyces cerevisiae, a special centromeric DNA sequence assembles a single nucleosome in which two copies of an H3 variant histone (called CENP-A in most organisms) replace the normal H3. (b) How peptide sequences unique to this variant histone (see Figure 4–35) help to assemble additional proteins, some of which form a kinetochore. The yeast kinetochore is unusual in capturing only a single microtubule; humans have much larger centromeres and form kinetochores that can capture 20 or more microtubules (see Figure 4–43). The kinetochore is discussed in detail in Chapter 17. (Adapted from A. Joglekar et al., Nat. Cell Biol. 8:581–585, 2006. with permission from macmillan Publishers ltd.) Figure 4–43 evidence for the plasticity of human centromere formation. (A) A series of A-T-rich alpha satellite DNA sequences is repeated many thousands of times at each human centromere (red), and is surrounded by pericentric heterochromatin (brown). However, due to an ancient chromosome breakage-and-rejoining event, some human chromosomes contain two blocks of alpha satellite DNA, each of which presumably functioned as a centromere in its original chromosome. Usually, chromosomes with two functional centromeres are not stably propagated because they attach improperly to the spindle and are broken apart during mitosis. In chromosomes that do survive, however, one of the centromeres has somehow become inactivated, even though it contains all the necessary DNA sequences. This allows the chromosome to be stably propagated. (b) In a small fraction (1/2000) of human births, extra chromosomes are observed in cells of the offspring.The complexity of centromeric chromatin is not illustrated in these diagrams.The alpha satellite DNA that forms centromeric chromatin in humans is packaged into alternating blocks of chromatin.
Proper oral and nasal hygiene and routine dental care are extremely important ways for patients to protect themselves from disorders of the mouth and nose that can ultimately result in chemosensory disturbance.In some cases, a flavor enhancer like monosodium glutamate (MSG) can be added to foods to increase palatability and encourage intake.A report that theophylline improved smell function was uncontrolled and failed to account for the fact that some meaningful improvement occurs without treatment; indeed, the percentage of responders was about the same (∼50%) as that noted by others to show spontaneous improvement over a similar time period. Antiepileptics and some antidepressants (e.g., amitriptyline) have been used to treat dysosmias and smell distortions, particularly following head trauma. Ironically, amitriptyline is also frequently on the list of medications that can ultimately distort smell and taste function, possibly from its anticholinergic effects. A recent study suggests that the use of the centrally acting acetylcholinesterase inhibitor donepezil in AD resulted in improvements on smell identification measures that correlated with overall clinician-based impressions of change in dementia severity scores. Alternative therapies, such as acupuncture, meditation, cognitive-behavioral therapy, and yoga, can help patients manage uncomfortable experiences associated with chemosensory disturbance and oral pain syndromes and to cope with the psychosocial stressors surrounding the impairment. Additionally, modification of diet and eating habits is also important. By accentuating the other sensory experiences of a meal, such as food texture, aroma, temperature, and color, one can optimize the overall eating experience for a patient. In some cases, a flavor enhancer like monosodium glutamate (MSG) can be added to foods to increase palatability and encourage intake. Proper oral and nasal hygiene and routine dental care are extremely important ways for patients to protect themselves from disorders of the mouth and nose that can ultimately result in chemosensory disturbance.Smoking cessation and the discontinuance of oral tobacco use are essential in the management of any patient with smell and/or taste disturbance and should be repeatedly emphasized.A major and often overlooked element of therapy comes from chemosensory testing itself.
Pericardial Disease Chest pain with respiratory accentuation, accompanied by a friction rub, is diagnostic of pericarditis.Again, the use of these agents has not been of proven benefit for patients with advanced CKD.If dietary measures are not sufficient, preferred lipid-lowering medications, such as statins, should be used.Potassium-sparing diuretics should be used with caution or avoided altogether in most patients. There are many strategies available to treat the traditional and nontraditional risk factors in CKD patients. Although these have proved effective in the general population, there is little evidence for their benefit in patients with advanced CKD, especially those on dialysis. Certainly hypertension, elevated serum levels of homocysteine, and dyslipidemia promote atherosclerotic disease and are treatable complications of CKD. Renal disease complicated by nephrotic syndrome is associated with a very atherogenic lipid profile and hypercoagulability, which increases the risk of occlusive vascular disease. Because diabetes mellitus and hypertension are the two most frequent causes of advanced CKD, it is not surprising that cardiovascular disease is the most frequent cause of death in dialysis patients. The role of “inflammation” may be quantitatively more important in patients with kidney disease, and the treatment of more traditional risk factors may result in only modest success. However, modulation of traditional risk factors may be the only weapon in the therapeutic armamentarium for these patients until the nature of inflammation in CKD and its treatment are better understood. Lifestyle changes, including regular exercise, should be advocated. Hyperlipidemia in patients with CKD should be managed according to national guidelines. If dietary measures are not sufficient, preferred lipid-lowering medications, such as statins, should be used. Again, the use of these agents has not been of proven benefit for patients with advanced CKD. Pericardial Disease Chest pain with respiratory accentuation, accompanied by a friction rub, is diagnostic of pericarditis.Pericarditis can be accompanied by pericardial effusion that is seen on echocardiography and can rarely lead to tamponade.However, the pericardial effusion can be asymptomatic, and pericarditis can be seen without significant effusion.Pericarditis is observed in advanced uremia, and with the advent of timely initiation of dialysis, is not as common as it once was.
Intravenous ethanol is an alternative to fomepizole in ethylene glycol poisoning.Intravenous treatment with fomepizole is initiated immediately, as described above for methanol poisoning, and continued until the patient’s serum ethylene glycol concentration drops below a toxic threshold (20–30 mg/dL).Since folate-dependent systems are responsible for the oxidation of formic acid to CO2 in humans (Figure 23–3), folinic and folic acid are often administered to patients poisoned with methanol, although this has never been fully tested in clinical studies. Polyhydric alcohols such as ethylene glycol (CH2OHCH2OH) are used as heat exchangers, in antifreeze formulations, and as industrial solvents. Young children and animals are sometimes attracted by the sweet taste of ethylene glycol and, rarely, it is ingested intentionally as an ethanol substitute or in attempted suicide. Although ethylene glycol itself is relatively harmless and eliminated by the kidney, it is metabolized to toxic aldehydes and oxalate. Three stages of ethylene glycol overdose occur. Within the first few hours after ingestion, there is transient excitation followed by CNS depression. After a delay of 4–12 hours, severe metabolic acidosis develops from accumulation of acid metabolites and lactate. Finally, deposition of oxalate crystals in renal tubules occurs, followed by delayed renal insufficiency. The key to the diagnosis of ethylene glycol poisoning is recognition of anion gap acidosis, osmolar gap, and oxalate crystals in the urine in a patient without visual symptoms. As with methanol poisoning, early fomepizole is the standard treatment for ethylene glycol poisoning. Intravenous treatment with fomepizole is initiated immediately, as described above for methanol poisoning, and continued until the patient’s serum ethylene glycol concentration drops below a toxic threshold (20–30 mg/dL). Intravenous ethanol is an alternative to fomepizole in ethylene glycol poisoning.Fomepizole has reduced the need for hemodialysis, especially in patients with less severe acidosis and intact renal function.
A patient with a healthy family and premorbid history with an acute illness having many of the typical features of schizophrenia but associated with confusion, forgetfulness, and/or clouding of consciousness.On our services, less than 1 of 5 of the acute schizophreniform psychoses has proved to be a result of the disease schizophrenia. This distinction is made by the premorbid history and the course of the illness. If the patient had been reclusive, withdrawn, and socially maladapted and does not seem to recover fully from the acute psychosis, then the diagnosis of schizophrenia is more likely. Lacking these features, and in particular with a full remission, one assumes the occurrence of hypomania or of a toxic-metabolic psychosis, which can be detected by laboratory screening for drugs and endocrine diseases. Only 10 percent of patients with classic schizophrenia will have such an acute episode. Adherence to the criteria enumerated earlier, particularly to those devised by Feighner and colleagues will avoid most errors in diagnosis. It is the present authors’ opinion that the status of acute schizophrenia and of the so-called schizothymic and schizoaffective states brings to light a crucial nosologic problem. Is the traditional separation of depressive disease, bipolar disease, and schizophrenia biologically sound? The suggestion is that they are linked in some way by these transitional forms. Neurologists should keep an open mind about these and other theoretical problems that lack a firm genetic and neuropathologic basis. In addition to the acute schizophreniform psychosis described earlier, the authors have encountered the greatest difficulties in the diagnosis of schizophrenia in the following clinical situations: 1. A patient with a healthy family and premorbid history with an acute illness having many of the typical features of schizophrenia but associated with confusion, forgetfulness, and/or clouding of consciousness.This syndrome is characteristic of autoimmune encephalitis, particularly a form caused by anti-NMDA antibody (Chap.30), of hallucinogenic drug use, particularly phencyclidine intoxication, corticosteroid psychosis (drug-induced or Cushing disease), and thyrotoxic psychosis.
A number of cytoplasmic protein complexes regulate and control the cell cycle.Regulation of the Cell Cycle Passage through the cell cycle is driven by proteins that are cyclically synthesized and degraded during each cycle.If damage is too severe, even the reserve stem cells die, and there is no potential for regeneration.Malignant cells in culture continue to divide and may grow on top of one another rather then discontinuing growth when the plate is fully covered in a monolayer of cells. The malfunction of the restriction checkpoint may be facilitated by the viral proteins of several cancer-causing viruses, such as the T-antigen of simian virus (SV40) that binds to pRb. This binding alters the configuration of the pRb–T-antigen complex and renders the restriction checkpoint inoperable, thus facilitating the cell’s progression from the G1 to S phase of the cell cycle. This mechanism of carcinogenesis occurs in mesothelioma (cancer of the lining epithelium of the pleural cavities in the thorax), osteosarcoma (a type of bone cancer), and ependymoma (a type of childhood brain tumor). The reserve stem cell population may become activated and reenter the cell cycle. Cells identified as reserve stem cells may be thought of as GO cells that may be induced to reenter the cell cycle in response to injury of cells within the tissues of the body. Activation of these cells may occur in normal wound healing and in repopulation of the seminiferous epithelium after intense acute exposure of the testis to X-irradiation or during regeneration of an organ, such as the liver, after removal of a major portion. If damage is too severe, even the reserve stem cells die, and there is no potential for regeneration. Regulation of the Cell Cycle Passage through the cell cycle is driven by proteins that are cyclically synthesized and degraded during each cycle. A number of cytoplasmic protein complexes regulate and control the cell cycle.Cellular and molecular events induced during the increase and decrease of different protein levels are the basis of the cell-cycle “engine.” Other proteins actively monitor the quality of the molecular processes at the different checkpoints distributed throughout the cycle (described above).
Cholinoceptor stimulants are classified pharmacologically by their spectrum of action, depending on the type of receptor—muscarinic or nicotinic—that is activated.Acetylcholine-receptor stimulants and cholinesterase inhibitors make up a large group of drugs that mimic acetylcholine (cholinomimetics) (Figure 7–1).What should be done for his coworker?How would you proceed to evaluate and treat JM?Westfall DP, Todorov LD, Mihaylova-Todorova ST: ATP as a cotransmitter in sympathetic nerves and its inactivation by releasable enzymes. J Pharmacol Exp Ther 2002;303:439. Whittaker VP: Some currently neglected aspects of cholinergic function. J Mol Neurosci 2010;40:7. Blepharospasm and other manifestations of involuntary muscle spasm can be disabling and, in the case of large muscles, painful. Contraction of skeletal muscle is triggered by exocytotic release of acetylcholine (ACh) from motor nerves in response to calcium influx at the nerve ending. Release of ACh can be reduced or blocked by botulinum toxin, which interferes with the fusion of nerve ending ACh vesicles with the nerve ending membrane (see text). Depend-ing on dosage, botulinum blockade has an average duration of 1 to 3 months. Achilles J. Pappano, PhD In late morning, a coworker brings 43-year-old JM to the emergency department because he is agitated and unable to continue picking vegetables. His gait is unsteady, and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented. How would you proceed to evaluate and treat JM? What should be done for his coworker? Acetylcholine-receptor stimulants and cholinesterase inhibitors make up a large group of drugs that mimic acetylcholine (cholinomimetics) (Figure 7–1). Cholinoceptor stimulants are classified pharmacologically by their spectrum of action, depending on the type of receptor—muscarinic or nicotinic—that is activated.Early studies of the parasympathetic nervous system showed that the alkaloid muscarine mimicked the effects of parasympathetic nerve discharge; that is, the effects were parasympathomimetic.
Transient deficits when they do occur constitute reliable indicators of the site of the ruptured aneurysm (see below).An entirely separate problem of delayed vasospasm is responsible for focal signs that emerge after several days as discussed below.A momentary Valsalva maneuver, as in coughing or sneezing, has generally not caused aneurysmal rupture (it may cause arterial dissection). In patients who survive the initial rupture, the most feared complication is rerupture, an event that may occur at any time from minutes up to 2 or 3 weeks. In less-severe cases, consciousness, if lost, is regained within minutes or hours, but a residuum of drowsiness, confusion, and amnesia accompanied by severe headache and stiff neck persists for at least several days. Because the hemorrhage in most cases is confined to the subarachnoid space, there are few if any focal neurologic signs. That is to say, hemiparesis, hemianopia, and aphasia are absent. On occasion, a jet of blood emanating from an aneurysm ruptures into the adjacent brain or insular cistern and produces a hemiparesis or other focal syndrome. This may be more common when the aneurysm has bled in the past, after which it adheres to the brain, thus predisposing to intracerebral hemorrhage at the time of subsequent rupture. There is, however, a transient focal acute syndrome that occasionally occurs in the territory of the aneurysm-bearing artery. The pathogenesis of such manifestations is not fully understood, but a transitory fall in pressure in the circulation distal to the aneurysm or some form of acute transient vasospasm has been postulated. An entirely separate problem of delayed vasospasm is responsible for focal signs that emerge after several days as discussed below. Transient deficits when they do occur constitute reliable indicators of the site of the ruptured aneurysm (see below).These early seizures do not correlate with the location of the aneurysm and do not appear to alter the prognosis.Prior to rupture, saccular aneurysms are usually asymptomatic.Exceptionally, if large enough to compress pain-sensitive structures, they may cause localized cranial pain.
Bearing in mind the effects of the gonadal hormones on each of these disorders, the goals of therapy can then be defined and the risks of therapy assessed and discussed with the patient.These findings, however, have been disputed by the results of a large study from the Women’s Health Initiative (WHI) project showing no cardiovascular benefit from estrogen plus progestin replacement therapy in perimenopausal or older postmenopausal patients. In fact, there may be a small increase in cardiovascular problems as well as breast cancer in women who received the replacement therapy. Interestingly, a small protective effect against colon cancer was observed. Although current clinical guidelines do not recommend routine hormone therapy in postmenopausal women, the validity of the WHI report has been questioned. In any case, there is no increased risk for breast cancer if therapy is given immediately after menopause and for the first 7 years, while the cardiovascular risk depends on the degree of atherosclerosis at the onset of therapy. Transdermal or vaginal administration of estrogen may be associated with decreased cardiovascular risk because it bypasses the liver circulation. Women with premature menopause should definitely receive hormone therapy. In some studies, a protective effect of estrogen replacement therapy against Alzheimer’s disease was observed. However, several other studies have not supported these results. Progestins antagonize estrogen’s effects on LDL and HDL to a variable extent. However, one large study has shown that the addition of a progestin to estrogen replacement therapy does not influence the cardiovascular risk. Optimal management of the postmenopausal patient requires careful assessment of her symptoms as well as consideration of her age and the presence of (or risks for) cardiovascular disease, osteoporosis, breast cancer, and endometrial cancer. Bearing in mind the effects of the gonadal hormones on each of these disorders, the goals of therapy can then be defined and the risks of therapy assessed and discussed with the patient.Treatment may be required for only a limited period of time and the possible increased risk for breast cancer avoided.In women who have undergone hysterectomy, estrogens alone can be given 5 days per week or continuously, since progestins are not required to reduce the risk for endometrial hyperplasia and cancer.
In contrast, subacute or chronic osteomyelitis lasts for weeks or months before treatment is started.Acute hematogenous or contiguous osteomyelitis evolves over a short period—i.e., a few days or weeks.Whereas acute osteomyelitis can generally be treated with antibiotics alone, antibiotic treatment for chronic osteomyelitis should be combined with debridement surgery.Any of three mechanisms can underlie osteomyelitis: (1) hematogenous spread; (2) spread from a contiguous site following surgery; and (3) secondary infection in the setting of vascular insufficiency or concomitant neuropathy. Hematogenous osteomyelitis in adults typically involves the vertebral column. In only about half of patients can a primary focus be detected. The most common primary foci of infection are the urinary tract, skin/soft tissue, intravascular catheterization sites, and the endocardium. Spread from a contiguous source follows either bone trauma or surgical intervention. Wound infection leading to osteomyelitis typically occurs after cardiovascular intervention involving the sternum, orthopedic repair, or prosthetic joint insertion. Osteomyelitis secondary to vascular insufficiency or peripheral neuropathy most often follows chronic, progressively deep skin and soft tissue infection of the foot. The most common underlying condition is diabetes. In diabetes that is poorly controlled, the diabetic foot syndrome is caused by skin, soft tissue, and bone ischemia combined with motor, sensory, and autonomic neuropathy. Classification of osteomyelitis according to the duration of infection, although ill defined (because there is no clear time limit for the transition from acute to chronic osteomyelitis), is useful because the management of acute and chronic osteomyelitis differs. Whereas acute osteomyelitis can generally be treated with antibiotics alone, antibiotic treatment for chronic osteomyelitis should be combined with debridement surgery. Acute hematogenous or contiguous osteomyelitis evolves over a short period—i.e., a few days or weeks. In contrast, subacute or chronic osteomyelitis lasts for weeks or months before treatment is started.Chronic osteomyelitis develops when insufficient therapy leads to persistence or recurrence, most often after sternal, mandibular, or foot infection.Classification by location distinguishes among cases in the long bones, the vertebral column, and the periarticular bones.Long bones are generally involved after hematogenous seeding in children or contiguous spread following trauma or surgery.
The posterior cerebral artery may also be compressed, resulting in ischemic injury to tissue supplied by that vessel, including the primary visual cortex.As the temporal lobe is displaced, the third cranial nerve is compromised, resulting in pupillary dilation and impaired ocular movements on the side of the lesion (“blown pupil”).Once the sutures fuse, hydrocephalus causes ventricular expansion and increased intracranial pressure, but no change in head circumference ( Fig. 23.3 ). In contrast to these disorders, in which increased CSF volume is the primary process, a compensatory increase in CSF volume (hydrocephalus ex vacuo) may occur secondary to a loss of brain volume from any underlying cause (e.g., infarction, neurodegenerative disease). In such settings, the hydrocephalus merely reflects the primary disorder and is of no clinical significance. Herniation is the displacement of brain tissue from one compartment to another in response to increased intra-cranial pressure. The intra-cranial compartment is divided by rigid dural folds (falx and tentorium). If the pressure is sufficiently high, portions of the brain are displaced across these rigid structures. This herniation often leads to compromise of the blood supply to compressed tissue, producing infarction, additional swelling, and further herniation. There are three main types of herniation ( Fig. 23.4 Subfalcine (cingulate) herniation occurs when unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gyrus under the edge of the falx. This may compress the anterior cerebral artery. Transtentorial (uncinate) herniation occurs when the medial aspect of the temporal lobe is compressed against the free margin of the tentorium. As the temporal lobe is displaced, the third cranial nerve is compromised, resulting in pupillary dilation and impaired ocular movements on the side of the lesion (“blown pupil”). The posterior cerebral artery may also be compressed, resulting in ischemic injury to tissue supplied by that vessel, including the primary visual cortex.The compression of the peduncle creates a deformation known as Kernohan’s notch.Compression of the midbrain and the ascending reticular activating system with transtentorial herniation leads to depressed consciousness.Progression of transtentorial herniation is often accompanied by linear or flame-shaped hemorrhages in the midbrain and pons, termed Duret hemorrhages ( Fig.23.5 ).
However, the likelihood of micrometastatic distant disease is high, treatment is not expected to be curative, and radiation can result in toxicity.RT may slow the progression of local disease and possibly alleviate or prevent symptoms including pain, biliary obstruction, bleeding, and bowel obstruction.The role of RT in unresectable, locoregionally advanced pancreas cancer remains controversial.Endoscopic stents are definitely not as dura-ble as a surgical bypass. Recurrent obstruction and cholangitis is more common with stents and results in inferior palliation. However, the endoscopic approach is associated with consider-ably less initial morbidity and mortality than surgical bypass. Expandable metallic wall stents have superior patency and pro-vide better palliation than plastic stents (Fig. 33-72).If an initial diagnostic laparoscopy reveals a contraindica-tion to the Whipple procedure, such as liver metastases, it is not appropriate to perform a laparotomy simply to create a biliary bypass. In such a patient, it is better to place an endoscopic stent. In contrast, in the uncommon scenario where a laparotomy has already been performed as part of the assessment of resectability and the Whipple procedure is not possible, a surgical bypass is usually performed. However, if the patient has a functioning endoscopic stent already in place, it may be reasonable to forego surgical bypass.Chemotherapy and Radiation for Locally Advanced/ Metastatic Disease. Patients with locally advanced unresectable disease are treated with chemotherapy and possibly radiation, and patients with stage IV metastatic disease are treated with systemic chemotherapy. The role of RT in unresectable, locoregionally advanced pancreas cancer remains controversial. RT may slow the progression of local disease and possibly alleviate or prevent symptoms including pain, biliary obstruction, bleeding, and bowel obstruction. However, the likelihood of micrometastatic distant disease is high, treatment is not expected to be curative, and radiation can result in toxicity.
A plain abdominal x-ray to document excessive retained stool when history is consistent with constipation and encopresis is not necessary, as examination alone can confirm the diagnosis.Consultation with a radiologist is often advisable to discuss appropriate imaging, decide what variants of the technique to use, and learn how to prepare the patient for the study.Palpation can also detect enlargement of the liver or spleen as well as feces and masses. If detected, organomegaly should be measured (with a tape measure), noting abnormal firmness or contour. A rectal examination, including inspection for fissures, skin tags, abscesses, and fistulous openings, should be performed for children with history suggesting constipation, GI bleeding, abdominal pain, chronic diarrhea, and suspicion of inflammatory bowel disease (IBD). Digital rectal examination should include assessment of anal sphincter tone, anal canal size and elasticity, tenderness, extrinsic masses, presence of fecal impaction, and caliber of the rectum. Stool should be tested for occult blood. A complete blood count may provide evidence for inflammation (white blood cell [WBC] and platelet count), poornutrition or bleeding (hemoglobin, red blood cell volume, reticulocyte count), and infection (WBC number and differential, presence of toxic granulation). Serum electrolytes, bloodurea nitrogen (BUN), and creatinine help define hydration status. Tests of liver dysfunction include total and direct bilirubin, alanine aminotransferase, aspartate aminotransferase for evidence of hepatocellular injury, and γ-glutamyltransferase oralkaline phosphatase for evidence of bile duct injury. Hepatic synthetic function can be assessed by coagulation factor levels,prothrombin time, and albumin level. Pancreatic enzyme tests (amylase, lipase) provide evidence of pancreatic injury or inflammation. Urinalysis can gauge dehydration and identify a possible source of protein loss. Consultation with a radiologist is often advisable to discuss appropriate imaging, decide what variants of the technique to use, and learn how to prepare the patient for the study. A plain abdominal x-ray to document excessive retained stool when history is consistent with constipation and encopresis is not necessary, as examination alone can confirm the diagnosis.Video endoscopes may be used even in very small infants by pediatric gastroenterologists.Wireless capsule endoscopy (Fig.126-1) enables visualization of lesions beyond the reach of conventional endoscopes.
DNA–DNA hybridization is a method used for speciation in reference laboratories.The commonly used matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) systems are undergoing evaluation for species-level identification of Acinetobacter.Cephalosporinases from Kluyvera have been implicated as the progenitors of CTX-M ESBLs. Acinetobacter Infections David L. Paterson, Anton Y. Peleg Infections with bacteria of the genus Acinetobacter are established as a significant problem worldwide. Acinetobacter baumannii is par-ticularly formidable because of its propensity to acquire antibiotic resistance determinants. Endemic infections caused by strains of 187 A. baumannii resistant to multiple antibiotic classes, including carbapenems, are a serious concern in many specialized hospital units, especially intensive care units (ICUs). The foremost implication of infection with carbapenem-resistant A. baumannii is the need to use “last-line” antibiotics such as colistin, polymyxin B, or tigecycline; these options have the potential to render these bacteria resistant to all available antibiotics. Acinetobacter species are oxidase-negative, nonfermenting, short, gram-negative bacilli. They were traditionally thought of as nonmotile—a characteristic from which the genus name was derived (from the Greek akineto, meaning “nonmotile”). However, recent work has shown that Acinetobacter organisms demonstrate motility under certain growth conditions. The bacteria grow well at 37°C in aerobic conditions on a range of laboratory media (e.g., blood agar). Some species may not grow on MacConkey agar. Differentiation of Acinetobacter species is difficult with the means typically available to most clinical microbiology laboratories, including commercial semiautomated identification systems. The commonly used matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) systems are undergoing evaluation for species-level identification of Acinetobacter. DNA–DNA hybridization is a method used for speciation in reference laboratories.Widely distributed in nature, Acinetobacter species can be found in water, in soil, and on vegetables.Acinetobacter is a component of the human skin flora and is sometimes identified as a contaminant in blood samples collected for culture.Fecal carriage can be detected in both healthy and hospitalized individuals.
Arrays may use probes of different sizes (ranging from 50 to 200,000 base pairs of DNA) and different probe densities depending on the requirements of the application.test is a function of the number of probes or DNA sequences present on the array.The array can exactly identify the origin of the extra material, but by itself would not provide positional information.In contrast, array-based techniques permit analysis of many regions of the genome in a single analysis, with greatly increased resolution over standard cytogenetics. Array-based techniques allow for scanning of the genome for small deletions or duplications quickly and accurately. The resolution of the p13 –1.00 –0.75 –0.50 –0.25 0.00 0.25Log R ratio 0.50 0.75 1.00 p12 p11.2 q11.2 q14 q21.1 q21.3 q22.2 q23 q26.1 q26.2 q26.3 15 FIGuRE 83e-2 G-banding, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism (SNP) array demonstrate an abnormal chromosome 15. A. G-banding shows an abnormal chromosome 15, with unrecognizable material in place of the p arm in the chromosome on the right (top arrow). B. Metaphase FISH (only chromosome 15s are shown) using a probe from the 15q telomere region (red) and a control probe that maps outside of the duplicated region (green). C. Interphase FISH demonstrates three copies of the 15q tel probe in red, and two copies of the 15q control probe (green). D. Genome-wide SNP array demonstrates the increased copy number for a portion of 15q. Note that the G-banding alone indicates the abnormal chromosome 15, but the origin of the extra material can only be demonstrated by FISH or array. The FISH analysis requires additional information about possible genetic causes to select the correct probe. The array can exactly identify the origin of the extra material, but by itself would not provide positional information. test is a function of the number of probes or DNA sequences present on the array. Arrays may use probes of different sizes (ranging from 50 to 200,000 base pairs of DNA) and different probe densities depending on the requirements of the application.Depending on the size of the probes and the probe placement across the genome, array-based testing may be able to detect single exon deletions or duplications.Comparative Genomic Hybridization (CGH) and Single Nucleotide Polymorphism (SNP) Analysis CGH and SNP-based genotyping arrays can both be used for the analysis of genomic deletions and duplications.
The chronic hypergastrinemia results in marked gastric acid hypersecretion and growth of the gastric mucosa with increased numbers of parietal cells and proliferation of gastric ECL cells.A gastrinoma is an NET that secretes gastrin; the resultant hypergastrinemia causes gastric acid hypersecretion (Zollinger-Ellison syndrome [ZES]).Only late in the course of the disease does the tumor per se cause prominent symptoms such as abdominal pain. In contrast, all the symptoms due to nonfunctional pNETs are due to the tumor per se. The overall result of this is that some functional pNETs may present with severe symptoms with a small or undetectable primary tumor, whereas nonfunctional tumors usually present late in the disease course with large tumors, which are frequently metastatic. The mean delay between onset of continuous symptoms and diagnosis of a functional pNET syndrome is 4–7 years. Therefore, the diagnoses frequently are missed for extended periods. Endocrine Tumors of the Gastrointestinal Tract and Pancreas Treatment of pNETs requires two different strategies. First, treatment must be directed at the hormone-excess state such as the gastric acid hypersecretion in gastrinomas or the hypoglycemia in insulinomas. Ectopic hormone secretion usually causes the presenting symptoms and can cause life-threatening complications. Second, with all the tumors except insulinomas, >50% are malignant (Table 113-2); therefore, treatment must also be directed against the tumor per se. Because in many patients these tumors are not surgically curable due to the presence of advanced disease at diagnosis, surgical resection for cure, which addresses both treatment aspects, is often not possible. A gastrinoma is an NET that secretes gastrin; the resultant hypergastrinemia causes gastric acid hypersecretion (Zollinger-Ellison syndrome [ZES]). The chronic hypergastrinemia results in marked gastric acid hypersecretion and growth of the gastric mucosa with increased numbers of parietal cells and proliferation of gastric ECL cells.The most common presenting symptoms are abdominal pain (70–100%), diarrhea (37–73%), and gastroesophageal reflux disease (GERD) (30–35%); 10–20% of patients have diarrhea only.Although peptic ulcers may occur in unusual locations, most patients have a typical duodenal ulcer.
(Figure 10–4) chromatin Complex of DNA, histones, and non-histone proteins found in the nucleus of a eukaryotic cell.An important component of the plasma membranes of animal cells.cholesterol An abundant lipid molecule with a characteristic four-ring steroid structure.chemical carcinogens Disparate chemicals that are carcinogenic—due to the ability to cause mutations—when fed to experimental animals or painted repeatedly on their skin. chemical group Certain combinations of atoms—such as methyl (–CH3), hydroxyl (–OH), carboxyl (–COOH), carbonyl (–C=O), phosphate (–PO32–), sulfhydryl (–SH), and amino (–NH2) groups—that have distinct chemical and physical properties and influence the behavior of the molecule in which the group occurs. chemiosmotic coupling (chemiosmosis) Mechanism in which an electrochemical proton gradient across a membrane (composed of a pH gradient plus a membrane potential) is used to drive an energy-requiring process, such as ATP production or the rotation of bacterial flagella. chemotaxis Movement of a cell toward or away from some diffusible chemical. chiasma (plural chiasmata) X-shaped connection visible between paired homologous chromosomes during meiosis. Represents a site of chromosomal crossing-over, a form of genetic recombination. chlorophyll Light-absorbing green pigment that plays a central part in photosynthesis in bacteria, plants, and algae. chloroplast Organelle in green algae and plants that contains chlorophyll and carries out photosynthesis. cholera toxin Secreted toxic protein of Vibrio cholerae responsible for causing the watery diarrhea associated with cholera. Comprises an A subunit with enzymatic activity and a B subunit that binds to host-cell receptors to direct subunit A to the host-cell cytosol. cholesterol An abundant lipid molecule with a characteristic four-ring steroid structure. An important component of the plasma membranes of animal cells. (Figure 10–4) chromatin Complex of DNA, histones, and non-histone proteins found in the nucleus of a eukaryotic cell.chromatin immunoprecipitation Technique by which chromosomal DNA bound by a particular protein can be isolated and identified by precipitating it by means of an antibody against the protein.(Figures 8–66 and 8–67) chromosome Structure composed of a very long DNA molecule and associated proteins that carries part (or all) of the hereditary information of an organism.
It helps to facilitate the full range of positive emotions—love, hope, faith, the will to live, festivity, purpose, and determination (43).Laughter is a “metaphor for the full range of the positive emotions.” It is the response of human beings to incongruities and one of the highest manifestations of the cerebral process.A discussion and comprehension of the rationale for therapy, along with the potential benefits and risks, are necessary components of successful use; but they may not be sufficient in the face of practical barriers. The specifics of when and how to take medication, including what to do when medication is missed, have an impact on successful use. Positive physician–patient communication is correlated with patient adherence to medical advice (42). The style of the presentation of information is key to its effectiveness. As noted, the physician should establish a balance of power in the relationship, including conducting serious discussions about diagnosis and management strategies when the patient is fully clothed and face-to-face with the physician in a private room. Body language is important during interactions with patients. The physician should avoid an overly casual manner, which can communicate a lack of respect or compassion. The patient should be viewed directly and spoken to with eye contact so that the physician is not perceived as “looking off into the distance” (9). Laughter and Humor Humor is an essential component that promotes open communication. It can be either appropriate or inappropriate. Appropriate humor allows the patient to diffuse anxiety and understand that (even in difficult situations) laughter can be healthy (43,44). Inappropriate humor would horrify, disgust, offend, or generally make a patient feel uncomfortable or insulted. Laughter can be used as an appropriate means of relaxing the patient and making her feel better. Laughter is a “metaphor for the full range of the positive emotions.” It is the response of human beings to incongruities and one of the highest manifestations of the cerebral process. It helps to facilitate the full range of positive emotions—love, hope, faith, the will to live, festivity, purpose, and determination (43).Illness, or the prospect of illness, heightens our awareness of the incongruity between our existence and our ability to control the events that shape our lives and our outcomes.We use laughter to combat stress, and stress reduction is an essential mechanism used to cope with illness.All physicians should appreciate the importance of the art of communication during the medical interview.
They are often painful.This usually begins in the pretibial region as an erythematous plaque or papules that gradually enlarge, darken, and develop irregular margins, Diabetes Mellitus: Complications 2430 with atrophic centers and central ulceration.Necrobiosis lipoidica diabeticorum is an uncommon disorder, accompanying diabetes in predominantly young women.In general, the organisms that cause pulmonary infections are similar to those found in the nondiabetic population; however, gram-negative organisms, S. aureus, and Mycobacterium tuberculosis are more frequent pathogens. Urinary tract infections (either lower tract or pyelonephritis) are the result of common bacterial agents such as Escherichia coli, although several yeast species (Candida and Torulopsis glabrata) are commonly observed. Complications of urinary tract infections include emphysematous pyelonephritis and emphysematous cystitis. Bacteriuria occurs frequently in individuals with diabetic cystopathy. Susceptibility to furunculosis, superficial candidal infections, and vulvovaginitis are increased. Poor glycemic control is a common denominator in individuals with these infections. Diabetic individuals have an increased rate of colonization of S. aureus in the skinfolds and nares. Diabetic patients also have a greater risk of postoperative wound infections. The most common skin manifestations of DM are xerosis and pruritus and are usually relieved by skin moisturizers. Protracted wound healing and skin ulcerations are also frequent complications. Diabetic dermopathy, sometimes termed pigmented pretibial papules, or “diabetic skin spots,” begins as an erythematous macule or papule that evolves into an area of circular hyperpigmentation. These lesions result from minor mechanical trauma in the pretibial region and are more common in elderly men with DM. Bullous diseases, such as bullosa diabeticorum (shallow ulcerations or erosions in the pretibial region), are also seen. Necrobiosis lipoidica diabeticorum is an uncommon disorder, accompanying diabetes in predominantly young women. This usually begins in the pretibial region as an erythematous plaque or papules that gradually enlarge, darken, and develop irregular margins, Diabetes Mellitus: Complications 2430 with atrophic centers and central ulceration. They are often painful.Acanthosis nigricans (hyperpigmented velvety plaques seen on the neck, axilla, or extensor surfaces) is sometimes a feature of severe insulin resistance and accompanying diabetes.
CD8 cytotoxic T cells kill target cells infected with cytosolic pathogens, thus removing sites of pathogen replication.This triggering of effector T cells by peptide:MHC complexes occurs independently of co-stimulation, so that any infected target cell can be activated or destroyed by an effector T cell.CD8 cytotoxic T cells also produce IFN-γ, which inhibits viral replication and is an important inducer of MHC class I molecule expression and macrophage activation. Cytotoxic T cells kill infected targets with great precision, sparing adjacent normal cells. This precision is crucial in minimizing tissue damage while allowing the eradication of infected cells. Summary to Chapter 9. An adaptive immune response is initiated when naive T cells encounter specific antigen on the surface of an antigen-presenting cell in T-cell zones of secondary lymphoid tissues. In most cases, the antigen-presenting cells responsible for activating naive T cells, and inducing their clonal expansion, are conventional dendritic cells that express the co-stimulatory molecules B7.1 and B7.2. Conventional dendritic cells not only reside in lymphoid tissues, but they also survey the periphery, where they encounter pathogens, take up antigen at sites of infection, become activated through innate recognition, and migrate to local lymphoid tissue. The dendritic cell may become a potent direct activator of naive T cells, or it may transfer antigen to dendritic cells resident in secondary lymphoid organs for cross-presentation to naive CD8 T cells. Plasmacytoid dendritic cells contribute to rapid responses against viruses by producing type I interferons. Activated T cells produce IL-2, which is important in modulating early proliferation and differentiation of T cells; various other signals drive the differentiation of several types of effector T cells, which primarily act by releasing mediators directly onto their target cells. This triggering of effector T cells by peptide:MHC complexes occurs independently of co-stimulation, so that any infected target cell can be activated or destroyed by an effector T cell. CD8 cytotoxic T cells kill target cells infected with cytosolic pathogens, thus removing sites of pathogen replication.Thus, effector T cells control virtually all known effector mechanisms of the adaptive and innate immune response.In addition, subsets of CD4 regulatory T cells are produced that help control and limit immune responses by suppressing T-cell activity.Fig.9.47 Cytotoxic T cells kill target cells bearing specific antigen while sparing neighboring uninfected cells.
The patient displays a progressive hemispatial neglect or Bálint’s syndrome, usually accompanied by dressing and construction apraxia.A progressive form of spatial disorientation, known as the posterior cortical atrophy syndrome, most commonly represents a variant of AD with unusual concentrations of neurofibrillary degeneration in the parieto-occipital cortex and the superior colliculus.This is known as a construction apraxia and is much more severe if the lesion is in the right hemisphere. In some patients with right hemisphere lesions, the drawing difficulties are confined to the left side of the figure and represent a manifestation of hemispatial neglect; in others, there is a more universal deficit in reproducing contours and three-dimensional perspective. Impairments of route finding can be included in this group of disorders, which reflect an inability to orient the self with respect to external objects and landmarks. Causes of Spatial Disorientation Cerebrovascular lesions and neoplasms in the right hemisphere are common causes of hemispatial neglect. Depending on the site of the lesion, a patient with neglect also may have hemiparesis, hemihypesthesia, and hemianopia on the left, but these are not invariant findings. The majority of these patients display considerable improvement of hemispatial neglect, usually within the first several weeks. Bálint’s syndrome, dressing apraxia, and route finding impairments are more likely to result from bilateral dorsal parietal lesions; common settings for acute onset include watershed infarction between the middle and posterior cerebral artery territories, hypoglycemia, and sagittal sinus thrombosis. A progressive form of spatial disorientation, known as the posterior cortical atrophy syndrome, most commonly represents a variant of AD with unusual concentrations of neurofibrillary degeneration in the parieto-occipital cortex and the superior colliculus. The patient displays a progressive hemispatial neglect or Bálint’s syndrome, usually accompanied by dressing and construction apraxia.Both syndromes can impair route finding.PART 2 Cardinal Manifestations and Presentation of Diseases A patient with prosopagnosia cannot recognize familiar faces, including, sometimes, the reflection of his or her own face in the mirror.This is not a perceptual deficit because prosopagnosic patients easily can tell whether two faces are identical.
By combining one or more of these new inhibitors with imatinib as the initial therapy (see below), it seems that CML—at least in the chronic (early) stage—may be on its way to becoming a curable disease.Second-generation inhibitors that function effectively against a whole range of imatinib-resistant mutants have now been developed.The resulting fusion protein has the N-terminus of the Bcr protein joined to the C-terminus of the Abl tyrosine protein kinase; in consequence, the Abl kinase domain becomes inappropriately active, driving excessive proliferation of a clone of hemopoietic cells in the bone marrow. Figure 20–43 How imatinib (Gleevec) blocks the activity of Bcr-Abl protein and halts chronic myelogenous leukemia. (A) Imatinib sits in the ATP-binding pocket of the tyrosine kinase domain of Bcr-Abl and thereby prevents Bcr-Abl from transferring a phosphate group from ATP onto a tyrosine residue in a substrate protein. This blocks transmission of a signal for cell proliferation and survival. (B) The structure of the complex of imatinib (solid blue object) with the tyrosine kinase domain of the Abl protein (ribbon diagram), as determined by x-ray crystallography. (C) The chemical structure of the drug. It can be given by mouth; it has side effects, but they are usually quite tolerable. (B, from T. Schindler et al., Science 289:1938–1942, 2000. With permission from AAAS.) Results are not so good for those patients who have already progressed to the more acute phase of myeloid leukemia, known as blast crisis, where genetic instability has set in and the march of the disease is far more rapid. These patients show a response at first and then relapse because the cancer cells develop a resistance to imatinib. This resistance is usually associated with secondary mutations in the part of the Bcr-Abl gene that encodes the kinase domain, disrupting the ability of imatinib to bind to Bcr-Abl kinase. Second-generation inhibitors that function effectively against a whole range of imatinib-resistant mutants have now been developed. By combining one or more of these new inhibitors with imatinib as the initial therapy (see below), it seems that CML—at least in the chronic (early) stage—may be on its way to becoming a curable disease.This success story has fueled efforts to identify small-molecule inhibitors for other oncogenic protein kinases and to use them to attack the appropriate cancer cells.Increasing numbers are being developed.
• Ca2+ excretion.mEChANism Inhibit NaCl reabsorption in early DCT diluting capacity of nephron.Thiazide diuretics Hydrochlorothiazide, chlorthalidone, metolazone.Loop earrings hurt your ears.ADVERsE EFFECts Similar to furosemide, but more ototoxic.CLiNiCAL UsE Diuresis in patients allergic to sulfa drugs.Diuretics site of action 5Glomerulus A°erent Mannitol Acetazolamide Loop diuretics Thiazide diuretics K+ sparing diuretics Proximal convoluted tubule Loop of Henle Descending limb, loop of Henle (permeable to water) Ascending limb, loop of Henle (permeable to salts) Collecting duct Distal convoluted tubule Cortex Medulla 1234Sugars Amino acids Na+ Na+ K+ 2CI– Ca2+ Mg2+ Na+ CI– Na+ Na+ HCO3 – Ca2+ 34K+ H+ 5521E°erent H2O mEChANism Osmotic diuretic. tubular fluid osmolarity urine flow, intracranial/intraocular pressure. CLiNiCAL UsE Drug overdose, elevated intracranial/intraocular pressure. ADVERsE EFFECts Pulmonary edema, dehydration, hypoor hypernatremia. Contraindicated in anuria, HF. mEChANism Carbonic anhydrase inhibitor. Causes self-limited NaHCO3 diuresis and total body HCO3 − stores. Alkalinizes urine. CLiNiCAL UsE Glaucoma, metabolic alkalosis, altitude sickness, idiopathic intracranial hypertension. ADVERsE EFFECts Proximal renal tubular acidosis, paresthesias, “Acid”azolamide causes Acidosis. NH3 toxicity, sulfa allergy, hypokalemia. Promotes calcium phosphate stone formation (insoluble at high pH). Furosemide, bumetanide, torsemide mEChANism Sulfonamide loop diuretics. Inhibit cotransport system (Na+/K+/2Cl−) of thick ascending limb of loop of Henle. Abolish hypertonicity of medulla, preventing concentration of urine. Associated with PGE (vasodilatory effect on afferent arteriole); inhibited by NSAIDs. Ca2+ excretion. Loops Lose Ca2+. CLiNiCAL UsE Edematous states (HF, cirrhosis, nephrotic syndrome, pulmonary edema), hypertension, hypercalcemia. CLiNiCAL UsE Diuresis in patients allergic to sulfa drugs. ADVERsE EFFECts Similar to furosemide, but more ototoxic. Loop earrings hurt your ears. Thiazide diuretics Hydrochlorothiazide, chlorthalidone, metolazone. mEChANism Inhibit NaCl reabsorption in early DCT diluting capacity of nephron. • Ca2+ excretion.ADVERsE EFFECts Hypokalemic metabolic alkalosis, hyponatremia, hyperGlycemia, hyperLipidemia, hyperUricemia, hyperCalcemia.Sulfa allergy.HyperGLUC.Potassium-sparing Spironolactone, Eplerenone, Amiloride, Keep your SEAT diuretics Triamterene.mEChANism Spironolactone and eplerenone are competitive aldosterone receptor antagonists in cortical collecting tubule.
When EBV is associated with lymphoma in immunocompetent persons, virus-induced proliferation is but one step in a multi-step process of neoplastic transformation.If T cell immunity is compromised, EBV-infected B cells may begin to proliferate.Later in infection, human leukocyte antigen–restricted cytotoxic T cells that recognize EBNAs and LMPs and destroy EBV-infected cells are generated.During IM, there is an inverted CD4+/CD8+ T cell ratio. The percentage of CD4+ T cells decreases, while there are large clonal expansions of CD8+ T cells; up to 40% of CD8+ T cells are directed against EBV antigens during acute infection. Memory B cells, not epithelial cells, are the reservoir for EBV in the body. When patients are treated with acyclovir, shedding of EBV from the oropharynx stops but the virus persists in B cells. The EBV receptor (CD21) on the surface of B cells is also the receptor for the C3d component of complement. EBV infection of epithelial cells results in viral replication and production of virions. When B cells are infected by EBV in vitro, they become transformed and can proliferate indefinitely. During latent infection of B cells, only the EBV nuclear antigens (EBNAs), latent membrane proteins (LMPs), and small EBV RNAs (EBERs) are expressed in vitro. EBV-transformed B cells secrete immunoglobulin; only a small fraction of these cells produce virus. Cellular immunity is more important than humoral immunity in controlling EBV infection. In the initial phase of infection, suppressor T cells, natural killer cells, and nonspecific cytotoxic T cells are important in controlling the proliferation of EBV-infected B cells. Levels of markers of T cell activation and serum interferon γ are elevated. Later in infection, human leukocyte antigen–restricted cytotoxic T cells that recognize EBNAs and LMPs and destroy EBV-infected cells are generated. If T cell immunity is compromised, EBV-infected B cells may begin to proliferate. When EBV is associated with lymphoma in immunocompetent persons, virus-induced proliferation is but one step in a multi-step process of neoplastic transformation.CLINICAL MANIFESTATIONS Signs and Symptoms Most EBV infections in infants and young children either are asymptomatic or present as mild pharyngitis with or without tonsillitis.In contrast, ~75% of infections in adolescents present as IM.IM in the elderly often presents with nonspecific symptoms, including prolonged fever, fatigue, myalgia, and malaise.
Subtypes include the following: Acute sinusitis (symptoms lasting < 1 month): Most commonly associated with viruses, S. pneumoniae, H. inﬂ uenzae, and M. catarrhalis.Can be classifed by site, organism, or chronicity.The maxillary sinuses are most commonly affected.Refers to infammation of the paranasal sinuses.Treat with antibiotics and surgical drainage.A reaction with controls implies anergy from immunosuppression, old age, or malnutrition and thus does not rule out TB. FIGURE 2.8-4. PPD interpretation. The Centor criteria for identifying streptococcal pharyngitis are fever, tonsillar exudate, tender anterior cervical lymphadenopathy, and lack of cough (three of four are required). It is important to identify and treat streptococcal pharyngitis in order to prevent rheumatic fever, but overdiagnosis and overtreatment may lead to ↑ cost and antibiotic resistance. Always consider occult sinusitis in febrile ICU patients. Diagnosed by clinical evaluation, rapid GAS antigen detection, and throat culture. With three out of four of the Centor criteria, the sensitivity of rapid antigen testing is > 90%. If GAS is suspected, begin empiric antibiotic therapy with penicillin × 10 days. Cephalosporins, amoxicillin, and azithromycin are alternative options. Symptom relief can be attained with fuids, rest, antipyretics, and salt-water gargles. Nonsuppurative: Acute rheumatic fever (see the Cardiovascular chapter), poststreptococcal glomerulonephritis. Suppurative: Cervical lymphadenitis, mastoiditis, sinusitis, otitis media, retropharyngeal or peritonsillar abscess, and, rarely, thrombophlebitis of the jugular vein (Lemierre’s syndrome) due to Fusobacterium, an oral anaerobe. Peritonsillar abscess may present with odynophagia, trismus (“lockjaw”), a muffed voice, unilateral tonsillar enlargement, and erythema, with the uvula and soft palate deviated away from the affected side. Culture abscess fuid and localize the abscess via intraoral ultrasound or CT. Treat with antibiotics and surgical drainage. Refers to infammation of the paranasal sinuses. The maxillary sinuses are most commonly affected. Can be classifed by site, organism, or chronicity. Subtypes include the following: Acute sinusitis (symptoms lasting < 1 month): Most commonly associated with viruses, S. pneumoniae, H. inﬂ uenzae, and M. catarrhalis.Chronic sinusitis (symptoms persisting > 3 months): Represents a chronic infammatory process.Often due to obstruction of sinus drainage and ongoing low-grade anaerobic infections.In diabetic patients, mucormycosis should be considered.Presents with fever, facial pain/pressure, headache, nasal congestion, and discharge.Exam may reveal tenderness, erythema, and swelling over the affected area.
[Note: Eukaryotic 5S rRNA is synthesized by RNA pol III and modified separately.]31.15).The 23S, 16S, and 5S rRNA of prokaryotes are produced from a single pre-rRNA molecule, as are the 28S, 18S, and 5.8S rRNA of eukaryotes (Fig.A. Ribosomal RNA rRNA of both prokaryotic and eukaryotic cells are generated from long precursor molecules called pre-rRNA.31.14), and 3) occur on either strand of the DNA. Enhancers contain DNA sequences called response elements that bind STF. By bending or looping the DNA, STF can interact with other TF bound to a promoter and with RNA pol II, thereby stimulating transcription (see Fig. 31.13B). Mediator also binds enhancers. [Note: Although silencers are similar to enhancers in that they also can act over long distances, they reduce gene expression.] e. RNA polymerase II inhibitor: α-Amanitin, a potent toxin produced by the poisonous mushroom Amanita phalloides (sometimes called the “death cap”), binds RNA pol II tightly and slows its movement, thereby inhibiting mRNA synthesis. 3. RNA polymerase III: This enzyme synthesizes tRNA, 5S rRNA, and some snRNA and snoRNA. V. POSTTRANSCRIPTIONAL MODIFICATION OF RNA A primary transcript is the initial, linear, RNA copy of a transcription unit (the segment of DNA between specific initiation and termination sequences). The primary transcripts of both prokaryotic and eukaryotic tRNA and rRNA are posttranscriptionally modified by cleavage of the original transcripts by ribonucleases. tRNA are further modified to help give each species its unique identity. In contrast, prokaryotic mRNA is generally identical to its primary transcript, whereas eukaryotic mRNA is extensively modified both co-and posttranscriptionally. A. Ribosomal RNA rRNA of both prokaryotic and eukaryotic cells are generated from long precursor molecules called pre-rRNA. The 23S, 16S, and 5S rRNA of prokaryotes are produced from a single pre-rRNA molecule, as are the 28S, 18S, and 5.8S rRNA of eukaryotes (Fig. 31.15). [Note: Eukaryotic 5S rRNA is synthesized by RNA pol III and modified separately.][Note: In eukaryotes, rRNA genes are found in long, tandem arrays.rRNA synthesis and processing occur in the nucleolus, with base and sugar modifications facilitated by snoRNA.]B.Transfer RNA Both eukaryotic and prokaryotic tRNA are also made from longer precursor molecules that must be modified (Fig.31.16).
In certain disease states, the region of the splenic flexure of the colon can become ischemic.It is unusual for this area to become ischemic, whereas the watershed area between the superior mesenteric artery and the inferior mesenteric artery, at the splenic flexure, is extremely vulnerable to ischemia.The spleen is an organ of the reticuloendothelial system involved in hematopoiesis and immunological surveillance. Diseases that affect the reticuloendothelial system (e.g., leukemia or lymphoma) may produce generalized lymphadenopathy and enlargement of the spleen (splenomegaly) (Fig. 4.120). The spleen often enlarges when performing its normal physiological functions, such as when clearing microorganisms and particulates from the circulation, producing increased antibodies in the course of sepsis, or removing deficient or destroyed erythrocytes (e.g., in thalassemia and spherocytosis). Splenomegaly may also be a result of increased venous pressure caused by congestive heart failure, splenic vein thrombosis, or portal hypertension. An enlarged spleen is prone to rupture. In the clinic Vascular supply to the gastrointestinal system The abdominal parts of the gastrointestinal system are supplied mainly by the celiac trunk and the superior mesenteric and inferior mesenteric arteries (Fig. 4.129): The celiac trunk supplies the lower esophagus, stomach, superior part of the duodenum, and proximal half of the descending part of the duodenum. The superior mesenteric artery supplies the rest of the duodenum, the jejunum, the ileum, the ascending colon, and the proximal two-thirds of the transverse colon. The inferior mesenteric artery supplies the rest of the transverse colon, the descending colon, the sigmoid colon, and most of the rectum. Along the descending part of the duodenum there is a potential watershed area between the celiac trunk blood supply and the superior mesenteric arterial blood supply. It is unusual for this area to become ischemic, whereas the watershed area between the superior mesenteric artery and the inferior mesenteric artery, at the splenic flexure, is extremely vulnerable to ischemia. In certain disease states, the region of the splenic flexure of the colon can become ischemic.Arteriosclerosis may occur throughout the abdominal aorta and at the openings of the celiac trunk and the superior mesenteric and inferior mesenteric arteries.Not infrequently, the inferior mesenteric artery becomes occluded.
This led to new methods of prolonged mechanical ventilation.Initially called DaNang lung or shock lung, the clinical problem became recognized as acute respiratory dis-tress syndrome (ARDS).In 1947, Wiggers developed a sustainable, irreversible model of hemorrhagic shock based on uptake of shed blood into a reservoir to maintain a set level of hypotension.6 G. Tom Shires added further under-standing of hemorrhagic shock with a series of clinical stud-ies demonstrating that a large extracellular fluid deficit, greater than could be attributed to vascular refilling alone, occurred in severe hemorrhagic shock.7,8 The phenomenon of fluid redistri-bution after major trauma involving blood loss was termed third spacing and described the translocation of intravascular volume into the peritoneum, bowel, burned tissues, or crush injury sites. These seminal studies form the scientific basis for the current treatment of hemorrhagic shock with red blood cells and lac-tated Ringer’s solution or isotonic saline.As resuscitation strategies evolved and patients survived the initial consequences of hemorrhage, new challenges of sustained shock became apparent. During the Vietnam War, aggressive fluid resuscitation with red blood cells and crystal-loid solution or plasma resulted in survival of patients who pre-viously would have succumbed to hemorrhagic shock. Renal failure became a less frequent clinical problem; however, a new disease process, acute fulminant pulmonary failure, appeared as an early cause of death after seemingly successful surgery to control hemorrhage. Initially called DaNang lung or shock lung, the clinical problem became recognized as acute respiratory dis-tress syndrome (ARDS). This led to new methods of prolonged mechanical ventilation.
Moreover, many patients can recover comfortably after hospital discharge with nonopioid or nonaddictive pain regimens.THE SCIENCE OF PATIENT SAFETYMedicine is considered a high-risk system with a high error rate, but these two characteristics are not always correlated. Other high-risk industries have managed to maintain an impeccably low error rate. For example, one of the highest risk systems in existence today, the U.S. Navy’s nuclear submarine program, has an unmatched safety record.Much of the credit for their safety record is due to the culture of the nuclear submarine program, with its insistence on individual ownership, responsibility, attention to detail, professionalism, moral integrity, and mutual respect.6 These characteristics have created the cultural context necessary for high-quality communications under high-risk, high-stress con-ditions. Each reactor operator is aware of what is going on at all times and is responsible for understanding the implications and possible consequences of any action. Communication flows freely between crewmen and officers, and information about any mistakes that occur are dispersed rapidly through the entire system so that other workers can learn how to prevent similar mistakes in the future.High Reliability OrganizationsThe nuclear submarine program is an example of an organi-zation that has achieved the distinction of being considered a “high reliability organization.” High reliability organization theory recognizes that there are certain high-risk industries and organizations that have achieved very low accident and error rates compared to what would be expected given the inherent risks involved in their daily operations.
The initial macular rash is often detected by careful inspection of the axilla or the inner surface of the arm.Rash is present in only 13% of patients at presentation for medical care (usually ~4 days after onset of fever), appearing an average of 2 days later in half of the remaining patients and never appearing in the others.The duration of untreated illness averages 12 days (range, 9–18 days).ENDEMIC MuRINE TYPHuS Epidemiology R. typhi is maintained in mammalian host/flea cycles, with rats (Rattus rattus and R. norvegicus) and the Oriental rat flea (Xenopsylla cheopis) as the classic zoonotic niche. Fleas acquire R. typhi from rickettsemic rats and carry the organism throughout their life span. Nonimmune rats and humans are infected when rickettsia-laden flea feces contaminate pruritic bite lesions; less frequently, the flea bite transmits the organisms. Transmission can also occur via inhalation of aerosolized rickettsiae from flea feces. Infected rats appear healthy, although they are rickettsemic for ~2 weeks. Murine typhus occurs mainly in Texas and southern California, where the classic rat/flea cycle is absent and an opossum/cat flea (C. felis) cycle is prominent. Globally, endemic typhus occurs mainly in warm (often coastal) areas throughout the tropics and subtropics, where it is highly prevalent though often unrecognized. The incidence peaks from April through June in southern Texas and during the warm months of summer and early fall in other geographic locations. Patients seldom recall exposure to fleas, although exposure to animals such as cats, opossums, and rats is reported in nearly 40% of cases. Clinical Manifestations The incubation period of experimental murine typhus averages 11 days (range, 8–16 days). Headache, myalgia, arthralgia, nausea, and malaise develop 1–3 days before onset of chills and fever. Nearly all patients experience nausea and vomiting early in the illness. The duration of untreated illness averages 12 days (range, 9–18 days). Rash is present in only 13% of patients at presentation for medical care (usually ~4 days after onset of fever), appearing an average of 2 days later in half of the remaining patients and never appearing in the others. The initial macular rash is often detected by careful inspection of the axilla or the inner surface of the arm.A rash is detected in only 20% of patients with darkly pigmented skin.Pulmonary involvement is frequently prominent; 35% of patients have a hacking, nonproductive cough, and 23% of patients who undergo chest radiography have pulmonary densities due to interstitial pneumonia, pulmonary edema, and pleural effusions.Bibasilar rales are the most common pulmonary sign.
27-29).16 The 2017 Standards of Care for Dia-betes from the American Diabetes Association include those key indications in its recommendations for metabolic surgery, as well.COMPLICATIONS OF BARIATRIC SURGERYSurgical ComplicationsNone of the surgical procedures are without risks. The periop-erative mortality for the average patient is low (<0.5%) and declining, but can vary significantly across sub-groups with perioperative mortality rates of 2.0% or higher in some patient populations.1 The incidence of complications after the various surgical procedures varies from 4% to over 25% and depends on the definition of complication used, the type of bariatric procedure performed, and patient characteristics216,254,255 (see Table 27-5).8Brunicardi_Ch27_p1167-p1218.indd 120323/02/19 2:21 PM 1204SPECIFIC CONSIDERATIONSPART IIIn the 11 RCTs (794 patients) that have compared bariatric surgery to nonsurgical treatment, rates of adverse events were higher among surgical subjects, with follow-up up to 5 years for two of the studies and up to 2 to 3 years for others.82,252,256 There were very few cardiovascular events or deaths in either the surgical or the nonsurgical groups, and the most common adverse events after surgery were iron deficiency anemia (15% with intestinal bypass operations) and reoperations (8%).Other large observational studies, such as SOS, have shown higher rates of complications, with 14.5% having at least one nonfatal complication over the first 90 days, including pulmonary complications, vomiting, wound infection, hemorrhage, and anastomotic leak.However, the SOS included mostly open and VBG procedures, which are rarely performed today.